def runAdjust(self, targetWeight):
scaleModel = PKPDAllometricScale()
scaleModel.load(self.inputAllometric.get().fnScale.get())
self.population = self.readFitting(self.inputPopulation.get().fnFitting,cls="PKPDSampleFitBootstrap")
self.experiment = PKPDExperiment()
self.experiment.load(self.population.fnExperiment.get())
for sampleFit in self.population.sampleFits:
sample = self.experiment.samples[sampleFit.sampleName]
sampleWeight = float(sample.getDescriptorValue(scaleModel.predictor))
sample.setDescriptorValue(scaleModel.predictor,targetWeight)
for varName, varUnits in scaleModel.averaged_vars:
if varName in self.population.modelParameters:
idx = self.population.modelParameters.index(varName)
targetValue = scaleModel.models[varName][0]
sampleFit.parameters[0][idx] = targetValue
for varName, varUnits in scaleModel.scaled_vars:
if varName in self.population.modelParameters:
idx = self.population.modelParameters.index(varName)
k = scaleModel.models[varName][0]
a = scaleModel.models[varName][1]
targetValue = k*math.pow(targetWeight,a)
currentValue = k*math.pow(sampleWeight,a)
for j in range(sampleFit.parameters.shape[0]):
sampleFit.parameters[j][idx] *= targetValue/currentValue
self.experiment.write(self._getPath("experiment.pkpd"))
self.population.fnExperiment.set(self._getPath("experiment.pkpd"))
self.population.write(self._getPath("bootstrapPopulation.pkpd"))
def solve(self, objId1):
self.experiment = self.readExperiment(self.inputExperiment.get().fnPKPD)
# Create output object
self.outputExperiment = None
timeRange = self.experiment.getRange(self.timeVar.get())
for sampleName, sample in self.experiment.samples.items():
# Get t, A
t=np.asarray(sample.getValues(self.timeVar.get()),dtype=np.float64)
A=np.asarray(sample.getValues(self.amountVar.get()),dtype=np.float64)
if t[0]>0:
t=np.insert(t,0,0) # Add (0,0) to the profile
A=np.insert(A,0,0)
t, A = uniqueFloatValues(t, A)
if self.resampleT.get()>0:
B = InterpolatedUnivariateSpline(t, A, k=1)
t = np.arange(np.min(t),np.max(t)+self.resampleT.get(),self.resampleT.get())
A = B(t)
# Find C and Cp
C, Cp = self.calculateConcentrations2(t,A)
if self.outputExperiment is None:
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Cvar = PKPDVariable()
Cvar.varName = "C"
Cvar.varType = PKPDVariable.TYPE_NUMERIC
Cvar.role = PKPDVariable.ROLE_MEASUREMENT
Lunits = createUnit("L")
Cvar.units = createUnit(divideUnits(self.experiment.getVarUnits(self.amountVar.get()),Lunits.unit))
Cvar.comment = "Concentration central compartment"
Cpvar = PKPDVariable()
Cpvar.varName = "Cp"
Cpvar.varType = PKPDVariable.TYPE_NUMERIC
Cpvar.role = PKPDVariable.ROLE_MEASUREMENT
Cpvar.units = createUnit(divideUnits(self.experiment.getVarUnits(self.amountVar.get()),Lunits.unit))
Cpvar.comment = "Concentration peripheral compartment"
self.outputExperiment.variables[tvar.varName] = tvar
self.outputExperiment.variables[Cvar.varName] = Cvar
self.outputExperiment.variables[Cpvar.varName] = Cpvar
self.outputExperiment.general["title"]="Inverse Loo-Riegelman"
self.outputExperiment.general["comment"]=""
self.addSample(sampleName,t,C,Cp)
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def prepareForAnalysis(self):
if self.resampleT.get() > 0:
self.experimentSimulated = PKPDExperiment()
self.experimentSimulated.variables[
self.fitting.predicted.varName] = self.fitting.predicted
self.experimentSimulated.variables[
self.fitting.predictor.varName] = self.fitting.predictor
self.experimentSimulated.general[
"title"] = "Simulated response from dissolution profiles"
self.experimentSimulated.general[
"comment"] = "Simulated response from dissolution profiles"
def createOutputStep(self):
newFitting = PKPDFitting()
newFitting.fnExperiment.set(self.inputExperiment.get().fnPKPD)
experiment = PKPDExperiment()
experiment.load(self.inputExperiment.get().fnPKPD)
for ptrFitting in self.inputFittings:
newFitting.gather(self.readFitting(ptrFitting.get().fnFitting), experiment)
self.writeExperiment(newFitting, self._getPath("fitting.pkpd"))
self._defineOutputs(outputFitting=newFitting)
for ptrFitting in self.inputFittings:
self._defineSourceRelation(ptrFitting, newFitting)
def setupUnderlyingProtocol(self, prot):
prot.getXYvars()
prot.experiment = PKPDExperiment()
prot.experiment.load(prot.outputExperiment.fnPKPD.get())
prot.clearGroupParameters()
prot.createDrugSource()
prot.setupModel()
return prot.experiment
def createOutputStep(self, objId):
fnFile = os.path.basename(self.inputFile.get())
copyFile(self.inputFile.get(), self._getPath(fnFile))
tables = self.readTables(self._getPath(fnFile))
for tableName, sampleNames, allT, allMeasurements in tables:
self.experiment = PKPDExperiment()
self.experiment.general["title"] = self.title.get()
self.experiment.general["comment"] = self.comment.get()
# Add variables
if not self.addVar(self.experiment, self.tVar.get()):
raise Exception("Cannot process time variable")
if not self.addVar(self.experiment, self.xVar.get()):
raise Exception("Cannot process measurement variable")
tvarName = self.tVar.get().split(';')[0].replace(';', '')
xvarName = self.xVar.get().split(';')[0].replace(';', '')
# Create the samples
for sampleName in sampleNames:
self.experiment.samples[sampleName] = PKPDSample()
self.experiment.samples[sampleName].parseTokens(
[sampleName], self.experiment.variables,
self.experiment.doses, self.experiment.groups)
self.experiment.samples[sampleName].addMeasurementPattern(
[sampleName, tvarName, xvarName])
samplePtr = self.experiment.samples[sampleName]
exec("samplePtr.measurement_%s=%s" % (tvarName, allT))
# Fill the samples
for i in range(len(allT)):
for j in range(len(sampleNames)):
samplePtr = self.experiment.samples[sampleNames[j]]
exec('samplePtr.measurement_%s.append("%s")' %
(xvarName, allMeasurements[i][j]))
self.experiment.write(
self._getPath("experiment%s.pkpd" % tableName))
self.experiment._printToStream(sys.stdout)
self._defineOutputs(
**{"outputExperiment%s" % tableName: self.experiment})
def createOutputExperiment(self):
tvitroVar = PKPDVariable()
tvitroVar.varName = "tvitro"
tvitroVar.varType = PKPDVariable.TYPE_NUMERIC
tvitroVar.role = PKPDVariable.ROLE_TIME
tvitroVar.units = createUnit(self.experimentInVivo.getTimeUnits().unit)
tvitroVar.comment = "tvitro"
AdissolVar = PKPDVariable()
AdissolVar.varName = "Adissol"
AdissolVar.varType = PKPDVariable.TYPE_NUMERIC
AdissolVar.role = PKPDVariable.ROLE_MEASUREMENT
AdissolVar.units = createUnit(PKPDUnit.UNIT_NONE)
AdissolVar.comment = "Amount disolved in vitro"
self.outputExperiment = PKPDExperiment()
self.outputExperiment.variables[tvitroVar.varName] = tvitroVar
self.outputExperiment.variables[AdissolVar.varName] = AdissolVar
self.outputExperiment.general["title"] = "In-vitro target simulation"
self.outputExperiment.general["comment"] = ""
def getData(self, fnPKPD, XvarName, YvarName):
experiment = PKPDExperiment()
experiment.load(fnPKPD)
self.timeVarName = XvarName
self.CVarName = YvarName
xmin = 1e38
xmax = -1e38
for sampleName, sample in experiment.samples.items():
xValues, _ = self.getPlotValues(sample)
xmin = min(xmin, min(xValues))
xmax = max(xmax, max(xValues))
dataDict = {} # key will be time values
xrange = np.arange(xmin, xmax, (xmax - xmin) / 300.0)
for sampleName, sample in experiment.samples.items():
xValues, yValues = self.getPlotValues(sample)
xValuesUnique, yValuesUnique = uniqueFloatValues(xValues, yValues)
B = InterpolatedUnivariateSpline(xValuesUnique, yValuesUnique, k=1)
yrange = B(xrange)
for x, y in izip(xrange, yrange):
if x in dataDict:
dataDict[x].append(y)
else:
dataDict[x] = [y]
sortedTime = sorted(dataDict.keys())
if self.prot.showSummary.get():
# We will store five values (min, 25%, 50%, 75%, max)
# for each of the time entries computed
percentileList = [0, 25, 50, 75, 100]
Y = np.zeros((len(sortedTime), 5))
for i, t in enumerate(sortedTime):
Y[i, :] = np.percentile(dataDict[t], percentileList)
else:
Y = np.zeros((len(sortedTime), len(experiment.samples)))
for i, t in enumerate(sortedTime):
for j, C in enumerate(dataDict[t]):
Y[i, j] = C
return sortedTime, Y
def readExperiment(self, fnIn, show=True, fullRead=True):
experiment = PKPDExperiment()
experiment.load(fnIn, fullRead=fullRead)
if show:
self.printSection("Reading %s" % fnIn)
experiment._printToStream(sys.stdout)
return experiment
def createOutputStep(self):
fnTmp = self._getExtraPath("aux.pkpd")
fh = open(fnTmp, "w")
fh.write("[EXPERIMENT] ===========================\n")
fh.write("title=%s\n" % self.newTitle.get())
fh.write("comment=%s\n" % self.newComment.get())
fh.write("\n")
fh.write("[VARIABLES] ============================\n")
fh.write("%s\n" % self.newVariables.get())
fh.write("\n")
fh.write("[VIAS] ================================\n")
fh.write("%s\n" % self.newVias.get())
fh.write("\n")
fh.write("[DOSES] ================================\n")
fh.write("%s\n" % self.newDoses.get())
fh.write("\n")
fh.write("[GROUPS] ================================\n")
fh.write("%s\n" % self.newGroups.get())
fh.write("\n")
fh.write("[SAMPLES] ================================\n")
fh.write("%s\n" % self.newSamples.get())
fh.write("\n")
fh.write("[MEASUREMENTS] ===========================\n")
fh.write("%s\n" % self.newMeasurements.get())
fh.write("\n")
fh.close()
experiment = PKPDExperiment()
experiment.load(fnTmp, verifyIntegrity=False)
self.writeExperiment(experiment, self._getPath("experiment.pkpd"))
self._defineOutputs(outputExperiment=experiment)
def createOutputStep(self):
if self.splitOrGather.get() == 0:
experiment = self.readExperiment(self.inputExperiment.get().fnPKPD)
listOfSamples = []
g = 1
for sampleName in experiment.samples:
listOfSamples.append(sampleName)
if len(listOfSamples) == self.groupSize.get():
self.createSubGroup(g, experiment, listOfSamples)
listOfSamples = []
g += 1
if len(listOfSamples) != 0:
self.createSubGroup(g, experiment, listOfSamples)
else:
newExperiment = PKPDExperiment()
for ptrExperiment in self.inputExperiments:
newExperiment.gather(
self.readExperiment(ptrExperiment.get().fnPKPD))
self.writeExperiment(newExperiment,
self._getPath("experiment.pkpd"))
self._defineOutputs(outputExperiment=newExperiment)
for ptrExperiment in self.inputExperiments:
self._defineSourceRelation(ptrExperiment, newExperiment)
def _validate(self):
import re
errors = []
if self.prefix1.get() == self.prefix2.get():
experiment1 = PKPDExperiment()
experiment1.load(self.inputExperiment1.get().fnPKPD)
experiment2 = PKPDExperiment()
experiment2.load(self.inputExperiment2.get().fnPKPD)
# Check if there are repeated doses
for doseName1 in experiment1.doses:
if doseName1 in experiment2.doses:
errors.append("Dose %s is repeated in both experiments" %
doseName1)
# Check if there are repeated samples
for sampleName1 in experiment1.samples:
if sampleName1 in experiment2.samples:
errors.append("Sample %s is repeated in both experiments" %
sampleName1)
if len(errors) > 0:
errors.append("Use the prefixes in the Advanced options")
return errors
def calculateAllLevy(self):
L1 = []
for ptrExperiment in self.inputLevyplots:
experiment = PKPDExperiment()
experiment.load(ptrExperiment.get().fnPKPD.get())
x, y = experiment.getXYMeanValues("tvivo", "tvitro")
L1.append((x, y))
tvivo, tvitro = computeXYmean(L1, common=True)
x, y = twoWayUniqueFloatValues(tvivo, tvitro)
Bt = InterpolatedUnivariateSpline(x, y, k=1)
vtvitroReinterpolated = np.zeros(len(tvivo))
for i in range(len(tvivo)):
tvivoi = tvivo[i]
vtvitroReinterpolated[i] = Bt(tvivoi)
tvitroReinterpolatedVar = experiment.variables["tvitro"]
tvivoVar = experiment.variables["tvivo"]
self.outputExperimentSingle = PKPDExperiment()
self.outputExperimentSingle.variables[
tvitroReinterpolatedVar.varName] = tvitroReinterpolatedVar
self.outputExperimentSingle.variables[tvivoVar.varName] = tvivoVar
self.outputExperimentSingle.general["title"] = "Levy plot"
self.outputExperimentSingle.general["comment"] = "tvitro vs tvivo"
sampleName = "jointLevyPlot"
newSampleSingle = PKPDSample()
newSampleSingle.sampleName = sampleName
newSampleSingle.variableDictPtr = self.outputExperimentSingle.variables
newSampleSingle.descriptors = {}
newSampleSingle.addMeasurementColumn("tvitro", vtvitroReinterpolated)
newSampleSingle.addMeasurementColumn("tvivo", tvivo)
self.outputExperimentSingle.samples[sampleName] = newSampleSingle
self.outputExperimentSingle.addLabelToSample(sampleName, "from",
"individual---vesel",
"meanVivo---meanVitro")
self.outputExperimentSingle.write(self._getPath("experiment.pkpd"))
def runDrop(self, objId, varsToDrop):
import copy
experiment = self.readExperiment(self.inputExperiment.get().fnPKPD)
self.printSection("Dropping variables")
varsToDrop = []
for varName in self.varsToDrop.get().split(','):
varsToDrop.append(varName.strip())
filteredExperiment = PKPDExperiment()
filteredExperiment.general = copy.copy(experiment.general)
filteredExperiment.variables = {}
for varName, variable in experiment.variables.items():
if not varName in varsToDrop:
filteredExperiment.variables[varName] = copy.copy(variable)
filteredExperiment.samples = {}
filteredExperiment.doses = copy.copy(experiment.doses)
for sampleKey, sample in experiment.samples.items():
candidateSample = PKPDSample()
candidateSample.variableDictPtr = filteredExperiment.variables
candidateSample.doseDictPtr = filteredExperiment.doses
candidateSample.sampleName = copy.copy(sample.sampleName)
candidateSample.doseList = copy.copy(sample.doseList)
candidateSample.descriptors = copy.copy(sample.descriptors)
candidateSample.measurementPattern = []
for varName in sample.measurementPattern:
if not varName in varsToDrop:
candidateSample.measurementPattern.append(varName)
exec(
"candidateSample.measurement_%s = copy.copy(sample.measurement_%s)"
% (varName, varName))
filteredExperiment.samples[
candidateSample.varName] = candidateSample
self.writeExperiment(filteredExperiment,
self._getPath("experiment.pkpd"))
self.experiment = filteredExperiment
def deconvolve(self, objId1):
self.experiment = self.readExperiment(
self.inputExperiment.get().fnPKPD)
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Avar = PKPDVariable()
Avar.varName = "A"
Avar.varType = PKPDVariable.TYPE_NUMERIC
Avar.role = PKPDVariable.ROLE_MEASUREMENT
Avar.units = createUnit("none")
self.outputExperiment.variables[tvar.varName] = tvar
self.outputExperiment.variables[Avar.varName] = Avar
self.outputExperiment.general[
"title"] = "Deconvolution of the amount released"
self.outputExperiment.general[
"comment"] = "Amount released at any time t"
# Get the input sample from another experiment if necessary
sampleFrom = None
if self.externalIV.get() == self.ANOTHER_INPUT:
anotherExperiment = self.readExperiment(
self.externalIVODE.get().outputExperiment.fnPKPD)
for _, sampleFrom in anotherExperiment.samples.items(
): # Take the first sample from the reference
break
timeRange = self.experiment.getRange(self.timeVar.get())
for sampleName, sample in self.experiment.samples.items():
# Get t, Cp
t = np.asarray(sample.getValues(self.timeVar.get()),
dtype=np.float64)
Cp = np.asarray(sample.getValues(self.concVar.get()),
dtype=np.float64)
Cp = np.clip(Cp, 0.0, None)
t = np.insert(t, 0, 0) # Add (0,0) to the profile
Cp = np.insert(Cp, 0, 0)
t, Cp = uniqueFloatValues(t, Cp)
if self.resampleT.get() > 0:
B = InterpolatedUnivariateSpline(t, Cp, k=1)
t = np.arange(np.min(t),
np.max(t) + self.resampleT.get(),
self.resampleT.get())
Cp = B(t)
# Calculate AUC0t
AUC0t = calculateAUC0t(t, Cp)
AUC0inf = float(AUC0t[-1])
# Calculate peripheral
if self.externalIV.get() == self.SAME_INPUT:
sampleFrom = sample
Cl = float(sampleFrom.descriptors['Cl'])
V = float(sampleFrom.descriptors['V'])
Clp = float(sampleFrom.descriptors['Clp'])
Vp = float(sampleFrom.descriptors['Vp'])
k12 = Clp / V
k21 = Clp / Vp
Cperipheral = self.calculateCperipheral(t, Cp, k12, k21)
# Deconvolve
k10 = Cl / V
A = (Cp + Cperipheral + k10 * AUC0t) / k10
if self.normalize.get():
A *= 100 / AUC0inf
if self.saturate.get():
A = np.clip(A, None, 100.0)
A = np.clip(A, 0, None)
if self.smooth:
if t[0] > 0:
t = np.insert(t, 0, 0)
A = np.insert(A, 0, 0)
if self.saturate.get() and self.normalize.get():
A = np.clip(A, None, 100.0)
A = np.clip(smoothPchip(t, A), 0, None)
if self.considerBioaval.get() == self.BIOAVAIL_DIV:
A /= sample.getBioavailability()
elif self.considerBioaval.get() == self.BIOAVAIL_MULT:
A *= sample.getBioavailability()
self.addSample(sampleName, t, A)
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def runFilter(self, objId, filterType, condition):
import copy
experiment = self.readExperiment(self.inputExperiment.get().fnPKPD)
self.printSection("Filtering")
if self.filterType.get() == 0:
filterType = "exclude"
elif self.filterType.get() == 1:
filterType = "keep"
elif self.filterType.get() == 2:
filterType = "rmNA"
elif self.filterType.get() == 3:
filterType = "rmLL"
elif self.filterType.get() == 4:
filterType = "subsLL"
elif self.filterType.get() == 5:
filterType = "subsUL"
filteredExperiment = PKPDExperiment()
filteredExperiment.general = copy.copy(experiment.general)
filteredExperiment.variables = copy.copy(experiment.variables)
filteredExperiment.samples = {}
filteredExperiment.doses = {}
filteredExperiment.vias = {}
usedDoses = []
for sampleKey, sample in experiment.samples.items():
candidateSample = PKPDSample()
candidateSample.variableDictPtr = copy.copy(sample.variableDictPtr)
candidateSample.doseDictPtr = copy.copy(sample.doseDictPtr)
candidateSample.sampleName = copy.copy(sample.sampleName)
candidateSample.doseList = copy.copy(sample.doseList)
candidateSample.descriptors = copy.copy(sample.descriptors)
candidateSample.measurementPattern = copy.copy(
sample.measurementPattern)
N = 0 # Number of initial measurements
if len(sample.measurementPattern) > 0:
aux = getattr(sample,
"measurement_%s" % sample.measurementPattern[0])
N = len(aux)
if N == 0:
continue
# Create empty output variables
Nvar = len(sample.measurementPattern)
convertToFloat = []
for i in range(0, Nvar):
exec("candidateSample.measurement_%s = []" %
sample.measurementPattern[i])
convertToFloat.append(
sample.variableDictPtr[sample.measurementPattern[i]].
varType == PKPDVariable.TYPE_NUMERIC)
for n in range(0, N):
toAdd = []
okToAddTimePoint = True
conditionPython = copy.copy(condition)
for i in range(0, Nvar):
ldict = {}
exec(
"aux=sample.measurement_%s[%d]" %
(sample.measurementPattern[i], n), locals(), ldict)
aux = ldict['aux']
if filterType == "rmNA":
if aux == "NA" or aux == "None":
okToAddTimePoint = False
else:
toAdd.append(aux)
elif filterType == "rmLL":
if aux == "LLOQ" or aux == "ULOQ":
okToAddTimePoint = False
else:
toAdd.append(aux)
elif filterType == "subsLL":
okToAddTimePoint = True
if aux == "LLOQ":
toAdd.append(str(self.substitute.get()))
else:
toAdd.append(aux)
elif filterType == "subsUL":
okToAddTimePoint = True
if aux == "ULOQ":
toAdd.append(str(self.substitute.get()))
else:
toAdd.append(aux)
else:
# Keep or exclude
toAdd.append(aux)
varString = "$(%s)" % sample.measurementPattern[i]
if varString in conditionPython:
if aux == "NA":
okToAddTimePoint = False
else:
if convertToFloat[i]:
conditionPython = conditionPython.replace(
varString, "%f" % float(aux))
else:
conditionPython = conditionPython.replace(
varString, "'%s'" % aux)
if (filterType == "exclude"
or filterType == "keep") and okToAddTimePoint:
okToAddTimePoint = eval(conditionPython,
{"__builtins__": None}, {})
if filterType == "exclude":
okToAddTimePoint = not okToAddTimePoint
if okToAddTimePoint:
for i in range(0, Nvar):
exec("candidateSample.measurement_%s.append('%s')" %
(sample.measurementPattern[i], toAdd[i]))
N = len(
getattr(sample, "measurement_%s" % sample.measurementPattern[0]
)) # Number of final measurements
if N != 0:
filteredExperiment.samples[
candidateSample.sampleName] = candidateSample
for doseName in candidateSample.doseList:
if not doseName in usedDoses:
usedDoses.append(doseName)
if len(usedDoses) > 0:
for doseName in usedDoses:
filteredExperiment.doses[doseName] = copy.copy(
experiment.doses[doseName])
viaName = experiment.doses[doseName].via.viaName
if not viaName in filteredExperiment.vias:
filteredExperiment.vias[viaName] = copy.copy(
experiment.vias[viaName])
self.writeExperiment(filteredExperiment,
self._getPath("experiment.pkpd"))
self.experiment = filteredExperiment
class ProtPKPDInhSimulate(ProtPKPD):
""" Simulate inhalation PK\n
See Hartung2020.
Protocol created by http://www.kinestatpharma.com\n """
_label = 'simulate inhalation'
#--------------------------- DEFINE param functions --------------------------------------------
def _defineParams(self, form):
form.addSection('Input')
form.addParam('ptrDeposition',
params.PointerParam,
pointerClass='PKDepositionParameters',
label="Deposition")
form.addParam(
'doseMultiplier',
params.FloatParam,
default=1.0,
label='Dose multiplier',
expertLevel=LEVEL_ADVANCED,
help="Multiply the dose in the deposition file by this factor")
form.addParam(
'substanceMultiplier',
params.StringParam,
default="1 1 1 1 1 1 1 1",
label='Substance multiplier',
expertLevel=LEVEL_ADVANCED,
help=
'Multiply a substance related parameter by this factor. This is a vector with the order: \n'
'1. Solubility (br) \n'
'2. Solubility (alv) \n'
'3. Dissolution rate (br) \n'
'4. Dissolution rate (alv) \n'
'5. Permeability (br) \n'
'6. Permeability (alv) \n'
'7. Partition coefficient (br) \n'
'8. Partition coefficient (alv)')
form.addParam(
'physiologyMultiplier',
params.StringParam,
default="1 1 1 1 1 1 1 1 1",
label='Physiology multiplier',
expertLevel=LEVEL_ADVANCED,
help=
'Multiply a physiology related parameter by this factor. This is a vector with the order: \n'
'1. Mucociliary clearance\n'
'2. Fluid volume (br)\n'
'3. Fluid volume (alv)\n'
'4. Tissue volume (br)\n'
'5. Tissue volume (alv)\n'
'6. Surface area (br)\n'
'7. Surface area (alv)\n'
'8. Perfusion (br)\n'
'9. Perfusion (alv)\n')
form.addParam('ptrPK',
params.PointerParam,
pointerClass='PKPDExperiment',
label="PK parameters")
form.addParam(
'pkMultiplier',
params.StringParam,
default="1 1 1 1 1 1",
label='PK multiplier',
expertLevel=LEVEL_ADVANCED,
help=
'Multiply a substance related parameter by this factor. This is a vector with the order: \n'
'1. Systemic clearance (Cl)\n'
'2. Systemic apparent volume (V)\n'
'3. Flow between compartments (Q)\n'
'4. Peripheral apparent volume (Vp)\n'
'5. Absorption (k01)\n'
'6. Oral bioavailability (F)\n')
form.addParam('ciliarySpeedType',
params.EnumParam,
choices=['Exponential', 'Fit', 'Interpolated'],
default=2,
label='Ciliary speed',
expertLevel=LEVEL_ADVANCED)
form.addParam('simulationTime',
params.FloatParam,
label="Simulation time (min)",
default=10 * 24 * 60)
form.addParam('deltaT',
params.FloatParam,
label='Time step (min)',
default=1,
expertLevel=LEVEL_ADVANCED)
form.addParam(
'diameters',
params.StringParam,
label='Diameters (um)',
default="0.1,1.1,0.1; 1.2,9.2,0.2",
help=
'Diameters to analyze. Syntax: start1, stop1, step1; start2, stop2, step2; ... They will be '
'used as arguments of numpy.arange',
expertLevel=LEVEL_ADVANCED)
form.addParam('volMultiplier',
params.FloatParam,
label='Particle volume multiplier',
default=1,
expertLevel=LEVEL_ADVANCED)
#--------------------------- INSERT steps functions --------------------------------------------
def _insertAllSteps(self):
self._insertFunctionStep('runSimulation')
self._insertFunctionStep('createOutputStep')
#--------------------------- STEPS functions --------------------------------------------
def runSimulation(self):
self.deposition = PKDepositionParameters()
self.deposition.setFiles(self.ptrDeposition.get().fnSubstance.get(),
self.ptrDeposition.get().fnLung.get(),
self.ptrDeposition.get().fnDeposition.get())
self.deposition.doseMultiplier = self.doseMultiplier.get()
self.deposition.read()
substanceParams = PKSubstanceLungParameters()
substanceParams.multiplier = [
float(x) for x in self.substanceMultiplier.get().split()
]
substanceParams.read(self.ptrDeposition.get().fnSubstance.get())
lungParams = PKPhysiologyLungParameters()
lungParams.multiplier = [
float(x) for x in self.physiologyMultiplier.get().split()
]
lungParams.read(self.ptrDeposition.get().fnLung.get())
pkParams = PKPDExperiment()
pkParams.load(self.ptrPK.get().fnPKPD)
pkLungParams = PKLung()
pkLungParams.prepare(
substanceParams, lungParams, pkParams,
[float(x) for x in self.pkMultiplier.get().split()],
self.ciliarySpeedType.get())
# diameters = np.concatenate((np.arange(0.1,1.1,0.1),np.arange(1.2,9.2,0.2))) # [um]
evalStr = "np.concatenate((" + ",".join([
"np.arange(" + x.strip() + ")"
for x in self.diameters.get().split(";")
]) + "))"
diameters = eval(evalStr, {'np': np})
Sbnd = self.volMultiplier.get() * diam2vol(diameters)
tt = np.arange(0,
self.simulationTime.get() + self.deltaT.get(),
self.deltaT.get())
sol = saturable_2D_upwind_IE(lungParams, pkLungParams, self.deposition,
tt, Sbnd)
# Postprocessing
depositionData = self.deposition.getData()
alvDose = np.sum(depositionData['alveolar'])
bronchDose = np.sum(depositionData['bronchial'])
lungDose = alvDose + bronchDose
Aalvsolid = sol['A']['alv']['solid']
Aalvfluid = sol['A']['alv']['fluid']
Aalvtissue = sol['A']['alv']['tissue']
AsysGut = sol['A']['sys']['gut']
AsysPer = sol['A']['sys']['per']
AsysCtr = sol['A']['sys']['ctr']
Atisbr = sol['A']['br']['tissue']
Abrtissue = Atisbr
Vtisbr = lungParams.getBronchial()['fVol'] * lungParams.getSystemic(
)['OWlung']
Cavgbr = Atisbr / Vtisbr
Abrcleared = sol['A']['br']['clear']
Abrcleared = np.reshape(Abrcleared, Abrcleared.size)
Abrsolid = sol['A']['br']['solid']
Abrfluid = sol['A']['br']['fluid']
Acleared = sol['A']['sys']['clear'] + AsysGut - AsysGut[0]
lungRetention = 100 * (lungDose - Acleared) / lungDose
# in percent of lung dose
Csysnmol = sol['C']['sys']['ctr']
Csys = Csysnmol * substanceParams.getData()['MW']
CsysPer = AsysPer * substanceParams.getData(
)['MW'] / pkLungParams.pkData['Vp']
# Create output
self.experimentLungRetention = PKPDExperiment()
self.experimentLungRetention.general["title"] = "Inhalation simulate"
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit("min")
Rvar = PKPDVariable()
Rvar.varName = "Retention"
Rvar.varType = PKPDVariable.TYPE_NUMERIC
Rvar.role = PKPDVariable.ROLE_MEASUREMENT
Rvar.units = createUnit("none")
Rvar.comment = "Lung retention (% lung dose)"
Cnmolvar = PKPDVariable()
Cnmolvar.varName = "Cnmol"
Cnmolvar.varType = PKPDVariable.TYPE_NUMERIC
Cnmolvar.role = PKPDVariable.ROLE_MEASUREMENT
Cnmolvar.units = createUnit("nmol/mL")
Cnmolvar.comment = "Central compartment concentration"
Cvar = PKPDVariable()
Cvar.varName = "C"
Cvar.varType = PKPDVariable.TYPE_NUMERIC
Cvar.role = PKPDVariable.ROLE_MEASUREMENT
Cvar.units = createUnit("g/mL")
Cvar.comment = "Central compartment concentration"
alvTissueVar = PKPDVariable()
alvTissueVar.varName = "alvTissue"
alvTissueVar.varType = PKPDVariable.TYPE_NUMERIC
alvTissueVar.role = PKPDVariable.ROLE_MEASUREMENT
alvTissueVar.units = createUnit("nmol")
alvTissueVar.comment = "Amount in alveoli"
alvSolidVar = PKPDVariable()
alvSolidVar.varName = "alvSolid"
alvSolidVar.varType = PKPDVariable.TYPE_NUMERIC
alvSolidVar.role = PKPDVariable.ROLE_MEASUREMENT
alvSolidVar.units = createUnit("nmol")
alvSolidVar.comment = "Amount undissolved in alveoli"
alvFluidVar = PKPDVariable()
alvFluidVar.varName = "alvFluid"
alvFluidVar.varType = PKPDVariable.TYPE_NUMERIC
alvFluidVar.role = PKPDVariable.ROLE_MEASUREMENT
alvFluidVar.units = createUnit("nmol")
alvFluidVar.comment = "Amount in alveolar lining fluid"
brTissueVar = PKPDVariable()
brTissueVar.varName = "brTissue"
brTissueVar.varType = PKPDVariable.TYPE_NUMERIC
brTissueVar.role = PKPDVariable.ROLE_MEASUREMENT
brTissueVar.units = createUnit("nmol")
brTissueVar.comment = "Amount in bronchii"
brSolidVar = PKPDVariable()
brSolidVar.varName = "brSolid"
brSolidVar.varType = PKPDVariable.TYPE_NUMERIC
brSolidVar.role = PKPDVariable.ROLE_MEASUREMENT
brSolidVar.units = createUnit("nmol")
brSolidVar.comment = "Amount undissolved in bronchii"
brFluidVar = PKPDVariable()
brFluidVar.varName = "brFluid"
brFluidVar.varType = PKPDVariable.TYPE_NUMERIC
brFluidVar.role = PKPDVariable.ROLE_MEASUREMENT
brFluidVar.units = createUnit("nmol")
brFluidVar.comment = "Amount in bronchial lining fluid"
brClvar = PKPDVariable()
brClvar.varName = "brClear"
brClvar.varType = PKPDVariable.TYPE_NUMERIC
brClvar.role = PKPDVariable.ROLE_MEASUREMENT
brClvar.units = createUnit("nmol")
brClvar.comment = "Cumulative amount cleared by mucociliary elevator"
brCTisvar = PKPDVariable()
brCTisvar.varName = "CbrTis"
brCTisvar.varType = PKPDVariable.TYPE_NUMERIC
brCTisvar.role = PKPDVariable.ROLE_MEASUREMENT
brCTisvar.units = createUnit("nmol/mL")
brCTisvar.comment = "Concentration in bronchial tissue"
sysGutVar = PKPDVariable()
sysGutVar.varName = "sysAbsorption"
sysGutVar.varType = PKPDVariable.TYPE_NUMERIC
sysGutVar.role = PKPDVariable.ROLE_MEASUREMENT
sysGutVar.units = createUnit("nmol")
sysGutVar.comment = "Amount in absorption compartment"
sysCtrVar = PKPDVariable()
sysCtrVar.varName = "sysCentral"
sysCtrVar.varType = PKPDVariable.TYPE_NUMERIC
sysCtrVar.role = PKPDVariable.ROLE_MEASUREMENT
sysCtrVar.units = createUnit("nmol")
sysCtrVar.comment = "Amount in central compartment"
sysPerVar = PKPDVariable()
sysPerVar.varName = "sysPeripheral"
sysPerVar.varType = PKPDVariable.TYPE_NUMERIC
sysPerVar.role = PKPDVariable.ROLE_MEASUREMENT
sysPerVar.units = createUnit("nmol")
sysPerVar.comment = "Amount in peripheral compartment"
CsysPerVar = PKPDVariable()
CsysPerVar.varName = "Cp"
CsysPerVar.varType = PKPDVariable.TYPE_NUMERIC
CsysPerVar.role = PKPDVariable.ROLE_MEASUREMENT
CsysPerVar.units = createUnit("g/mL")
CsysPerVar.comment = "Concentration in peripheral compartment"
doseNmolVar = PKPDVariable()
doseNmolVar.varName = "dose_nmol"
doseNmolVar.varType = PKPDVariable.TYPE_NUMERIC
doseNmolVar.role = PKPDVariable.ROLE_LABEL
doseNmolVar.units = createUnit("nmol")
doseNmolVar.comment = "Input dose in nmol"
doseThroatVar = PKPDVariable()
doseThroatVar.varName = "throat_dose_nmol"
doseThroatVar.varType = PKPDVariable.TYPE_NUMERIC
doseThroatVar.role = PKPDVariable.ROLE_LABEL
doseThroatVar.units = createUnit("nmol")
doseThroatVar.comment = "Throat dose in nmol"
doseLungVar = PKPDVariable()
doseLungVar.varName = "lung_dose_nmol"
doseLungVar.varType = PKPDVariable.TYPE_NUMERIC
doseLungVar.role = PKPDVariable.ROLE_LABEL
doseLungVar.units = createUnit("nmol")
doseLungVar.comment = "Lung dose in nmol"
doseBronchialVar = PKPDVariable()
doseBronchialVar.varName = "bronchial_dose_nmol"
doseBronchialVar.varType = PKPDVariable.TYPE_NUMERIC
doseBronchialVar.role = PKPDVariable.ROLE_LABEL
doseBronchialVar.units = createUnit("nmol")
doseBronchialVar.comment = "Bronchial dose in nmol"
doseAlveolarVar = PKPDVariable()
doseAlveolarVar.varName = "alveolar_dose_nmol"
doseAlveolarVar.varType = PKPDVariable.TYPE_NUMERIC
doseAlveolarVar.role = PKPDVariable.ROLE_LABEL
doseAlveolarVar.units = createUnit("nmol")
doseAlveolarVar.comment = "Alveolar dose in nmol"
mccClearedLungDoseFractionVar = PKPDVariable()
mccClearedLungDoseFractionVar.varName = "mcc_cleared_lung_dose_fraction"
mccClearedLungDoseFractionVar.varType = PKPDVariable.TYPE_NUMERIC
mccClearedLungDoseFractionVar.role = PKPDVariable.ROLE_LABEL
mccClearedLungDoseFractionVar.units = createUnit("None")
mccClearedLungDoseFractionVar.comment = "MCC cleared lung dose fraction"
self.experimentLungRetention.variables["t"] = tvar
self.experimentLungRetention.variables["Retention"] = Rvar
self.experimentLungRetention.variables["Cnmol"] = Cnmolvar
self.experimentLungRetention.variables["C"] = Cvar
self.experimentLungRetention.variables["alvTissue"] = alvTissueVar
self.experimentLungRetention.variables["alvFluid"] = alvFluidVar
self.experimentLungRetention.variables["alvSolid"] = alvSolidVar
self.experimentLungRetention.variables["brTissue"] = brTissueVar
self.experimentLungRetention.variables["brFluid"] = brFluidVar
self.experimentLungRetention.variables["brSolid"] = brSolidVar
self.experimentLungRetention.variables["brClear"] = brClvar
self.experimentLungRetention.variables["CbrTis"] = brCTisvar
self.experimentLungRetention.variables["sysCentral"] = sysCtrVar
self.experimentLungRetention.variables["sysAbsoprtion"] = sysGutVar
self.experimentLungRetention.variables["sysPeripheral"] = sysPerVar
self.experimentLungRetention.variables["Cp"] = CsysPerVar
self.experimentLungRetention.variables["dose_nmol"] = doseNmolVar
self.experimentLungRetention.variables[
"throat_dose_nmol"] = doseThroatVar
self.experimentLungRetention.variables["lung_dose_nmol"] = doseLungVar
self.experimentLungRetention.variables[
"bronchial_dose_nmol"] = doseBronchialVar
self.experimentLungRetention.variables[
"alveolar_dose_nmol"] = doseAlveolarVar
self.experimentLungRetention.variables[
"mcc_cleared_lung_dose_fraction"] = mccClearedLungDoseFractionVar
# Samples
simulationSample = PKPDSample()
simulationSample.sampleName = "simulation"
simulationSample.addMeasurementColumn("t", tt)
simulationSample.addMeasurementColumn("Retention", lungRetention)
simulationSample.addMeasurementColumn("Cnmol", Csysnmol)
simulationSample.addMeasurementColumn("C", Csys)
simulationSample.addMeasurementColumn("alvFluid", Aalvfluid)
simulationSample.addMeasurementColumn("alvTissue", Aalvtissue)
simulationSample.addMeasurementColumn("alvSolid", Aalvsolid)
simulationSample.addMeasurementColumn("brFluid", Abrfluid)
simulationSample.addMeasurementColumn("brTissue", Abrtissue)
simulationSample.addMeasurementColumn("brSolid", Abrsolid)
simulationSample.addMeasurementColumn("brClear", Abrcleared)
simulationSample.addMeasurementColumn("CbrTis", Cavgbr)
simulationSample.addMeasurementColumn("sysAbsorption", AsysGut)
simulationSample.addMeasurementColumn("sysCentral", AsysCtr)
simulationSample.addMeasurementColumn("sysPeripheral", AsysPer)
simulationSample.addMeasurementColumn("Cp", CsysPer)
simulationSample.setDescriptorValue("dose_nmol",
depositionData['dose_nmol'])
simulationSample.setDescriptorValue("throat_dose_nmol",
depositionData['throat'])
lungDose = depositionData['dose_nmol'] - depositionData['throat']
simulationSample.setDescriptorValue("lung_dose_nmol", lungDose)
simulationSample.setDescriptorValue("bronchial_dose_nmol", bronchDose)
simulationSample.setDescriptorValue("alveolar_dose_nmol", alvDose)
simulationSample.setDescriptorValue("mcc_cleared_lung_dose_fraction",
Abrcleared[-1] / lungDose)
self.experimentLungRetention.samples[
"simulmvarNameation"] = simulationSample
self.experimentLungRetention.write(self._getPath("experiment.pkpd"))
# Plots
import matplotlib.pyplot as plt
lungData = lungParams.getBronchial()
Xbnd = np.sort([0] + lungData['end_cm'].tolist() +
lungData['pos'].tolist())
Xctr = Xbnd[:-1] + np.diff(Xbnd) / 2
tvec = tt / 60
T = np.max(tvec)
Cflu = sol['C']['br']['fluid']
Cs = substanceParams.getData()['Cs_br']
plt.figure(figsize=(15, 9))
plt.title('Concentration in bronchial fluid (Cs=%f [uM])' % Cs)
plt.imshow(Cflu,
interpolation='bilinear',
aspect='auto',
extent=[np.min(Xctr), np.max(Xctr), T, 0])
plt.clim(0, Cs)
plt.xlim(np.min(Xctr), np.max(Xctr))
plt.ylim(0, T)
plt.colorbar()
plt.ylabel('Time [h]')
plt.xlabel('Distance from throat [cm]')
plt.savefig(self._getPath('concentrationBronchialFluid.png'))
Ctis = sol['C']['br']['fluid']
plt.figure(figsize=(15, 9))
plt.title('Concentration in bronchial tissue')
plt.imshow(Ctis,
interpolation='bilinear',
aspect='auto',
extent=[np.min(Xctr), np.max(Xctr), T, 0])
plt.xlim(np.min(Xctr), np.max(Xctr))
plt.ylim(0, T)
plt.colorbar()
plt.ylabel('Time [h]')
plt.xlabel('Distance from throat [cm]')
plt.savefig(self._getPath('concentrationBronchialTissue.png'))
def createOutputStep(self):
self._defineOutputs(outputExperiment=self.experimentLungRetention)
self._defineSourceRelation(self.ptrDeposition.get(),
self.experimentLungRetention)
self._defineSourceRelation(self.ptrPK.get(),
self.experimentLungRetention)
def _citations(self):
return ['Hartung2020']
def runSimulation(self):
self.deposition = PKDepositionParameters()
self.deposition.setFiles(self.ptrDeposition.get().fnSubstance.get(),
self.ptrDeposition.get().fnLung.get(),
self.ptrDeposition.get().fnDeposition.get())
self.deposition.doseMultiplier = self.doseMultiplier.get()
self.deposition.read()
substanceParams = PKSubstanceLungParameters()
substanceParams.multiplier = [
float(x) for x in self.substanceMultiplier.get().split()
]
substanceParams.read(self.ptrDeposition.get().fnSubstance.get())
lungParams = PKPhysiologyLungParameters()
lungParams.multiplier = [
float(x) for x in self.physiologyMultiplier.get().split()
]
lungParams.read(self.ptrDeposition.get().fnLung.get())
pkParams = PKPDExperiment()
pkParams.load(self.ptrPK.get().fnPKPD)
pkLungParams = PKLung()
pkLungParams.prepare(
substanceParams, lungParams, pkParams,
[float(x) for x in self.pkMultiplier.get().split()],
self.ciliarySpeedType.get())
# diameters = np.concatenate((np.arange(0.1,1.1,0.1),np.arange(1.2,9.2,0.2))) # [um]
evalStr = "np.concatenate((" + ",".join([
"np.arange(" + x.strip() + ")"
for x in self.diameters.get().split(";")
]) + "))"
diameters = eval(evalStr, {'np': np})
Sbnd = self.volMultiplier.get() * diam2vol(diameters)
tt = np.arange(0,
self.simulationTime.get() + self.deltaT.get(),
self.deltaT.get())
sol = saturable_2D_upwind_IE(lungParams, pkLungParams, self.deposition,
tt, Sbnd)
# Postprocessing
depositionData = self.deposition.getData()
alvDose = np.sum(depositionData['alveolar'])
bronchDose = np.sum(depositionData['bronchial'])
lungDose = alvDose + bronchDose
Aalvsolid = sol['A']['alv']['solid']
Aalvfluid = sol['A']['alv']['fluid']
Aalvtissue = sol['A']['alv']['tissue']
AsysGut = sol['A']['sys']['gut']
AsysPer = sol['A']['sys']['per']
AsysCtr = sol['A']['sys']['ctr']
Atisbr = sol['A']['br']['tissue']
Abrtissue = Atisbr
Vtisbr = lungParams.getBronchial()['fVol'] * lungParams.getSystemic(
)['OWlung']
Cavgbr = Atisbr / Vtisbr
Abrcleared = sol['A']['br']['clear']
Abrcleared = np.reshape(Abrcleared, Abrcleared.size)
Abrsolid = sol['A']['br']['solid']
Abrfluid = sol['A']['br']['fluid']
Acleared = sol['A']['sys']['clear'] + AsysGut - AsysGut[0]
lungRetention = 100 * (lungDose - Acleared) / lungDose
# in percent of lung dose
Csysnmol = sol['C']['sys']['ctr']
Csys = Csysnmol * substanceParams.getData()['MW']
CsysPer = AsysPer * substanceParams.getData(
)['MW'] / pkLungParams.pkData['Vp']
# Create output
self.experimentLungRetention = PKPDExperiment()
self.experimentLungRetention.general["title"] = "Inhalation simulate"
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit("min")
Rvar = PKPDVariable()
Rvar.varName = "Retention"
Rvar.varType = PKPDVariable.TYPE_NUMERIC
Rvar.role = PKPDVariable.ROLE_MEASUREMENT
Rvar.units = createUnit("none")
Rvar.comment = "Lung retention (% lung dose)"
Cnmolvar = PKPDVariable()
Cnmolvar.varName = "Cnmol"
Cnmolvar.varType = PKPDVariable.TYPE_NUMERIC
Cnmolvar.role = PKPDVariable.ROLE_MEASUREMENT
Cnmolvar.units = createUnit("nmol/mL")
Cnmolvar.comment = "Central compartment concentration"
Cvar = PKPDVariable()
Cvar.varName = "C"
Cvar.varType = PKPDVariable.TYPE_NUMERIC
Cvar.role = PKPDVariable.ROLE_MEASUREMENT
Cvar.units = createUnit("g/mL")
Cvar.comment = "Central compartment concentration"
alvTissueVar = PKPDVariable()
alvTissueVar.varName = "alvTissue"
alvTissueVar.varType = PKPDVariable.TYPE_NUMERIC
alvTissueVar.role = PKPDVariable.ROLE_MEASUREMENT
alvTissueVar.units = createUnit("nmol")
alvTissueVar.comment = "Amount in alveoli"
alvSolidVar = PKPDVariable()
alvSolidVar.varName = "alvSolid"
alvSolidVar.varType = PKPDVariable.TYPE_NUMERIC
alvSolidVar.role = PKPDVariable.ROLE_MEASUREMENT
alvSolidVar.units = createUnit("nmol")
alvSolidVar.comment = "Amount undissolved in alveoli"
alvFluidVar = PKPDVariable()
alvFluidVar.varName = "alvFluid"
alvFluidVar.varType = PKPDVariable.TYPE_NUMERIC
alvFluidVar.role = PKPDVariable.ROLE_MEASUREMENT
alvFluidVar.units = createUnit("nmol")
alvFluidVar.comment = "Amount in alveolar lining fluid"
brTissueVar = PKPDVariable()
brTissueVar.varName = "brTissue"
brTissueVar.varType = PKPDVariable.TYPE_NUMERIC
brTissueVar.role = PKPDVariable.ROLE_MEASUREMENT
brTissueVar.units = createUnit("nmol")
brTissueVar.comment = "Amount in bronchii"
brSolidVar = PKPDVariable()
brSolidVar.varName = "brSolid"
brSolidVar.varType = PKPDVariable.TYPE_NUMERIC
brSolidVar.role = PKPDVariable.ROLE_MEASUREMENT
brSolidVar.units = createUnit("nmol")
brSolidVar.comment = "Amount undissolved in bronchii"
brFluidVar = PKPDVariable()
brFluidVar.varName = "brFluid"
brFluidVar.varType = PKPDVariable.TYPE_NUMERIC
brFluidVar.role = PKPDVariable.ROLE_MEASUREMENT
brFluidVar.units = createUnit("nmol")
brFluidVar.comment = "Amount in bronchial lining fluid"
brClvar = PKPDVariable()
brClvar.varName = "brClear"
brClvar.varType = PKPDVariable.TYPE_NUMERIC
brClvar.role = PKPDVariable.ROLE_MEASUREMENT
brClvar.units = createUnit("nmol")
brClvar.comment = "Cumulative amount cleared by mucociliary elevator"
brCTisvar = PKPDVariable()
brCTisvar.varName = "CbrTis"
brCTisvar.varType = PKPDVariable.TYPE_NUMERIC
brCTisvar.role = PKPDVariable.ROLE_MEASUREMENT
brCTisvar.units = createUnit("nmol/mL")
brCTisvar.comment = "Concentration in bronchial tissue"
sysGutVar = PKPDVariable()
sysGutVar.varName = "sysAbsorption"
sysGutVar.varType = PKPDVariable.TYPE_NUMERIC
sysGutVar.role = PKPDVariable.ROLE_MEASUREMENT
sysGutVar.units = createUnit("nmol")
sysGutVar.comment = "Amount in absorption compartment"
sysCtrVar = PKPDVariable()
sysCtrVar.varName = "sysCentral"
sysCtrVar.varType = PKPDVariable.TYPE_NUMERIC
sysCtrVar.role = PKPDVariable.ROLE_MEASUREMENT
sysCtrVar.units = createUnit("nmol")
sysCtrVar.comment = "Amount in central compartment"
sysPerVar = PKPDVariable()
sysPerVar.varName = "sysPeripheral"
sysPerVar.varType = PKPDVariable.TYPE_NUMERIC
sysPerVar.role = PKPDVariable.ROLE_MEASUREMENT
sysPerVar.units = createUnit("nmol")
sysPerVar.comment = "Amount in peripheral compartment"
CsysPerVar = PKPDVariable()
CsysPerVar.varName = "Cp"
CsysPerVar.varType = PKPDVariable.TYPE_NUMERIC
CsysPerVar.role = PKPDVariable.ROLE_MEASUREMENT
CsysPerVar.units = createUnit("g/mL")
CsysPerVar.comment = "Concentration in peripheral compartment"
doseNmolVar = PKPDVariable()
doseNmolVar.varName = "dose_nmol"
doseNmolVar.varType = PKPDVariable.TYPE_NUMERIC
doseNmolVar.role = PKPDVariable.ROLE_LABEL
doseNmolVar.units = createUnit("nmol")
doseNmolVar.comment = "Input dose in nmol"
doseThroatVar = PKPDVariable()
doseThroatVar.varName = "throat_dose_nmol"
doseThroatVar.varType = PKPDVariable.TYPE_NUMERIC
doseThroatVar.role = PKPDVariable.ROLE_LABEL
doseThroatVar.units = createUnit("nmol")
doseThroatVar.comment = "Throat dose in nmol"
doseLungVar = PKPDVariable()
doseLungVar.varName = "lung_dose_nmol"
doseLungVar.varType = PKPDVariable.TYPE_NUMERIC
doseLungVar.role = PKPDVariable.ROLE_LABEL
doseLungVar.units = createUnit("nmol")
doseLungVar.comment = "Lung dose in nmol"
doseBronchialVar = PKPDVariable()
doseBronchialVar.varName = "bronchial_dose_nmol"
doseBronchialVar.varType = PKPDVariable.TYPE_NUMERIC
doseBronchialVar.role = PKPDVariable.ROLE_LABEL
doseBronchialVar.units = createUnit("nmol")
doseBronchialVar.comment = "Bronchial dose in nmol"
doseAlveolarVar = PKPDVariable()
doseAlveolarVar.varName = "alveolar_dose_nmol"
doseAlveolarVar.varType = PKPDVariable.TYPE_NUMERIC
doseAlveolarVar.role = PKPDVariable.ROLE_LABEL
doseAlveolarVar.units = createUnit("nmol")
doseAlveolarVar.comment = "Alveolar dose in nmol"
mccClearedLungDoseFractionVar = PKPDVariable()
mccClearedLungDoseFractionVar.varName = "mcc_cleared_lung_dose_fraction"
mccClearedLungDoseFractionVar.varType = PKPDVariable.TYPE_NUMERIC
mccClearedLungDoseFractionVar.role = PKPDVariable.ROLE_LABEL
mccClearedLungDoseFractionVar.units = createUnit("None")
mccClearedLungDoseFractionVar.comment = "MCC cleared lung dose fraction"
self.experimentLungRetention.variables["t"] = tvar
self.experimentLungRetention.variables["Retention"] = Rvar
self.experimentLungRetention.variables["Cnmol"] = Cnmolvar
self.experimentLungRetention.variables["C"] = Cvar
self.experimentLungRetention.variables["alvTissue"] = alvTissueVar
self.experimentLungRetention.variables["alvFluid"] = alvFluidVar
self.experimentLungRetention.variables["alvSolid"] = alvSolidVar
self.experimentLungRetention.variables["brTissue"] = brTissueVar
self.experimentLungRetention.variables["brFluid"] = brFluidVar
self.experimentLungRetention.variables["brSolid"] = brSolidVar
self.experimentLungRetention.variables["brClear"] = brClvar
self.experimentLungRetention.variables["CbrTis"] = brCTisvar
self.experimentLungRetention.variables["sysCentral"] = sysCtrVar
self.experimentLungRetention.variables["sysAbsoprtion"] = sysGutVar
self.experimentLungRetention.variables["sysPeripheral"] = sysPerVar
self.experimentLungRetention.variables["Cp"] = CsysPerVar
self.experimentLungRetention.variables["dose_nmol"] = doseNmolVar
self.experimentLungRetention.variables[
"throat_dose_nmol"] = doseThroatVar
self.experimentLungRetention.variables["lung_dose_nmol"] = doseLungVar
self.experimentLungRetention.variables[
"bronchial_dose_nmol"] = doseBronchialVar
self.experimentLungRetention.variables[
"alveolar_dose_nmol"] = doseAlveolarVar
self.experimentLungRetention.variables[
"mcc_cleared_lung_dose_fraction"] = mccClearedLungDoseFractionVar
# Samples
simulationSample = PKPDSample()
simulationSample.sampleName = "simulation"
simulationSample.addMeasurementColumn("t", tt)
simulationSample.addMeasurementColumn("Retention", lungRetention)
simulationSample.addMeasurementColumn("Cnmol", Csysnmol)
simulationSample.addMeasurementColumn("C", Csys)
simulationSample.addMeasurementColumn("alvFluid", Aalvfluid)
simulationSample.addMeasurementColumn("alvTissue", Aalvtissue)
simulationSample.addMeasurementColumn("alvSolid", Aalvsolid)
simulationSample.addMeasurementColumn("brFluid", Abrfluid)
simulationSample.addMeasurementColumn("brTissue", Abrtissue)
simulationSample.addMeasurementColumn("brSolid", Abrsolid)
simulationSample.addMeasurementColumn("brClear", Abrcleared)
simulationSample.addMeasurementColumn("CbrTis", Cavgbr)
simulationSample.addMeasurementColumn("sysAbsorption", AsysGut)
simulationSample.addMeasurementColumn("sysCentral", AsysCtr)
simulationSample.addMeasurementColumn("sysPeripheral", AsysPer)
simulationSample.addMeasurementColumn("Cp", CsysPer)
simulationSample.setDescriptorValue("dose_nmol",
depositionData['dose_nmol'])
simulationSample.setDescriptorValue("throat_dose_nmol",
depositionData['throat'])
lungDose = depositionData['dose_nmol'] - depositionData['throat']
simulationSample.setDescriptorValue("lung_dose_nmol", lungDose)
simulationSample.setDescriptorValue("bronchial_dose_nmol", bronchDose)
simulationSample.setDescriptorValue("alveolar_dose_nmol", alvDose)
simulationSample.setDescriptorValue("mcc_cleared_lung_dose_fraction",
Abrcleared[-1] / lungDose)
self.experimentLungRetention.samples[
"simulmvarNameation"] = simulationSample
self.experimentLungRetention.write(self._getPath("experiment.pkpd"))
# Plots
import matplotlib.pyplot as plt
lungData = lungParams.getBronchial()
Xbnd = np.sort([0] + lungData['end_cm'].tolist() +
lungData['pos'].tolist())
Xctr = Xbnd[:-1] + np.diff(Xbnd) / 2
tvec = tt / 60
T = np.max(tvec)
Cflu = sol['C']['br']['fluid']
Cs = substanceParams.getData()['Cs_br']
plt.figure(figsize=(15, 9))
plt.title('Concentration in bronchial fluid (Cs=%f [uM])' % Cs)
plt.imshow(Cflu,
interpolation='bilinear',
aspect='auto',
extent=[np.min(Xctr), np.max(Xctr), T, 0])
plt.clim(0, Cs)
plt.xlim(np.min(Xctr), np.max(Xctr))
plt.ylim(0, T)
plt.colorbar()
plt.ylabel('Time [h]')
plt.xlabel('Distance from throat [cm]')
plt.savefig(self._getPath('concentrationBronchialFluid.png'))
Ctis = sol['C']['br']['fluid']
plt.figure(figsize=(15, 9))
plt.title('Concentration in bronchial tissue')
plt.imshow(Ctis,
interpolation='bilinear',
aspect='auto',
extent=[np.min(Xctr), np.max(Xctr), T, 0])
plt.xlim(np.min(Xctr), np.max(Xctr))
plt.ylim(0, T)
plt.colorbar()
plt.ylabel('Time [h]')
plt.xlabel('Distance from throat [cm]')
plt.savefig(self._getPath('concentrationBronchialTissue.png'))
class ProtPKPDDissolutionSimulate(ProtPKPD):
""" Simulate a dissolution profile\n
Protocol created by http://www.kinestatpharma.com\n"""
_label = 'simulate dissolution'
# --------------------------- DEFINE param functions --------------------------------------------
def _defineParams(self, form):
form.addSection('Input')
form.addParam(
'allowTlag',
params.BooleanParam,
label="Allow lag",
default=False,
help='Allow lag time before starting dissolution (t-tlag)')
form.addParam('modelType', params.EnumParam, choices=["Zero order", "First order", "Fractional", "Weibull",
"Double Weibull", "Triple Weibull", "Higuchi",
"Korsmeyer-Peppas", "Hixson-Crowell", "Hopfenberg",
"Hill",
"Makoid-Banakar",
"Splines2", "Splines3", "Splines4", "Spline5", "Splines6",
"Splines7", "Splines8", "Splines9", "Splines10"],
label="Dissolution model", default=3,
help='Zero order: Y=K*(t-[tlag])\n' \
'First order: Y=Ymax*(1-exp(-beta*(t-[tlag])))\n' \
'Fractional order: Y=Ymax-pow(Ymax^alpha-alpha*beta*t,1/alpha))\n' \
'Weibull: Y=Ymax*(1-exp(-lambda*t^b))\n' \
'Double Weibull: Y=Ymax*(F1*(1-exp(-lambda1*t^b1))+(1-F1)*(1-exp(-lambda2*(t-tlag2)^b2)))\n' \
'Triple Weibull: Y=Ymax*(F1*(1-exp(-lambda1*t^b1))+F2*(1-exp(-lambda2*(t-tlag2)^b2))+(1-F1-F2)*(1-exp(-lambda3*(t-tlag3)^b3)))\n' \
'Higuchi: Y=Ymax*t^0.5\n' \
'Korsmeyer-Peppas: Y=Ymax*t^m\n' \
'Hixson-Crowell: Y=Ymax*(1-(1-K*t)^3)\n'
'Hopfenberg: Y=Ymax*(1-(1-K*t)^m)\n'
'Hill: Y = Ymax*t^d/(g^d+t^d)\n'
'Makoid-Banakar: Ymax*(t/tmax)^b*exp(b*(1-t/tmax))\n'
'SplinesN: Y= Ymax*Bspline(t;N,tmax)\n')
form.addParam(
'parameters',
params.StringParam,
label="Parameters",
default="",
help=
'Parameter values for the simulation.\nExample: 2;5 is 2 for the first parameter, 5 for the second parameter\n'
'Zero order: [tlag];K\n'
'First order: [tlag];Ymax;beta\n'
'Fractional order: [tlag]; Ymax;beta;alpha\n'
'Weibull: [tlag]; Ymax;lambda;b\n'
'Double Weibull: [tlag]; Ymax; lambda1; b1; F1; tlag2; lambda2; b2\n'
'Triple Weibull: [tlag]; Ymax; lambda1; b1; F1; tlag2; lambda2; b2; F2; tlag3; lambda3; b3\n'
'Higuchi: [tlag]; Ymax\n'
'Korsmeyer-Peppas: [tlag]; Ymax; m\n'
'Hixson-Crowell: [tlag]; Ymax; K\n'
'Hopfenberg: [tlag]; Ymax; K; m\n'
'Hill: [tlag]; Ymax; g; d\n'
'Makoid-Banakar: [tlag]; Ymax; Tmax; b\n'
'SplinesN: [tlag]; Ymax; tmax; c1; c2; ...; cN\n')
form.addParam('timeUnits',
params.EnumParam,
choices=["min", "h"],
label="Time units",
default=0)
form.addParam('resampleT',
params.FloatParam,
label='Simulation model time step=',
default=1)
form.addParam('resampleT0',
params.FloatParam,
label='Initial time for simulation',
default=0)
form.addParam('resampleTF',
params.FloatParam,
label='Final time for simulation',
default=100)
form.addParam('AUnits',
params.StringParam,
label="Dissolution units",
default="%",
help="%, mg/dL, ...")
form.addParam('noiseType', params.EnumParam, label="Type of noise to add",
choices=["None", "Additive", "Multiplicative"],
default=0, expertLevel=LEVEL_ADVANCED,
help='Additive: noise is normally distributed (mean=0 and standard deviation=sigma)\n' \
'Multiplicative: noise is normally distributed (mean=0 and standard deviation=sigma*X)\n')
form.addParam('noiseSigma',
params.FloatParam,
label="Noise sigma",
default=0.0,
expertLevel=LEVEL_ADVANCED,
condition="noiseType>0",
help='See help of Type of noise to add\n')
# --------------------------- STEPS functions --------------------------------------------
def _insertAllSteps(self):
self._insertFunctionStep('runSimulate')
self._insertFunctionStep('createOutputStep')
def addNoise(self, y):
if self.noiseType.get() == 0:
return y
elif self.noiseType.get() == 1:
return y + np.random.normal(0.0, self.noiseSigma.get(), y.shape)
elif self.noiseType.get() == 2:
return y * (1 +
np.random.normal(0.0, self.noiseSigma.get(), y.shape))
def runSimulate(self):
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
if self.timeUnits.get() == 0:
tvar.units = createUnit("min")
elif self.timeUnits.get() == 1:
tvar.units = createUnit("h")
Avar = PKPDVariable()
Avar.varName = "A"
Avar.varType = PKPDVariable.TYPE_NUMERIC
Avar.role = PKPDVariable.ROLE_MEASUREMENT
if self.AUnits.get() != "%":
Avar.units = createUnit(self.AUnits.get())
else:
Avar.units = createUnit("none")
self.experimentSimulated = PKPDExperiment()
self.experimentSimulated.variables["t"] = tvar
self.experimentSimulated.variables["A"] = Avar
self.experimentSimulated.general[
"title"] = "Simulated dissolution profile"
self.experimentSimulated.general["comment"] = ""
if self.modelType.get() == 0:
self.model = Dissolution0()
elif self.modelType.get() == 1:
self.model = Dissolution1()
elif self.modelType.get() == 2:
self.model = DissolutionAlpha()
elif self.modelType.get() == 3:
self.model = DissolutionWeibull()
elif self.modelType.get() == 4:
self.model = DissolutionDoubleWeibull()
elif self.modelType.get() == 5:
self.model = DissolutionTripleWeibull()
elif self.modelType.get() == 6:
self.model = DissolutionHiguchi()
elif self.modelType.get() == 7:
self.model = DissolutionKorsmeyer()
elif self.modelType.get() == 8:
self.model = DissolutionHixson()
elif self.modelType.get() == 9:
self.model = DissolutionHopfenberg()
elif self.modelType.get() == 10:
self.model = DissolutionHill()
elif self.modelType.get() == 11:
self.model = DissolutionMakoidBanakar()
elif self.modelType.get() == 12:
self.model = DissolutionSplines2()
elif self.modelType.get() == 13:
self.model = DissolutionSplines3()
elif self.modelType.get() == 14:
self.model = DissolutionSplines4()
elif self.modelType.get() == 15:
self.model = DissolutionSplines5()
elif self.modelType.get() == 16:
self.model = DissolutionSplines6()
elif self.modelType.get() == 17:
self.model = DissolutionSplines7()
elif self.modelType.get() == 18:
self.model = DissolutionSplines8()
elif self.modelType.get() == 19:
self.model = DissolutionSplines9()
elif self.modelType.get() == 20:
self.model = DissolutionSplines10()
self.model.allowTlag = self.allowTlag.get()
self.model.parameters = [
float(x) for x in self.parameters.get().split(';')
]
newSample = PKPDSample()
newSample.sampleName = "simulatedProfile"
newSample.variableDictPtr = self.experimentSimulated.variables
newSample.descriptors = {}
newSample.addMeasurementPattern(["A"])
t0 = self.resampleT0.get()
tF = self.resampleTF.get()
deltaT = self.resampleT.get()
t = np.arange(t0, tF + deltaT, deltaT)
self.model.setExperiment(self.experimentSimulated)
self.model.setXVar("t")
self.model.setYVar("A")
self.model.calculateParameterUnits(newSample)
y = self.model.forwardModel(self.model.parameters, t)
newSample.addMeasurementColumn("t", t)
newSample.addMeasurementColumn("A", y[0])
self.experimentSimulated.samples[newSample.sampleName] = newSample
fnExperiment = self._getPath("experimentSimulated.pkpd")
self.experimentSimulated.write(fnExperiment)
self.fittingSimulated = PKPDFitting()
self.fittingSimulated.fnExperiment.set(fnExperiment)
self.fittingSimulated.predictor = self.experimentSimulated.variables[
"t"]
self.fittingSimulated.predicted = self.experimentSimulated.variables[
"A"]
self.fittingSimulated.modelDescription = self.model.getDescription()
self.fittingSimulated.modelParameters = self.model.getParameterNames()
self.fittingSimulated.modelParameterUnits = self.model.parameterUnits
sampleFit = PKPDSampleFit()
sampleFit.sampleName = newSample.sampleName
sampleFit.x = [t]
sampleFit.y = y
sampleFit.yp = y
sampleFit.yl = y
sampleFit.yu = y
sampleFit.parameters = self.model.parameters
sampleFit.modelEquation = self.model.getEquation()
sampleFit.R2 = -1
sampleFit.R2adj = -1
sampleFit.AIC = -1
sampleFit.AICc = -1
sampleFit.BIC = -1
sampleFit.significance = ["NA" for prm in sampleFit.parameters]
sampleFit.lowerBound = ["NA" for prm in sampleFit.parameters]
sampleFit.upperBound = ["NA" for prm in sampleFit.parameters]
self.fittingSimulated.sampleFits.append(sampleFit)
fnFitting = self._getPath("fittingSimulated.pkpd")
self.fittingSimulated.write(fnFitting)
def createOutputStep(self):
self._defineOutputs(outputExperiment=self.experimentSimulated)
self._defineOutputs(outputFitting=self.fittingSimulated)
def runSimulate(self):
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
if self.timeUnits.get() == 0:
tvar.units = createUnit("min")
elif self.timeUnits.get() == 1:
tvar.units = createUnit("h")
Avar = PKPDVariable()
Avar.varName = "A"
Avar.varType = PKPDVariable.TYPE_NUMERIC
Avar.role = PKPDVariable.ROLE_MEASUREMENT
if self.AUnits.get() != "%":
Avar.units = createUnit(self.AUnits.get())
else:
Avar.units = createUnit("none")
self.experimentSimulated = PKPDExperiment()
self.experimentSimulated.variables["t"] = tvar
self.experimentSimulated.variables["A"] = Avar
self.experimentSimulated.general[
"title"] = "Simulated dissolution profile"
self.experimentSimulated.general["comment"] = ""
if self.modelType.get() == 0:
self.model = Dissolution0()
elif self.modelType.get() == 1:
self.model = Dissolution1()
elif self.modelType.get() == 2:
self.model = DissolutionAlpha()
elif self.modelType.get() == 3:
self.model = DissolutionWeibull()
elif self.modelType.get() == 4:
self.model = DissolutionDoubleWeibull()
elif self.modelType.get() == 5:
self.model = DissolutionTripleWeibull()
elif self.modelType.get() == 6:
self.model = DissolutionHiguchi()
elif self.modelType.get() == 7:
self.model = DissolutionKorsmeyer()
elif self.modelType.get() == 8:
self.model = DissolutionHixson()
elif self.modelType.get() == 9:
self.model = DissolutionHopfenberg()
elif self.modelType.get() == 10:
self.model = DissolutionHill()
elif self.modelType.get() == 11:
self.model = DissolutionMakoidBanakar()
elif self.modelType.get() == 12:
self.model = DissolutionSplines2()
elif self.modelType.get() == 13:
self.model = DissolutionSplines3()
elif self.modelType.get() == 14:
self.model = DissolutionSplines4()
elif self.modelType.get() == 15:
self.model = DissolutionSplines5()
elif self.modelType.get() == 16:
self.model = DissolutionSplines6()
elif self.modelType.get() == 17:
self.model = DissolutionSplines7()
elif self.modelType.get() == 18:
self.model = DissolutionSplines8()
elif self.modelType.get() == 19:
self.model = DissolutionSplines9()
elif self.modelType.get() == 20:
self.model = DissolutionSplines10()
self.model.allowTlag = self.allowTlag.get()
self.model.parameters = [
float(x) for x in self.parameters.get().split(';')
]
newSample = PKPDSample()
newSample.sampleName = "simulatedProfile"
newSample.variableDictPtr = self.experimentSimulated.variables
newSample.descriptors = {}
newSample.addMeasurementPattern(["A"])
t0 = self.resampleT0.get()
tF = self.resampleTF.get()
deltaT = self.resampleT.get()
t = np.arange(t0, tF + deltaT, deltaT)
self.model.setExperiment(self.experimentSimulated)
self.model.setXVar("t")
self.model.setYVar("A")
self.model.calculateParameterUnits(newSample)
y = self.model.forwardModel(self.model.parameters, t)
newSample.addMeasurementColumn("t", t)
newSample.addMeasurementColumn("A", y[0])
self.experimentSimulated.samples[newSample.sampleName] = newSample
fnExperiment = self._getPath("experimentSimulated.pkpd")
self.experimentSimulated.write(fnExperiment)
self.fittingSimulated = PKPDFitting()
self.fittingSimulated.fnExperiment.set(fnExperiment)
self.fittingSimulated.predictor = self.experimentSimulated.variables[
"t"]
self.fittingSimulated.predicted = self.experimentSimulated.variables[
"A"]
self.fittingSimulated.modelDescription = self.model.getDescription()
self.fittingSimulated.modelParameters = self.model.getParameterNames()
self.fittingSimulated.modelParameterUnits = self.model.parameterUnits
sampleFit = PKPDSampleFit()
sampleFit.sampleName = newSample.sampleName
sampleFit.x = [t]
sampleFit.y = y
sampleFit.yp = y
sampleFit.yl = y
sampleFit.yu = y
sampleFit.parameters = self.model.parameters
sampleFit.modelEquation = self.model.getEquation()
sampleFit.R2 = -1
sampleFit.R2adj = -1
sampleFit.AIC = -1
sampleFit.AICc = -1
sampleFit.BIC = -1
sampleFit.significance = ["NA" for prm in sampleFit.parameters]
sampleFit.lowerBound = ["NA" for prm in sampleFit.parameters]
sampleFit.upperBound = ["NA" for prm in sampleFit.parameters]
self.fittingSimulated.sampleFits.append(sampleFit)
fnFitting = self._getPath("fittingSimulated.pkpd")
self.fittingSimulated.write(fnFitting)
class ProtPKPDDeconvolutionWagnerNelson(ProtPKPD):
""" Calculate the absorption profile of an in vivo concentration profile using
the Wagner-Nelson approach. This is only valid for profiles that have been
modelled with a monocompartment PK model.
The formula is Fabs(t)=(Cp(t)+Ke*AUC0t(t))/(Ke*AUC0inf)
where Ke=Cl/V
In this implementation it is assumed that AUC0inf is the last AUC0t observed,
meaning that Cp(t) has almost vanished in the last samples"""
_label = 'deconvolution Wagner Nelson'
SAME_INPUT = 0
ANOTHER_INPUT = 1
BIOAVAIL_NONE = 0
BIOAVAIL_MULT = 1
BIOAVAIL_DIV = 2
#--------------------------- DEFINE param functions --------------------------------------------
def _defineParams(self, form):
form.addSection('Input')
form.addParam(
'inputExperiment',
params.PointerParam,
label="In-vivo profiles",
pointerClass='PKPDExperiment',
help=
'Make sure that it has a clearance parameter (Cl) and central volume (V)'
)
form.addParam(
'externalIV',
params.EnumParam,
choices=[
'Get impulse response from the same input fit',
'Get impulse response from another fit'
],
label='Impulse response source',
default=self.SAME_INPUT,
help=
"The impulse response is an estimate of the intravenous response")
form.addParam('externalIVODE', params.PointerParam, label="External impulse response ODE model",
condition='externalIV==1',
pointerClass='ProtPKPDMonoCompartment, ProtPKPDTwoCompartments,ProtPKPDODERefine,' \
' ProtPKPDTwoCompartmentsClint, ProtPKPDTwoCompartmentsClintCl',
help='Select a run of an ODE model. It should be ideally the intravenous response.')
form.addParam('timeVar',
params.StringParam,
label="Time variable",
default="t",
help='Which variable contains the time stamps.')
form.addParam('concVar',
params.StringParam,
label="Concentration variable",
default="Cp",
help='Which variable contains the plasma concentration.')
form.addParam(
'normalize',
params.BooleanParam,
label="Normalize by dose",
default=True,
help=
'Normalize the output by AUC0inf, so that a total absorption is represented by 100.'
)
form.addParam(
'saturate',
params.BooleanParam,
label="Saturate at 100%",
default=True,
condition='normalize',
help=
'Saturate the absorption so that there cannot be values beyond 100'
)
form.addParam('considerBioaval',
params.EnumParam,
label="Consider bioavailability",
default=self.BIOAVAIL_NONE,
choices=[
'Do not correct',
'Multiply deconvolution by bioavailability',
'Divide deconvolution by bioavailability'
],
help='Take into account the bioavailability')
form.addParam(
'resampleT',
params.FloatParam,
label="Resample profiles (time step)",
default=-1,
help=
'Resample the input profiles at this time step (make sure it is in the same units as the input). '
'Leave it to -1 for no resampling')
form.addParam(
'smooth',
params.BooleanParam,
label="Monotonic smooth",
default=True,
help=
'Apply a Pchip interpolation to make sure that the Adissolved is monotonically increasing'
)
#--------------------------- INSERT steps functions --------------------------------------------
def _insertAllSteps(self):
self._insertFunctionStep('deconvolve',
self.inputExperiment.get().getObjId())
self._insertFunctionStep('createOutputStep')
#--------------------------- STEPS functions --------------------------------------------
def addSample(self, sampleName, t, y):
newSample = PKPDSample()
newSample.sampleName = sampleName
newSample.variableDictPtr = self.outputExperiment.variables
newSample.descriptors = {}
newSample.addMeasurementPattern(["A"])
newSample.addMeasurementColumn("t", t)
newSample.addMeasurementColumn("A", y)
self.outputExperiment.samples[sampleName] = newSample
def estimateAUCrightTail(self, t, Cp, Cl, V):
idx = Cp > 0
x = t[idx]
y = np.log10(Cp[idx])
ydiff = np.diff(y)
idx = -1
while ydiff[idx] < 0:
idx -= 1
if idx < -3:
p = np.polyfit(x[idx:], y[idx:], 1)
Ke = Cl / V
lastCt = np.power(10, p[0] * x[-1] + p[1])
return lastCt / np.abs(Ke)
else:
return 0
def deconvolve(self, objId1):
self.experiment = self.readExperiment(
self.inputExperiment.get().fnPKPD)
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Avar = PKPDVariable()
Avar.varName = "A"
Avar.varType = PKPDVariable.TYPE_NUMERIC
Avar.role = PKPDVariable.ROLE_MEASUREMENT
Avar.units = createUnit("none")
self.outputExperiment.variables[tvar.varName] = tvar
self.outputExperiment.variables[Avar.varName] = Avar
self.outputExperiment.general[
"title"] = "Deconvolution of the amount released"
self.outputExperiment.general[
"comment"] = "Amount released at any time t"
# Get the input sample from another experiment if necessary
sampleFrom = None
if self.externalIV.get() == self.ANOTHER_INPUT:
anotherExperiment = self.readExperiment(
self.externalIVODE.get().outputExperiment.fnPKPD)
for _, sampleFrom in anotherExperiment.samples.items(
): # Take the first sample from the reference
break
timeRange = self.experiment.getRange(self.timeVar.get())
for sampleName, sample in self.experiment.samples.items():
# Get t, Cp
t = np.asarray(sample.getValues(self.timeVar.get()),
dtype=np.float64)
Cp = np.asarray(sample.getValues(self.concVar.get()),
dtype=np.float64)
Cp = np.clip(Cp, 0.0, None)
t = np.insert(t, 0, 0) # Add (0,0) to the profile
Cp = np.insert(Cp, 0, 0)
t, Cp = uniqueFloatValues(t, Cp)
if self.resampleT.get() > 0:
B = InterpolatedUnivariateSpline(t, Cp, k=1)
t = np.arange(np.min(t),
np.max(t) + self.resampleT.get(),
self.resampleT.get())
Cp = B(t)
# Calculate AUC0t
AUC0t = calculateAUC0t(t, Cp)
# Deconvolve
if self.externalIV.get() == self.SAME_INPUT:
sampleFrom = sample
Cl = float(sampleFrom.descriptors['Cl'])
V = float(sampleFrom.descriptors['V'])
Ke = Cl / V
AUC0inf = float(AUC0t[-1]) + self.estimateAUCrightTail(
t, Cp, Cl, V)
A = (Cp + Ke * AUC0t) / Ke
if self.normalize.get():
A *= 100 / AUC0inf
if self.saturate.get():
A = np.clip(A, None, 100.0)
A = np.clip(A, 0, None)
if self.smooth:
if t[0] > 0:
t = np.insert(t, 0, 0)
A = np.insert(A, 0, 0)
if self.saturate.get() and self.normalize.get():
A = np.clip(A, None, 100.0)
A = np.clip(smoothPchip(t, A), 0, None)
if self.saturate.get() and self.normalize.get():
A = np.clip(A, None, 100.0)
if self.considerBioaval.get() == self.BIOAVAIL_DIV:
A /= sample.getBioavailability()
elif self.considerBioaval.get() == self.BIOAVAIL_MULT:
A *= sample.getBioavailability()
self.addSample(sampleName, t, A)
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def createOutputStep(self):
self._defineOutputs(outputExperiment=self.outputExperiment)
self._defineSourceRelation(self.inputExperiment.get(),
self.outputExperiment)
def _validate(self):
retval = []
if self.externalIV.get() == self.ANOTHER_INPUT:
sample = self.readExperiment(self.externalIVODE.get(
).outputExperiment.fnPKPD).getFirstSample()
else:
sample = self.readExperiment(
self.inputExperiment.get().fnPKPD).getFirstSample()
if sample is None:
reval.append('Cannot find a sample in the input experiment')
else:
if sample.getDescriptorValue('Cl') is None:
retval.append('Cannot find Cl in the input experiment')
if sample.getDescriptorValue('V') is None:
retval.append('Cannot find V in the input experiment')
return retval
def _summary(self):
retval = []
return retval
class ProtPKPDODESimulate2(ProtPKPDODEBase):
""" Simulate a complex sequence of doses. Each dose has its own PK profile, and the overall profile is the
addition of all the individual profiles. Only the parameters from the first fitting of each model are
considered.
The first dose goes with the first model, the second dose with the second model, ...
A single profile is simulated that is the addition of the different simulations for each one of the input
models."""
_label = 'PK simulate (complex)'
#--------------------------- DEFINE param functions --------------------------------------------
def _defineParams(self, form):
form.addSection('Input')
form.addParam('inputODEs', params.MultiPointerParam, label="Input ODE models",
pointerClass='ProtPKPDMonoCompartment, ProtPKPDTwoCompartments, ProtPKPDMonoCompartmentPD, ProtPKPDTwoCompartmentsBothPD, '\
'ProtPKPDODERefine, ProtPKPDTwoCompartmentsClint, ProtPKPDTwoCompartmentsClintCl',
help='Select a run of an ODE model')
form.addParam('doses', params.TextParam, label="Doses", height=5, width=50,
default="",
help="Structure: [Dose Name] ; [Via] ; [Dose type] ; [time] ; [dose] \n"\
"The dose name should have no space or special character\n"\
"The via should be one present in the input experiment to the ODE model.\n"\
"Valid units are: h, mg, ug, ...\n"\
"The description is either a bolus or an infusion as shown in the examples\n"\
"\nIt is important that there are two semicolons.\n"\
"Examples:\n"\
"Infusion0; via=Intravenous; infusion; t=0.500000:0.750000 h; d=60 mg/h\n"\
"Bolus0; via=Oral; bolus; t=0.000000 min; d=60 mg\n"\
"RepeatedBolus; via=Oral; repeated_bolus; t=0:24:120 h; d=60 mg")
form.addParam('t0',
params.FloatParam,
label="Initial time (see help)",
default=0,
help="Same units as input experiment")
form.addParam('tF',
params.FloatParam,
label="Final time (see help)",
default=24 * 7,
help="Same units as input experiment")
form.addParam('deltaT',
params.FloatParam,
label="Time step (see help)",
default=0.5,
expertLevel=LEVEL_ADVANCED,
help="Same units as input experiment")
#--------------------------- INSERT steps functions --------------------------------------------
def _insertAllSteps(self):
self._insertFunctionStep('runSimulate')
self._insertFunctionStep('createOutputStep')
#--------------------------- STEPS functions --------------------------------------------
def addSample(self, sampleName, doseList, simulationsX, y):
newSample = PKPDSample()
newSample.sampleName = sampleName
newSample.variableDictPtr = self.outputExperiment.variables
newSample.doseDictPtr = self.outputExperiment.doses
newSample.descriptors = {}
newSample.doseList = doseList
if type(self.varNameY) != list:
newSample.addMeasurementPattern([self.varNameY])
newSample.addMeasurementColumn("t", simulationsX)
newSample.addMeasurementColumn(self.varNameY, y)
else:
for j in range(len(self.varNameY)):
newSample.addMeasurementPattern([self.varNameY[j]])
newSample.addMeasurementColumn("t", simulationsX)
for j in range(len(self.varNameY)):
newSample.addMeasurementColumn(self.varNameY[j], y[j])
self.outputExperiment.samples[sampleName] = newSample
def runSimulate(self):
# Take first experiment
self.protODE = self.inputODEs[0].get()
if hasattr(self.protODE, "outputExperiment"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment.fnPKPD, show=False)
elif hasattr(self.protODE, "outputExperiment1"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment1.fnPKPD, show=False)
else:
raise Exception("Cannot find an outputExperiment in the input ODE")
if hasattr(self.protODE, "outputFitting"):
self.fitting = self.readFitting(
self.protODE.outputFitting.fnFitting, show=False)
elif hasattr(self.protODE, "outputFitting1"):
self.fitting = self.readFitting(
self.protODE.outputFitting1.fnFitting, show=False)
self.varNameX = self.fitting.predictor.varName
if type(self.fitting.predicted) != list:
self.varNameY = self.fitting.predicted.varName
else:
self.varNameY = [var.varName for var in self.fitting.predicted]
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Nsamples = int(
math.ceil((self.tF.get() - self.t0.get()) / self.deltaT.get())) + 1
if tvar.units == PKPDUnit.UNIT_TIME_MIN:
Nsamples *= 60
self.outputExperiment.variables[self.varNameX] = tvar
if type(self.fitting.predicted) != list:
self.outputExperiment.variables[
self.varNameY] = self.experiment.variables[self.varNameY]
else:
for varName in self.varNameY:
self.outputExperiment.variables[
varName] = self.experiment.variables[varName]
self.outputExperiment.general["title"] = "Simulated ODE response"
self.outputExperiment.general["comment"] = "Simulated ODE response"
self.outputExperiment.vias = self.experiment.vias
# Read the doses
doseLines = []
for line in self.doses.get().replace('\n', ';;').split(';;'):
doseLines.append(line)
doseIdx = 0
simulationsY = None
doseList = []
for protODEPtr in self.inputODEs:
self.protODE = protODEPtr.get()
if hasattr(self.protODE, "outputExperiment"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment.fnPKPD, show=False)
elif hasattr(self.protODE, "outputExperiment1"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment1.fnPKPD, show=False)
else:
raise Exception(
"Cannot find an outputExperiment in the input ODE")
if hasattr(self.protODE, "outputFitting"):
self.fitting = self.readFitting(
self.protODE.outputFitting.fnFitting, show=False)
elif hasattr(self.protODE, "outputFitting1"):
self.fitting = self.readFitting(
self.protODE.outputFitting1.fnFitting, show=False)
for viaName in self.experiment.vias:
if not viaName in self.outputExperiment.vias:
self.outputExperiment.vias[viaName] = copy.copy(
self.experiment.vias[viaName])
# Create drug source
self.clearGroupParameters()
self.createDrugSource()
# Setup model
self.model = self.protODE.createModel()
self.model.setExperiment(self.outputExperiment)
self.model.deltaT = self.deltaT.get()
self.model.setXVar(self.varNameX)
self.model.setYVar(self.varNameY)
self.model.x = [
self.t0.get() + i * self.model.deltaT
for i in range(0, Nsamples)
]
self.modelList.append(self.model)
tokens = doseLines[doseIdx].split(';')
if len(tokens) < 5:
print("Skipping dose: ", line)
continue
dosename = tokens[0].strip()
self.outputExperiment.doses[dosename] = PKPDDose()
self.outputExperiment.doses[dosename].parseTokens(
tokens, self.outputExperiment.vias)
doseList.append(dosename)
auxSample = PKPDSample()
auxSample.descriptors = {}
auxSample.doseDictPtr = self.outputExperiment.doses
auxSample.variableDictPtr = self.outputExperiment.variables
auxSample.doseList = [dosename]
auxSample.interpretDose()
self.drugSource.setDoses(auxSample.parsedDoseList,
self.t0.get() - 10,
self.tF.get() + 10)
self.model.drugSource = self.drugSource
# Simulate the different responses
simulationsX = self.model.x
self.setTimeRange(None)
parameters = self.fitting.sampleFits[0].parameters
print("Input model: %s" % self.protODE.getObjLabel())
print("Sample name: %s" % self.fitting.sampleFits[0].sampleName)
print("Parameters: ", parameters)
print("Dose: %s" % doseLines[doseIdx])
print(" ")
# Prepare source and this object
self.protODE.configureSource(self.drugSource)
parameterNames = self.getParameterNames(
) # Necessary to count the number of source and PK parameters
# Prepare the model
y = self.forwardModel(parameters,
[simulationsX] * self.getResponseDimension())
# Keep results
if simulationsY is None:
simulationsY = copy.copy(y)
else:
for j in range(self.getResponseDimension()):
simulationsY[j] += y[j]
doseIdx += 1
self.addSample("Simulation", doseList, simulationsX, simulationsY[0])
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def createOutputStep(self):
self._defineOutputs(outputExperiment=self.outputExperiment)
for protODEPtr in self.inputODEs:
self._defineSourceRelation(protODEPtr.get(), self.outputExperiment)
#--------------------------- INFO functions --------------------------------------------
def _summary(self):
msg = []
return msg
def _validate(self):
msg = []
return msg
def testDissolutionWorkflow(self):
# Create invivo data
experimentStr = """
[EXPERIMENT] ===========================
comment =
title = Dissolution
[VARIABLES] ============================
C ; none ; numeric[%f] ; measurement ; Concentration in solution (%)
t ; min ; numeric[%f] ; time ; Time in minutes since start
[VIAS] ================================
[DOSES] ================================
[GROUPS] ================================
__Profile
[SAMPLES] ================================
Profile; group=__Profile
[MEASUREMENTS] ===========================
Profile ; t; C
0 0
2.5 1.7
5 8.3
7.5 13.3
10 20.0
20 44.0
30 61.0
40 70.7
60 78.0
80 79.7
100 80.7
120 80.0
160 81.3
200 82.0
240 82.3
"""
fnExperiment = "experimentInVitro.pkpd"
fhExperiment = open(fnExperiment, "w")
fhExperiment.write(experimentStr)
fhExperiment.close()
print("Import Experiment in vitro")
protImport = self.newProtocol(ProtImportExperiment,
objLabel='pkpd - import experiment in vitro',
inputFile=fnExperiment)
self.launchProtocol(protImport)
self.assertIsNotNone(protImport.outputExperiment.fnPKPD, "There was a problem with the import")
self.validateFiles('protImport', protImport)
os.remove(fnExperiment)
# Fit a Weibull dissolution
print("Fitting Weibull model ...")
protWeibull = self.newProtocol(ProtPKPDDissolutionFit,
objLabel='pkpd - fit dissolution Weibull',
globalSearch=True, modelType=3)
protWeibull.inputExperiment.set(protImport.outputExperiment)
self.launchProtocol(protWeibull)
self.assertIsNotNone(protWeibull.outputExperiment.fnPKPD, "There was a problem with the dissolution model ")
self.assertIsNotNone(protWeibull.outputFitting.fnFitting, "There was a problem with the dissolution model ")
self.validateFiles('ProtPKPDDissolutionFit', ProtPKPDDissolutionFit)
experiment = PKPDExperiment()
experiment.load(protWeibull.outputExperiment.fnPKPD)
Vmax = float(experiment.samples['Profile'].descriptors['Vmax'])
self.assertTrue(Vmax>80 and Vmax<82)
lambdda = float(experiment.samples['Profile'].descriptors['lambda'])
self.assertTrue(lambdda>0.009 and lambdda<0.011)
b = float(experiment.samples['Profile'].descriptors['b'])
self.assertTrue(b>1.4 and b<1.5)
fitting = PKPDFitting()
fitting.load(protWeibull.outputFitting.fnFitting)
self.assertTrue(fitting.sampleFits[0].R2>0.997)
# Create invivo data
experimentStr = """
[EXPERIMENT] ===========================
comment = Generated as C(t)=D0/V*Ka/(Ka-Ke)*)(exp(-Ke*t)-exp(-Ka*t))
title = My experiment
[VARIABLES] ============================
Cp ; ug/L ; numeric[%f] ; measurement ; Plasma concentration
t ; min ; numeric[%f] ; time ;
[VIAS] ================================
Oral; splineXY5; tlag min; bioavailability=1.000000
[DOSES] ================================
Bolus1; via=Oral; bolus; t=0.000000 h; d=200 ug
[GROUPS] ================================
__Individual1
[SAMPLES] ================================
Individual1; dose=Bolus1; group=__Individual1
[MEASUREMENTS] ===========================
Individual1 ; t; Cp
"""
t = np.arange(0,1000,10)
Cp = unitResponse(100,50,0.05,0.2,t-20)+unitResponse(100,50,0.05,0.2,t-120)
for n in range(t.size):
experimentStr+="%f %f\n"%(t[n],Cp[n])
fnExperiment ="experimentInVivo.pkpd"
fhExperiment = open(fnExperiment,"w")
fhExperiment.write(experimentStr)
fhExperiment.close()
print("Import Experiment in vivo")
protImportInVivo = self.newProtocol(ProtImportExperiment,
objLabel='pkpd - import experiment in vivo',
inputFile=fnExperiment)
self.launchProtocol(protImportInVivo)
self.assertIsNotNone(protImportInVivo.outputExperiment.fnPKPD, "There was a problem with the import")
self.validateFiles('protImport', protImportInVivo)
os.remove(fnExperiment)
# NCA numeric
print("NCA numeric ...")
protNCA = self.newProtocol(ProtPKPDNCANumeric,
objLabel='pkpd - nca numeric')
protNCA.inputExperiment.set(protImportInVivo.outputExperiment)
self.launchProtocol(protNCA)
self.assertIsNotNone(protNCA.outputExperiment.fnPKPD, "There was a problem with the NCA numeric")
self.validateFiles('prot', protNCA)
experiment = PKPDExperiment()
experiment.load(protNCA.outputExperiment.fnPKPD)
AUC0t = float(experiment.samples['Individual1'].descriptors['AUC0t'])
self.assertTrue(AUC0t > 960 and AUC0t < 980)
AUMC0t = float(experiment.samples['Individual1'].descriptors['AUMC0t'])
self.assertTrue(AUMC0t > 305000 and AUMC0t < 306000)
Cmax = float(experiment.samples['Individual1'].descriptors['Cmax'])
self.assertTrue(Cmax > 2.7 and Cmax < 2.9)
Tmax = float(experiment.samples['Individual1'].descriptors['Tmax'])
self.assertTrue(Tmax > 155 and Tmax < 165)
MRT = float(experiment.samples['Individual1'].descriptors['MRT'])
self.assertTrue(MRT > 314 and MRT < 315)
# Fit Order 1
print("Fitting splines5-monocompartment model ...")
protModelInVivo = self.newProtocol(ProtPKPDMonoCompartment,
objLabel='pkpd - fit monocompartment',
bounds="(15.0, 30.0); (0.0, 400.0); (0.0, 1.0); (0.0, 1.0); (0.0, 1.0); (0.0, 1.0); (0.0, 1.0); (0.0, 1.0); (0.0, 1.0); (0.0, 1.0); (0.0, 1.0); (0.0, 1.0); (0.15, 0.25); (47, 53)"
)
protModelInVivo.inputExperiment.set(protImportInVivo.outputExperiment)
self.launchProtocol(protModelInVivo)
self.assertIsNotNone(protModelInVivo.outputExperiment.fnPKPD, "There was a problem with the PK model")
self.assertIsNotNone(protModelInVivo.outputFitting.fnFitting, "There was a problem with the PK model")
self.validateFiles('ProtPKPDMonoCompartment', ProtPKPDMonoCompartment)
experiment = PKPDExperiment()
experiment.load(protModelInVivo.outputExperiment.fnPKPD)
V = float(experiment.samples['Individual1'].descriptors['V'])
self.assertTrue(V>46 and V<54)
Cl = float(experiment.samples['Individual1'].descriptors['Cl'])
self.assertTrue(Cl>0.18 and Cl<0.22)
fitting = PKPDFitting()
fitting.load(protModelInVivo.outputFitting.fnFitting)
self.assertTrue(fitting.sampleFits[0].R2>0.995)
# Deconvolve the in vivo
print("Deconvolving in vivo ...")
protDeconv = self.newProtocol(ProtPKPDDeconvolve,
objLabel='pkpd - deconvolution'
)
protDeconv.inputODE.set(protModelInVivo)
self.launchProtocol(protDeconv)
self.assertIsNotNone(protDeconv.outputExperiment.fnPKPD, "There was a problem with the deconvolution")
self.validateFiles('ProtPKPDDeconvolve', ProtPKPDDeconvolve)
# Levy plot
print("Levy plot ...")
protLevy = self.newProtocol(ProtPKPDDissolutionLevyPlot,
objLabel='pkpd - levy plot'
)
protLevy.inputInVitro.set(protWeibull)
protLevy.inputInVivo.set(protDeconv)
self.launchProtocol(protLevy)
self.assertIsNotNone(protLevy.outputExperiment.fnPKPD, "There was a problem with the Levy plot")
self.validateFiles('ProtPKPDDissolutionLevyPlot', ProtPKPDDissolutionLevyPlot)
# IVIVC
print("In vitro-in vivo correlation ...")
protIVIVC = self.newProtocol(ProtPKPDDissolutionIVIVC,
timeScale=5,
responseScale=1,
objLabel='pkpd - ivivc'
)
protIVIVC.inputInVitro.set(protWeibull)
protIVIVC.inputInVivo.set(protDeconv)
self.launchProtocol(protIVIVC)
self.assertIsNotNone(protIVIVC.outputExperimentFabs.fnPKPD, "There was a problem with the IVIVC")
self.assertIsNotNone(protIVIVC.outputExperimentAdissol.fnPKPD, "There was a problem with the IVIVC")
self.validateFiles('ProtPKPDDissolutionIVIVC', ProtPKPDDissolutionIVIVC)
# IVIVC generic
print("In vitro-in vivo generic ...")
protIVIVCG = self.newProtocol(ProtPKPDDissolutionIVIVCGeneric,
timeScale='$[k1]*$(t)+$[k2]*np.power($(t),2)+$[k3]*np.power($(t),3)',
timeBounds='k1: [0,3]; k2: [-0.1,0.01]; k3: [0,1e-3]',
responseScale='$[A]*$(Adissol)+$[B]+$[C]*np.power($(Adissol),2)',
responseBounds='A: [0.01,1]; B: [-50,30]; C: [-0.05,0.05]',
objLabel='pkpd - ivivc generic'
)
protIVIVCG.inputInVitro.set(protWeibull)
protIVIVCG.inputInVivo.set(protDeconv)
self.launchProtocol(protIVIVCG)
self.assertIsNotNone(protIVIVCG.outputExperimentFabs.fnPKPD, "There was a problem with the IVIVC Generic")
self.validateFiles('ProtPKPDDissolutionIVIVCG', ProtPKPDDissolutionIVIVCGeneric)
# IVIVC splines
print("In vitro-in vivo splies ...")
protIVIVCS = self.newProtocol(ProtPKPDDissolutionIVIVCSplines,
timeScale=1,
responseScale=1,
objLabel='pkpd - ivivc splines'
)
protIVIVCS.inputInVitro.set(protWeibull)
protIVIVCS.inputInVivo.set(protDeconv)
self.launchProtocol(protIVIVCS)
self.assertIsNotNone(protIVIVCS.outputExperimentFabs.fnPKPD, "There was a problem with the IVIVC Splines")
self.validateFiles('ProtPKPDDissolutionIVIVCS', ProtPKPDDissolutionIVIVCSplines)
# Dissolution simulation
print("IVIV+PK simulation ...")
protIVIVPKL = self.newProtocol(ProtPKPDDissolutionPKSimulation,
objLabel='pkpd - ivivc+pk',
conversionType=1,
inputN=1,
tF=16.66,
addIndividuals=True,
inputDose=200
)
protIVIVPKL.inputInVitro.set(protWeibull.outputFitting)
protIVIVPKL.inputPK.set(protModelInVivo.outputFitting)
protIVIVPKL.inputLevy.set(protLevy.outputExperiment)
self.launchProtocol(protIVIVPKL)
self.assertIsNotNone(protIVIVPKL.outputExperiment.fnPKPD, "There was a problem with the simulation")
self.validateFiles('ProtPKPDDissolutionPKSimulation', ProtPKPDDissolutionPKSimulation)
# Dissolution simulation
print("IVIV+PK simulation ...")
protIVIVPKS = self.newProtocol(ProtPKPDDissolutionPKSimulation,
objLabel='pkpd - ivivc+pk',
inputN=1,
tF=16.66,
addIndividuals=True,
inputDose=200
)
protIVIVPKS.inputInVitro.set(protWeibull.outputFitting)
protIVIVPKS.inputPK.set(protModelInVivo.outputFitting)
protIVIVPKS.inputIvIvC.set(protIVIVCS.outputExperimentFabs)
self.launchProtocol(protIVIVPKS)
self.assertIsNotNone(protIVIVPKS.outputExperiment.fnPKPD, "There was a problem with the simulation")
self.validateFiles('ProtPKPDDissolutionPKSimulation', ProtPKPDDissolutionPKSimulation)
# Internal validity
print("Internal validity ...")
protInternal = self.newProtocol(ProtPKPDIVIVCInternalValidity,
objLabel='pkpd - internal validity')
protInternal.inputExperiment.set(protNCA.outputExperiment)
protInternal.inputSimulated.set(protIVIVPKL.outputExperiment)
self.launchProtocol(protInternal)
fnSummary = protInternal._getPath("summary.txt")
self.assertTrue(os.path.exists(fnSummary))
lineNo = 0
for line in open(fnSummary).readlines():
tokens = line.split('=')
if lineNo == 0:
AUCmean = np.abs(float(tokens[-1]))
self.assertTrue(AUCmean < 20)
elif lineNo == 1:
Cmaxmean = np.abs(float(tokens[-1]))
self.assertTrue(Cmaxmean < 13)
lineNo += 1
# Internal validity
print("Internal validity ...")
protInternal = self.newProtocol(ProtPKPDIVIVCInternalValidity,
objLabel='pkpd - internal validity')
protInternal.inputExperiment.set(protNCA.outputExperiment)
protInternal.inputSimulated.set(protIVIVPKS.outputExperiment)
self.launchProtocol(protInternal)
fnSummary = protInternal._getPath("summary.txt")
self.assertTrue(os.path.exists(fnSummary))
lineNo = 0
for line in open(fnSummary).readlines():
tokens = line.split('=')
if lineNo == 0:
AUCmean = np.abs(float(tokens[-1]))
self.assertTrue(AUCmean < 10)
elif lineNo == 1:
Cmaxmean = np.abs(float(tokens[-1]))
self.assertTrue(Cmaxmean < 20)
lineNo += 1
class ProtPKPDDissolutionIVIVCJoin(ProtPKPD):
""" Join several IVIVCs into a single one. The strategy is to compute the average of all the plots involved in the
IVIVC process: 1) tvivo -> tvitro; 2) tvitro -> Adissol; 3) Adissol->FabsPredicted. The plot tvivo-Fabs comes
after the IVIVC process, while the plot tvivo-FabsOrig is the observed one in the input files. These two
plots need not be exactly the same. """
_label = 'dissol ivivc join avg'
#--------------------------- DEFINE param functions --------------------------------------------
def _defineParams(self, form):
form.addSection('Input')
form.addParam(
'inputIVIVCs',
params.MultiPointerParam,
label="IVIVCs Fabs",
pointerClass='PKPDExperiment',
help=
'Choose experiments with IVIV correlations (only the Fabs experiments)'
)
#--------------------------- INSERT steps functions --------------------------------------------
def _insertAllSteps(self):
self._insertFunctionStep('calculateAllIvIvC')
self._insertFunctionStep('createOutputStep')
#--------------------------- STEPS functions --------------------------------------------
def calculateAllIvIvC(self):
L1 = []
L2 = []
L3 = []
L4 = []
L5 = []
for ptrExperiment in self.inputIVIVCs:
experiment = PKPDExperiment()
experiment.load(ptrExperiment.get().fnPKPD.get())
x, y = experiment.getXYMeanValues("tvivo", "tvitroReinterpolated")
L1.append((x, y))
x, y = experiment.getXYMeanValues("tvivo", "Fabs")
L2.append((x, y))
x, y = experiment.getXYMeanValues("AdissolReinterpolated",
"FabsPredicted")
L3.append((x, y))
x, y = experiment.getXYMeanValues("FabsPredicted", "Fabs")
L4.append((x, y))
x, y = experiment.getXYMeanValues("tvitroReinterpolated",
"AdissolReinterpolated")
L5.append((x, y))
tvivo1, tvitroReinterpolatedY = computeXYmean(L1, common=True)
tvivoOrig, FabsOrig = computeXYmean(L2, common=True)
AdissolReinterpolatedX, FabsPredictedY = computeXYmean(L3, common=True)
FabsPredictedX, Fabs = computeXYmean(L4, common=True)
tvitroReinterpolatedX, AdissolReinterpolatedY = computeXYmean(
L5, common=True)
x, y = twoWayUniqueFloatValues(tvivo1, tvitroReinterpolatedY)
Bt = InterpolatedUnivariateSpline(x, y, k=1)
x, y = twoWayUniqueFloatValues(tvitroReinterpolatedX,
AdissolReinterpolatedY)
BtA = InterpolatedUnivariateSpline(x, y, k=1)
x, y = twoWayUniqueFloatValues(tvivoOrig, FabsOrig)
BtF = InterpolatedUnivariateSpline(x, y, k=1)
x, y = twoWayUniqueFloatValues(AdissolReinterpolatedX, FabsPredictedY)
BAF = InterpolatedUnivariateSpline(x, y, k=1)
x, y = twoWayUniqueFloatValues(FabsPredictedX, Fabs)
BFF = InterpolatedUnivariateSpline(x, y, k=1)
vtvitroReinterpolated = np.zeros(len(tvivo1))
vAdissolReinterpolated = np.zeros(len(tvivo1))
vFabs = np.zeros(len(tvivo1))
vFabsPredicted = np.zeros(len(tvivo1))
vFabsOrig = np.zeros(len(tvivo1))
for i in range(len(tvivo1)):
tvivoi = tvivo1[i]
vtvitroReinterpolated[i] = Bt(tvivoi)
vAdissolReinterpolated[i] = BtA(vtvitroReinterpolated[i])
vFabsPredicted[i] = BAF(vAdissolReinterpolated[i])
vFabs[i] = BFF(vFabsPredicted[i])
vFabsOrig[i] = BtF(tvivoi)
tvitroReinterpolatedVar = experiment.variables["tvitroReinterpolated"]
AdissolReinterpolatedVar = experiment.variables[
"AdissolReinterpolated"]
tvivoVar = experiment.variables["tvivo"]
FabsOrigVar = copy.copy(experiment.variables["Fabs"])
FabsOrigVar.varName = "FabsOriginal"
FabsVar = experiment.variables["Fabs"]
FabsVar.comment += ". After IVIVC: tvivo->tvitro->Adissol->Fabs "
FabsPredictedVar = experiment.variables["FabsPredicted"]
self.outputExperimentFabsSingle = PKPDExperiment()
self.outputExperimentFabsSingle.variables[
tvitroReinterpolatedVar.varName] = tvitroReinterpolatedVar
self.outputExperimentFabsSingle.variables[
AdissolReinterpolatedVar.varName] = AdissolReinterpolatedVar
self.outputExperimentFabsSingle.variables[tvivoVar.varName] = tvivoVar
self.outputExperimentFabsSingle.variables[FabsVar.varName] = FabsVar
self.outputExperimentFabsSingle.variables[
FabsPredictedVar.varName] = FabsPredictedVar
self.outputExperimentFabsSingle.variables[
FabsOrigVar.varName] = FabsOrigVar
self.outputExperimentFabsSingle.general[
"title"] = "In-vitro In-vivo correlation"
self.outputExperimentFabsSingle.general[
"comment"] = "Fabs vs Predicted Fabs"
sampleName = "jointIVIVC"
newSampleFabsSingle = PKPDSample()
newSampleFabsSingle.sampleName = sampleName
newSampleFabsSingle.variableDictPtr = self.outputExperimentFabsSingle.variables
newSampleFabsSingle.descriptors = {}
newSampleFabsSingle.addMeasurementColumn("tvitroReinterpolated",
vtvitroReinterpolated)
newSampleFabsSingle.addMeasurementColumn("AdissolReinterpolated",
vAdissolReinterpolated)
newSampleFabsSingle.addMeasurementColumn("tvivo", tvivo1)
newSampleFabsSingle.addMeasurementColumn("FabsPredicted",
vFabsPredicted)
newSampleFabsSingle.addMeasurementColumn("Fabs", vFabs)
newSampleFabsSingle.addMeasurementColumn("FabsOriginal", vFabsOrig)
self.outputExperimentFabsSingle.samples[
sampleName] = newSampleFabsSingle
self.outputExperimentFabsSingle.addLabelToSample(
sampleName, "from", "individual---vesel", "AvgVivo---AvgVitro")
self.outputExperimentFabsSingle.write(
self._getPath("experimentFabsSingle.pkpd"))
def createOutputStep(self):
self._defineOutputs(
outputExperimentFabsSingle=self.outputExperimentFabsSingle)
for ptrExperiment in self.inputIVIVCs:
self._defineSourceRelation(ptrExperiment.get(),
self.outputExperimentFabsSingle)
def _validate(self):
retval = []
for ptrExperiment in self.inputIVIVCs:
if not "experimentFabs" in ptrExperiment.get().fnPKPD.get():
retval.append("You can only take Fabs files")
return retval
def _summary(self):
return []
def calculateAllIvIvC(self):
L1 = []
L2 = []
L3 = []
L4 = []
L5 = []
for ptrExperiment in self.inputIVIVCs:
experiment = PKPDExperiment()
experiment.load(ptrExperiment.get().fnPKPD.get())
x, y = experiment.getXYMeanValues("tvivo", "tvitroReinterpolated")
L1.append((x, y))
x, y = experiment.getXYMeanValues("tvivo", "Fabs")
L2.append((x, y))
x, y = experiment.getXYMeanValues("AdissolReinterpolated",
"FabsPredicted")
L3.append((x, y))
x, y = experiment.getXYMeanValues("FabsPredicted", "Fabs")
L4.append((x, y))
x, y = experiment.getXYMeanValues("tvitroReinterpolated",
"AdissolReinterpolated")
L5.append((x, y))
tvivo1, tvitroReinterpolatedY = computeXYmean(L1, common=True)
tvivoOrig, FabsOrig = computeXYmean(L2, common=True)
AdissolReinterpolatedX, FabsPredictedY = computeXYmean(L3, common=True)
FabsPredictedX, Fabs = computeXYmean(L4, common=True)
tvitroReinterpolatedX, AdissolReinterpolatedY = computeXYmean(
L5, common=True)
x, y = twoWayUniqueFloatValues(tvivo1, tvitroReinterpolatedY)
Bt = InterpolatedUnivariateSpline(x, y, k=1)
x, y = twoWayUniqueFloatValues(tvitroReinterpolatedX,
AdissolReinterpolatedY)
BtA = InterpolatedUnivariateSpline(x, y, k=1)
x, y = twoWayUniqueFloatValues(tvivoOrig, FabsOrig)
BtF = InterpolatedUnivariateSpline(x, y, k=1)
x, y = twoWayUniqueFloatValues(AdissolReinterpolatedX, FabsPredictedY)
BAF = InterpolatedUnivariateSpline(x, y, k=1)
x, y = twoWayUniqueFloatValues(FabsPredictedX, Fabs)
BFF = InterpolatedUnivariateSpline(x, y, k=1)
vtvitroReinterpolated = np.zeros(len(tvivo1))
vAdissolReinterpolated = np.zeros(len(tvivo1))
vFabs = np.zeros(len(tvivo1))
vFabsPredicted = np.zeros(len(tvivo1))
vFabsOrig = np.zeros(len(tvivo1))
for i in range(len(tvivo1)):
tvivoi = tvivo1[i]
vtvitroReinterpolated[i] = Bt(tvivoi)
vAdissolReinterpolated[i] = BtA(vtvitroReinterpolated[i])
vFabsPredicted[i] = BAF(vAdissolReinterpolated[i])
vFabs[i] = BFF(vFabsPredicted[i])
vFabsOrig[i] = BtF(tvivoi)
tvitroReinterpolatedVar = experiment.variables["tvitroReinterpolated"]
AdissolReinterpolatedVar = experiment.variables[
"AdissolReinterpolated"]
tvivoVar = experiment.variables["tvivo"]
FabsOrigVar = copy.copy(experiment.variables["Fabs"])
FabsOrigVar.varName = "FabsOriginal"
FabsVar = experiment.variables["Fabs"]
FabsVar.comment += ". After IVIVC: tvivo->tvitro->Adissol->Fabs "
FabsPredictedVar = experiment.variables["FabsPredicted"]
self.outputExperimentFabsSingle = PKPDExperiment()
self.outputExperimentFabsSingle.variables[
tvitroReinterpolatedVar.varName] = tvitroReinterpolatedVar
self.outputExperimentFabsSingle.variables[
AdissolReinterpolatedVar.varName] = AdissolReinterpolatedVar
self.outputExperimentFabsSingle.variables[tvivoVar.varName] = tvivoVar
self.outputExperimentFabsSingle.variables[FabsVar.varName] = FabsVar
self.outputExperimentFabsSingle.variables[
FabsPredictedVar.varName] = FabsPredictedVar
self.outputExperimentFabsSingle.variables[
FabsOrigVar.varName] = FabsOrigVar
self.outputExperimentFabsSingle.general[
"title"] = "In-vitro In-vivo correlation"
self.outputExperimentFabsSingle.general[
"comment"] = "Fabs vs Predicted Fabs"
sampleName = "jointIVIVC"
newSampleFabsSingle = PKPDSample()
newSampleFabsSingle.sampleName = sampleName
newSampleFabsSingle.variableDictPtr = self.outputExperimentFabsSingle.variables
newSampleFabsSingle.descriptors = {}
newSampleFabsSingle.addMeasurementColumn("tvitroReinterpolated",
vtvitroReinterpolated)
newSampleFabsSingle.addMeasurementColumn("AdissolReinterpolated",
vAdissolReinterpolated)
newSampleFabsSingle.addMeasurementColumn("tvivo", tvivo1)
newSampleFabsSingle.addMeasurementColumn("FabsPredicted",
vFabsPredicted)
newSampleFabsSingle.addMeasurementColumn("Fabs", vFabs)
newSampleFabsSingle.addMeasurementColumn("FabsOriginal", vFabsOrig)
self.outputExperimentFabsSingle.samples[
sampleName] = newSampleFabsSingle
self.outputExperimentFabsSingle.addLabelToSample(
sampleName, "from", "individual---vesel", "AvgVivo---AvgVitro")
self.outputExperimentFabsSingle.write(
self._getPath("experimentFabsSingle.pkpd"))
class ProtPKPDDeconvolve(ProtPKPDODEBase):
""" Deconvolve the drug dissolution from a compartmental model."""
_label = 'dissol deconv'
BIOAVAIL_NONE = 0
BIOAVAIL_MULT = 1
BIOAVAIL_DIV = 2
#--------------------------- DEFINE param functions --------------------------------------------
def _defineParams(self, form):
form.addSection('Input')
form.addParam('inputODE', params.PointerParam, label="Input ODE model",
pointerClass='ProtPKPDMonoCompartment, ProtPKPDTwoCompartments,ProtPKPDODERefine,'\
' ProtPKPDTwoCompartmentsClint, ProtPKPDTwoCompartmentsClintCl',
help='Select a run of an ODE model')
form.addParam('normalize', params.BooleanParam, label="Normalize by dose", default=True,
help='Normalize the output by the input dose, so that a total absorption is represented by 100.')
form.addParam('considerBioaval', params.EnumParam, label="Consider bioavailability", default=self.BIOAVAIL_NONE,
choices=['Do not correct','Multiply deconvolution by bioavailability','Divide deconvolution by bioavailability'],
help='Take into account the bioavailability')
form.addParam('saturate', params.BooleanParam, label="Saturate at 100%", default=True,
condition='normalize',
help='Saturate the absorption so that there cannot be values beyond 100')
form.addParam('removeTlag', params.BooleanParam, label="Remove tlag effect", default=True,
help='If set to True, then the deconvolution is performed ignoring the the tlag in the absorption.'
'This homogeneizes the different responses.')
#--------------------------- INSERT steps functions --------------------------------------------
def _insertAllSteps(self):
self._insertFunctionStep('deconvolve',self.inputODE.get().getObjId())
self._insertFunctionStep('createOutputStep')
#--------------------------- STEPS functions --------------------------------------------
def addSample(self, sampleName, t, y):
newSample = PKPDSample()
newSample.sampleName = sampleName
newSample.variableDictPtr = self.outputExperiment.variables
newSample.descriptors = {}
newSample.addMeasurementPattern(["A"])
tUnique, yUnique = twoWayUniqueFloatValues(t,y)
newSample.addMeasurementColumn("t", tUnique)
newSample.addMeasurementColumn("A",yUnique)
self.outputExperiment.samples[sampleName] = newSample
def deconvolve(self, objId):
self.protODE = self.inputODE.get()
self.experiment = self.readExperiment(self.protODE.outputExperiment.fnPKPD)
self.fitting = self.readFitting(self.protODE.outputFitting.fnFitting)
self.varNameX = self.fitting.predictor.varName
self.varNameY = self.fitting.predicted.varName
# Create drug source
self.clearGroupParameters()
self.createDrugSource()
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Avar = PKPDVariable()
Avar.varName = "A"
Avar.varType = PKPDVariable.TYPE_NUMERIC
Avar.role = PKPDVariable.ROLE_MEASUREMENT
if self.normalize.get():
Avar.units = createUnit("none")
else:
Avar.units = createUnit(self.experiment.getDoseUnits())
self.outputExperiment.variables[tvar.varName] = tvar
self.outputExperiment.variables[Avar.varName] = Avar
self.outputExperiment.general["title"]="Deconvolution of the amount released"
self.outputExperiment.general["comment"]="Amount released at any time t"
# Simulate the different responses
timeRange = self.experiment.getRange(self.varNameX)
deltaT = 0.5
t = np.arange(0.0,timeRange[1],deltaT)
for sampleName, sample in self.experiment.samples.items():
self.printSection("Deconvolving "+sampleName)
sample.interpretDose()
drugSource = DrugSource()
drugSource.setDoses(sample.parsedDoseList, 0.0, timeRange[1])
p=[]
tlag=0
for paramName in drugSource.getParameterNames():
p.append(float(sample.getDescriptorValue(paramName)))
if paramName.endswith('_tlag') and self.removeTlag.get():
tlag=float(sample.getDescriptorValue(paramName))
drugSource.setParameters(p)
cumulatedDose=0.0
A=t*0.0 # Allocate memory
totalReleased = drugSource.getAmountReleasedUpTo(10*t[-1])
print("t(min) A(%s)"%Avar.units._toString())
for i in range(t.size):
cumulatedDose+=drugSource.getAmountReleasedAt(t[i],deltaT)
A[i]=cumulatedDose
if self.normalize.get():
A[i] *= 100.0/totalReleased
print("%f %f"%(t[i],A[i]))
# print("%f %f %f %f"%(t[i], A[i], drugSource.getAmountReleasedAt(t[i], 0.5), drugSource.getAmountReleasedUpTo(t[i] + 0.5)))
if self.saturate.get() and self.normalize.get():
A = np.clip(A,None,100.0)
if self.considerBioaval.get()==self.BIOAVAIL_DIV:
A /= sample.getBioavailability()
elif self.considerBioaval.get()==self.BIOAVAIL_MULT:
A *= sample.getBioavailability()
self.addSample(sampleName,t-tlag,A)
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def createOutputStep(self):
self._defineOutputs(outputExperiment=self.outputExperiment)
self._defineSourceRelation(self.inputODE.get(), self.outputExperiment)
def _validate(self):
return []
def _summary(self):
return []
class ProtPKPDDeconvolutionLooRiegelmanInverse(ProtPKPD):
""" Given a profile of amount absorbed, find the central and peripheral concentrations that gave raise to it.
This is an inverse Loo-Riegelman problem.
The parameters of this protocol are defined as microconstants. Remind that k10=Cl*V, k12=Clp*V, k21=Clp*Vp
"""
# Reference: Humbert, H., Cabiac, M.D., Bosshardt, H. In vitro-in vivo correlation of a modified-release oral
# form of ketotifen: in vitro dissolution rate specification. J. Pharm Sci 1994, 83, 131-136
_label = 'inverse Loo-Riegelman'
#--------------------------- DEFINE param functions --------------------------------------------
def _defineParams(self, form):
form.addSection('Input')
form.addParam('inputExperiment', params.PointerParam, label="In-vivo profiles",
pointerClass='PKPDExperiment', help='It should have the amount absorbed')
form.addParam('timeVar', params.StringParam, label="Time variable", default="t",
help='Which variable contains the time stamps.')
form.addParam('amountVar', params.StringParam, label="Absorbed amount variable", default="A",
help='Which variable contains the amount absorbed.')
form.addParam('resampleT', params.FloatParam, label="Resample profiles (time step)", default=0.1,
help='Resample the input profiles at this time step (make sure it is in the same units as the input). '
'Leave it to -1 for no resampling')
form.addParam('k10', params.FloatParam, label="Elimination rate (k10)",
help='Units t^-1')
form.addParam('k12', params.FloatParam, label="Rate from central to peripheral (k12)",
help='Units t^-1')
form.addParam('k21', params.FloatParam, label="Rate from peripheral to central (k21)",
help='Units t^-1')
form.addParam('V', params.FloatParam, label="Central volume (V) [L]")
form.addParam('Vp', params.FloatParam, label="Peripheral volume (Vp) [L]")
#--------------------------- INSERT steps functions --------------------------------------------
def _insertAllSteps(self):
self._insertFunctionStep('solve',self.inputExperiment.get().getObjId())
self._insertFunctionStep('createOutputStep')
#--------------------------- STEPS functions --------------------------------------------
def addSample(self, sampleName, t, C, Cp):
newSample = PKPDSample()
newSample.sampleName = sampleName
newSample.variableDictPtr = self.outputExperiment.variables
newSample.descriptors = {}
newSample.addMeasurementPattern(["C","Cp"])
newSample.addMeasurementColumn("t", t)
newSample.addMeasurementColumn("C", C)
newSample.addMeasurementColumn("Cp", Cp)
self.outputExperiment.samples[sampleName] = newSample
def calculateConcentrations(self,t,A):
k10 = float(self.k10.get())
k12 = float(self.k12.get())
k21 = float(self.k21.get())
V = float(self.V.get())
Vp = float(self.Vp.get())
C = np.zeros(t.shape)
Cp = np.zeros(t.shape)
AUC0t = np.zeros(t.shape)
for n in range(1,C.size):
DeltaA=np.abs(A[n]-A[n-1])
DeltaT=t[n]-t[n-1]
DeltaT2=DeltaT/2
K1 = np.exp(-k21 * DeltaT)
K2 = k10/(1+k12*DeltaT2+k10*DeltaT2)
C[n] = DeltaA/V - Vp*Cp[n-1]/V*K1 + C[n-1]*k12*DeltaT2-C[n-1]*k12/k21*(1-K1)\
-C[n-1]*k10*DeltaT2-AUC0t[n-1]*K2
DeltaC = C[n]-C[n-1]
# Update AUC0t
if DeltaC>0: # Trapezoidal in the raise
AUC0t[n] = AUC0t[n-1] + DeltaT/2 * (C[n - 1] + C[n])
else: # Log-trapezoidal in the decay
if C[n-1] > 0 and C[n] > 0:
decrement = C[n-1] / C[n]
K = math.log(decrement)
AUC0t[n] = AUC0t[n - 1] + DeltaT * (C[n-1] - C[n]) / K
else:
AUC0t[n] = AUC0t[n - 1]
Cp[n] = Cp[n-1]*K1+k12/k21*C[n-1]*(1-K1)+k12*DeltaC*DeltaT2
if C[n]<0.0:
C[n]=0.0
if Cp[n]<0.0:
Cp[n]=0.0
return C, Cp
def calculateConcentrations2(self,t,A):
k10 = float(self.k10.get())
k12 = float(self.k12.get())
k21 = float(self.k21.get())
V = float(self.V.get())
Vp = float(self.Vp.get())
C = np.zeros(t.shape)
Cp = np.zeros(t.shape)
# Clp = k12*V
for n in range(1,C.size):
DeltaA=np.abs(A[n]-A[n-1])
DeltaT=t[n]-t[n-1]
# Q12 = Clp*(C[n-1]-Cp[n-1])
# C[n]=C[n-1]+(-Cl*C[n-1]/V-Q12/V)*DeltaT+DeltaA/V
# Cp[n]=Cp[n-1]+Q12/Vp*DeltaT
# Q12 = Clp*(C[n-1]-Cp[n-1])
# C[n]=C[n-1]-k10*C[n-1]*DeltaT-Q12/V*DeltaT+DeltaA/V
# Cp[n]=Cp[n-1]+Q12/Vp*DeltaT
# C[n]=C[n-1]-k10*C[n-1]*DeltaT-(Clp*(C[n-1]-Cp[n-1]))/V*DeltaT+DeltaA/V
# Cp[n]=Cp[n-1]+(Clp*(C[n-1]-Cp[n-1]))/Vp*DeltaT
# C[n]=C[n-1]-k10*C[n-1]*DeltaT-Clp/V*C[n-1]*DeltaT+Clp/V*Cp[n-1]*DeltaT+DeltaA/V
# Cp[n]=Cp[n-1]+Clp/Vp*C[n-1]*DeltaT-Clp/Vp*Cp[n-1]*DeltaT
C[n]=C[n-1]-k10*C[n-1]*DeltaT-k12*C[n-1]*DeltaT+k21*Vp/V*Cp[n-1]*DeltaT+DeltaA/V
Cp[n]=Cp[n-1]+k12*V/Vp*C[n-1]*DeltaT-k21*Cp[n-1]*DeltaT
if C[n]<0.0:
C[n]=0.0
if Cp[n]<0.0:
Cp[n]=0.0
return C, Cp
def solve(self, objId1):
self.experiment = self.readExperiment(self.inputExperiment.get().fnPKPD)
# Create output object
self.outputExperiment = None
timeRange = self.experiment.getRange(self.timeVar.get())
for sampleName, sample in self.experiment.samples.items():
# Get t, A
t=np.asarray(sample.getValues(self.timeVar.get()),dtype=np.float64)
A=np.asarray(sample.getValues(self.amountVar.get()),dtype=np.float64)
if t[0]>0:
t=np.insert(t,0,0) # Add (0,0) to the profile
A=np.insert(A,0,0)
t, A = uniqueFloatValues(t, A)
if self.resampleT.get()>0:
B = InterpolatedUnivariateSpline(t, A, k=1)
t = np.arange(np.min(t),np.max(t)+self.resampleT.get(),self.resampleT.get())
A = B(t)
# Find C and Cp
C, Cp = self.calculateConcentrations2(t,A)
if self.outputExperiment is None:
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Cvar = PKPDVariable()
Cvar.varName = "C"
Cvar.varType = PKPDVariable.TYPE_NUMERIC
Cvar.role = PKPDVariable.ROLE_MEASUREMENT
Lunits = createUnit("L")
Cvar.units = createUnit(divideUnits(self.experiment.getVarUnits(self.amountVar.get()),Lunits.unit))
Cvar.comment = "Concentration central compartment"
Cpvar = PKPDVariable()
Cpvar.varName = "Cp"
Cpvar.varType = PKPDVariable.TYPE_NUMERIC
Cpvar.role = PKPDVariable.ROLE_MEASUREMENT
Cpvar.units = createUnit(divideUnits(self.experiment.getVarUnits(self.amountVar.get()),Lunits.unit))
Cpvar.comment = "Concentration peripheral compartment"
self.outputExperiment.variables[tvar.varName] = tvar
self.outputExperiment.variables[Cvar.varName] = Cvar
self.outputExperiment.variables[Cpvar.varName] = Cpvar
self.outputExperiment.general["title"]="Inverse Loo-Riegelman"
self.outputExperiment.general["comment"]=""
self.addSample(sampleName,t,C,Cp)
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def createOutputStep(self):
self._defineOutputs(outputExperiment=self.outputExperiment)
self._defineSourceRelation(self.inputExperiment.get(), self.outputExperiment)
def _validate(self):
return []
def _summary(self):
retval = []
return retval
def deconvolve(self, objId):
self.protODE = self.inputODE.get()
self.experiment = self.readExperiment(self.protODE.outputExperiment.fnPKPD)
self.fitting = self.readFitting(self.protODE.outputFitting.fnFitting)
self.varNameX = self.fitting.predictor.varName
self.varNameY = self.fitting.predicted.varName
# Create drug source
self.clearGroupParameters()
self.createDrugSource()
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Avar = PKPDVariable()
Avar.varName = "A"
Avar.varType = PKPDVariable.TYPE_NUMERIC
Avar.role = PKPDVariable.ROLE_MEASUREMENT
if self.normalize.get():
Avar.units = createUnit("none")
else:
Avar.units = createUnit(self.experiment.getDoseUnits())
self.outputExperiment.variables[tvar.varName] = tvar
self.outputExperiment.variables[Avar.varName] = Avar
self.outputExperiment.general["title"]="Deconvolution of the amount released"
self.outputExperiment.general["comment"]="Amount released at any time t"
# Simulate the different responses
timeRange = self.experiment.getRange(self.varNameX)
deltaT = 0.5
t = np.arange(0.0,timeRange[1],deltaT)
for sampleName, sample in self.experiment.samples.items():
self.printSection("Deconvolving "+sampleName)
sample.interpretDose()
drugSource = DrugSource()
drugSource.setDoses(sample.parsedDoseList, 0.0, timeRange[1])
p=[]
tlag=0
for paramName in drugSource.getParameterNames():
p.append(float(sample.getDescriptorValue(paramName)))
if paramName.endswith('_tlag') and self.removeTlag.get():
tlag=float(sample.getDescriptorValue(paramName))
drugSource.setParameters(p)
cumulatedDose=0.0
A=t*0.0 # Allocate memory
totalReleased = drugSource.getAmountReleasedUpTo(10*t[-1])
print("t(min) A(%s)"%Avar.units._toString())
for i in range(t.size):
cumulatedDose+=drugSource.getAmountReleasedAt(t[i],deltaT)
A[i]=cumulatedDose
if self.normalize.get():
A[i] *= 100.0/totalReleased
print("%f %f"%(t[i],A[i]))
# print("%f %f %f %f"%(t[i], A[i], drugSource.getAmountReleasedAt(t[i], 0.5), drugSource.getAmountReleasedUpTo(t[i] + 0.5)))
if self.saturate.get() and self.normalize.get():
A = np.clip(A,None,100.0)
if self.considerBioaval.get()==self.BIOAVAIL_DIV:
A /= sample.getBioavailability()
elif self.considerBioaval.get()==self.BIOAVAIL_MULT:
A *= sample.getBioavailability()
self.addSample(sampleName,t-tlag,A)
self.outputExperiment.write(self._getPath("experiment.pkpd"))
class ProtPKPDDeconvolutionLooRiegelman(ProtPKPD):
""" Calculate the absorption profile of an in vivo concentration profile using
the Loo-Riegelman approach. This is only valid for profiles that have been
modelled with a two-compartments PK model.
The formula is Fabs(t)=(Cp(t)+Cperipheral(t)+K10*AUC0t(t))/(K10*AUC0inf)
where K10=Cl/V and
Cperipheral(t_n)=k12*Delta Cp*Delta t/2+k12/k21 * Cp(t_n-1)(1-exp(-k21*Delta t))+Cperipheral(t_n-1)*exp(-k21*Delta t)
In this implementation it is assumed that AUC0inf is the last AUC0t observed,
meaning that Cp(t) has almost vanished in the last samples.
This protocol is much more accurate when the input Cp(t) is reinterpolated to a small time step like 0.5 minutes.
Reference: Leon Shargel, Susanna Wu-Pong, Andrew B.C. Yu. Applied Biopharmaceutics & Pharmacokinetics, 6e. McGraw Hill, 1999. Chap. 7"""
_label = 'deconvolution Loo-Riegelman'
SAME_INPUT = 0
ANOTHER_INPUT = 1
BIOAVAIL_NONE = 0
BIOAVAIL_MULT = 1
BIOAVAIL_DIV = 2
#--------------------------- DEFINE param functions --------------------------------------------
def _defineParams(self, form):
form.addSection('Input')
form.addParam(
'inputExperiment',
params.PointerParam,
label="In-vivo profiles",
pointerClass='PKPDExperiment',
help=
'Make sure that it has a clearance parameter (Cl) and central volume (V)'
)
form.addParam(
'externalIV',
params.EnumParam,
choices=[
'Get impulse response from the same input fit',
'Get impulse response from another fit'
],
label='Impulse response source',
default=self.SAME_INPUT,
help=
"The impulse response is an estimate of the intravenous response")
form.addParam('externalIVODE', params.PointerParam, label="External impulse response ODE model",
condition='externalIV==1',
pointerClass='ProtPKPDMonoCompartment, ProtPKPDTwoCompartments,ProtPKPDODERefine,' \
' ProtPKPDTwoCompartmentsClint, ProtPKPDTwoCompartmentsClintCl',
help='Select a run of an ODE model. It should be ideally the intravenous response.')
form.addParam('timeVar',
params.StringParam,
label="Time variable",
default="t",
help='Which variable contains the time stamps.')
form.addParam('concVar',
params.StringParam,
label="Concentration variable",
default="Cp",
help='Which variable contains the plasma concentration.')
form.addParam(
'normalize',
params.BooleanParam,
label="Normalize by dose",
default=True,
help=
'Normalize the output by AUC0inf, so that a total absorption is represented by 100.'
)
form.addParam(
'saturate',
params.BooleanParam,
label="Saturate at 100%",
default=True,
help=
'Saturate the absorption so that there cannot be values beyond 100'
)
form.addParam('considerBioaval',
params.EnumParam,
label="Consider bioavailability",
default=self.BIOAVAIL_NONE,
choices=[
'Do not correct',
'Multiply deconvolution by bioavailability',
'Divide deconvolution by bioavailability'
],
help='Take into account the bioavailability')
form.addParam(
'resampleT',
params.FloatParam,
label="Resample profiles (time step)",
default=0.5,
help=
'Resample the input profiles at this time step (make sure it is in the same units as the input). '
'Leave it to -1 for no resampling')
form.addParam(
'smooth',
params.BooleanParam,
label="Monotonic smooth",
default=True,
help=
'Apply a Pchip interpolation to make sure that the Adissolved is monotonically increasing'
)
#--------------------------- INSERT steps functions --------------------------------------------
def _insertAllSteps(self):
self._insertFunctionStep('deconvolve',
self.inputExperiment.get().getObjId())
self._insertFunctionStep('createOutputStep')
#--------------------------- STEPS functions --------------------------------------------
def addSample(self, sampleName, t, y):
newSample = PKPDSample()
newSample.sampleName = sampleName
newSample.variableDictPtr = self.outputExperiment.variables
newSample.descriptors = {}
newSample.addMeasurementPattern(["A"])
newSample.addMeasurementColumn("t", t)
newSample.addMeasurementColumn("A", y)
self.outputExperiment.samples[sampleName] = newSample
def calculateCperipheral(self, t, Cp, k12, k21):
Cperipheral = np.zeros(t.shape)
for n in range(1, Cperipheral.size):
DeltaCp = np.abs(Cp[n] - Cp[n - 1])
DeltaT = t[n] - t[n - 1]
Cperipheral[n] = k12*DeltaCp*DeltaT*0.5 + \
k12 / k21 * Cp[n-1]*(1 - np.exp(-k21 * DeltaT)) + \
Cperipheral[n-1] * np.exp(-k21 * DeltaT)
if Cperipheral[n] < 0.0:
Cperipheral[n] = 0.0
return Cperipheral
def deconvolve(self, objId1):
self.experiment = self.readExperiment(
self.inputExperiment.get().fnPKPD)
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Avar = PKPDVariable()
Avar.varName = "A"
Avar.varType = PKPDVariable.TYPE_NUMERIC
Avar.role = PKPDVariable.ROLE_MEASUREMENT
Avar.units = createUnit("none")
self.outputExperiment.variables[tvar.varName] = tvar
self.outputExperiment.variables[Avar.varName] = Avar
self.outputExperiment.general[
"title"] = "Deconvolution of the amount released"
self.outputExperiment.general[
"comment"] = "Amount released at any time t"
# Get the input sample from another experiment if necessary
sampleFrom = None
if self.externalIV.get() == self.ANOTHER_INPUT:
anotherExperiment = self.readExperiment(
self.externalIVODE.get().outputExperiment.fnPKPD)
for _, sampleFrom in anotherExperiment.samples.items(
): # Take the first sample from the reference
break
timeRange = self.experiment.getRange(self.timeVar.get())
for sampleName, sample in self.experiment.samples.items():
# Get t, Cp
t = np.asarray(sample.getValues(self.timeVar.get()),
dtype=np.float64)
Cp = np.asarray(sample.getValues(self.concVar.get()),
dtype=np.float64)
Cp = np.clip(Cp, 0.0, None)
t = np.insert(t, 0, 0) # Add (0,0) to the profile
Cp = np.insert(Cp, 0, 0)
t, Cp = uniqueFloatValues(t, Cp)
if self.resampleT.get() > 0:
B = InterpolatedUnivariateSpline(t, Cp, k=1)
t = np.arange(np.min(t),
np.max(t) + self.resampleT.get(),
self.resampleT.get())
Cp = B(t)
# Calculate AUC0t
AUC0t = calculateAUC0t(t, Cp)
AUC0inf = float(AUC0t[-1])
# Calculate peripheral
if self.externalIV.get() == self.SAME_INPUT:
sampleFrom = sample
Cl = float(sampleFrom.descriptors['Cl'])
V = float(sampleFrom.descriptors['V'])
Clp = float(sampleFrom.descriptors['Clp'])
Vp = float(sampleFrom.descriptors['Vp'])
k12 = Clp / V
k21 = Clp / Vp
Cperipheral = self.calculateCperipheral(t, Cp, k12, k21)
# Deconvolve
k10 = Cl / V
A = (Cp + Cperipheral + k10 * AUC0t) / k10
if self.normalize.get():
A *= 100 / AUC0inf
if self.saturate.get():
A = np.clip(A, None, 100.0)
A = np.clip(A, 0, None)
if self.smooth:
if t[0] > 0:
t = np.insert(t, 0, 0)
A = np.insert(A, 0, 0)
if self.saturate.get() and self.normalize.get():
A = np.clip(A, None, 100.0)
A = np.clip(smoothPchip(t, A), 0, None)
if self.considerBioaval.get() == self.BIOAVAIL_DIV:
A /= sample.getBioavailability()
elif self.considerBioaval.get() == self.BIOAVAIL_MULT:
A *= sample.getBioavailability()
self.addSample(sampleName, t, A)
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def createOutputStep(self):
self._defineOutputs(outputExperiment=self.outputExperiment)
self._defineSourceRelation(self.inputExperiment.get(),
self.outputExperiment)
def _validate(self):
return []
def _summary(self):
retval = []
return retval
def runSimulate(self):
# Take first experiment
self.protODE = self.inputODEs[0].get()
if hasattr(self.protODE, "outputExperiment"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment.fnPKPD, show=False)
elif hasattr(self.protODE, "outputExperiment1"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment1.fnPKPD, show=False)
else:
raise Exception("Cannot find an outputExperiment in the input ODE")
if hasattr(self.protODE, "outputFitting"):
self.fitting = self.readFitting(
self.protODE.outputFitting.fnFitting, show=False)
elif hasattr(self.protODE, "outputFitting1"):
self.fitting = self.readFitting(
self.protODE.outputFitting1.fnFitting, show=False)
self.varNameX = self.fitting.predictor.varName
if type(self.fitting.predicted) != list:
self.varNameY = self.fitting.predicted.varName
else:
self.varNameY = [var.varName for var in self.fitting.predicted]
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit(self.experiment.getTimeUnits().unit)
Nsamples = int(
math.ceil((self.tF.get() - self.t0.get()) / self.deltaT.get())) + 1
if tvar.units == PKPDUnit.UNIT_TIME_MIN:
Nsamples *= 60
self.outputExperiment.variables[self.varNameX] = tvar
if type(self.fitting.predicted) != list:
self.outputExperiment.variables[
self.varNameY] = self.experiment.variables[self.varNameY]
else:
for varName in self.varNameY:
self.outputExperiment.variables[
varName] = self.experiment.variables[varName]
self.outputExperiment.general["title"] = "Simulated ODE response"
self.outputExperiment.general["comment"] = "Simulated ODE response"
self.outputExperiment.vias = self.experiment.vias
# Read the doses
doseLines = []
for line in self.doses.get().replace('\n', ';;').split(';;'):
doseLines.append(line)
doseIdx = 0
simulationsY = None
doseList = []
for protODEPtr in self.inputODEs:
self.protODE = protODEPtr.get()
if hasattr(self.protODE, "outputExperiment"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment.fnPKPD, show=False)
elif hasattr(self.protODE, "outputExperiment1"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment1.fnPKPD, show=False)
else:
raise Exception(
"Cannot find an outputExperiment in the input ODE")
if hasattr(self.protODE, "outputFitting"):
self.fitting = self.readFitting(
self.protODE.outputFitting.fnFitting, show=False)
elif hasattr(self.protODE, "outputFitting1"):
self.fitting = self.readFitting(
self.protODE.outputFitting1.fnFitting, show=False)
for viaName in self.experiment.vias:
if not viaName in self.outputExperiment.vias:
self.outputExperiment.vias[viaName] = copy.copy(
self.experiment.vias[viaName])
# Create drug source
self.clearGroupParameters()
self.createDrugSource()
# Setup model
self.model = self.protODE.createModel()
self.model.setExperiment(self.outputExperiment)
self.model.deltaT = self.deltaT.get()
self.model.setXVar(self.varNameX)
self.model.setYVar(self.varNameY)
self.model.x = [
self.t0.get() + i * self.model.deltaT
for i in range(0, Nsamples)
]
self.modelList.append(self.model)
tokens = doseLines[doseIdx].split(';')
if len(tokens) < 5:
print("Skipping dose: ", line)
continue
dosename = tokens[0].strip()
self.outputExperiment.doses[dosename] = PKPDDose()
self.outputExperiment.doses[dosename].parseTokens(
tokens, self.outputExperiment.vias)
doseList.append(dosename)
auxSample = PKPDSample()
auxSample.descriptors = {}
auxSample.doseDictPtr = self.outputExperiment.doses
auxSample.variableDictPtr = self.outputExperiment.variables
auxSample.doseList = [dosename]
auxSample.interpretDose()
self.drugSource.setDoses(auxSample.parsedDoseList,
self.t0.get() - 10,
self.tF.get() + 10)
self.model.drugSource = self.drugSource
# Simulate the different responses
simulationsX = self.model.x
self.setTimeRange(None)
parameters = self.fitting.sampleFits[0].parameters
print("Input model: %s" % self.protODE.getObjLabel())
print("Sample name: %s" % self.fitting.sampleFits[0].sampleName)
print("Parameters: ", parameters)
print("Dose: %s" % doseLines[doseIdx])
print(" ")
# Prepare source and this object
self.protODE.configureSource(self.drugSource)
parameterNames = self.getParameterNames(
) # Necessary to count the number of source and PK parameters
# Prepare the model
y = self.forwardModel(parameters,
[simulationsX] * self.getResponseDimension())
# Keep results
if simulationsY is None:
simulationsY = copy.copy(y)
else:
for j in range(self.getResponseDimension()):
simulationsY[j] += y[j]
doseIdx += 1
self.addSample("Simulation", doseList, simulationsX, simulationsY[0])
self.outputExperiment.write(self._getPath("experiment.pkpd"))