Role of Population Approaches in IVIVC - PQRI

A Brief Introduction ofIVIVC Using Population ApproachJohn Duan, Ph.D.Biopharmaceutics TeamONDQA/CDER/FDAThe findings and conclusions in this presentation have not been formallydisseminated by the FDA and should not be construed to represent anyAgency determination or policy1

Conc (ng/mL)0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5% Dissolved0 20 40 60 80 100Conc (ng/mL)1 2 3 4 5% Absorbed in vivo20 40 60 80% Absorbed0 20 40 60 80 100Traditionally, an IVIVC isEstablished by a 2-Stage MethodIn vivo profileUIR FunctionAbsorption0 10 20 30 40 50 60Time (h)0 50 100 150 200 250Time (min)DissolutionIVIVC0 50 100 150 200 250Time (min)0 50 100 150 200 250Time (min)20 40 60 80% Dissolved in vitro2

Alternatively, 1-Stage Method Can Be used• 1-Stage method may overcome the following limitationsof the deconvolution based 2-stage method– Deconvolution is not stable;– Study objectives are often related to the drug concentrations, notthe fraction of drug dissolved.• 1-Stage method may use a population approach– Convolution-based approach– Compartment approach based on differential equations• Population IVIVC is similar to population PK/PD, seekingthe sources and correlation of the variability in vivo, invitro and their relationship.• A better understanding of population PK will be helpful.3

Conc (ng/mL)Considering BothInter-Subject and Residue Variability108Inter-subject VariabilityData points for IDPopulation fitIndividual fitData points for ID 164Residual Variability20 5 10 15Time (h)4

Variability Is Modeled Simultaneouslywith the Parameter EstimatesCLVWT2CL2V2}}Typical valueCovariatePREDyInter-Individual Variability (IIV)Residue variabilityPopulationpredictionCLVWT2CL2V2}Typical value2 2Covariate......}CLiViIIVResidue variabilityObsyiCLCL1VV1......IPRDyIndividualprediction5

Population IVIVC Uses a Similar ApproachK2KIn Vitro Typical valueIn Vitro VariabilityIn VitropredictionIVIVC2IVIVCIVIVC EstimateIVIVC VariabilityCLVWT2CL2}}In VivoTypical valueCovariateIIV in vivoPREDyIPRDyPopulationpredictionIndividualpredictionV2Vivo Residue variability6

An Example ofPopulation IVIVC Structural Model1 2In VitroDosage3 4 5In VivoDosageDissolutionIVIVC LinkDissolutionIn VitroSolutionIn VivoSolutionAbsorptionBloodConc.Elimination7

Group Discussion• What are the advantages and limitations ofthe population approach?• What is the significance of the populationapproach?• What are the possible applications of thepopulation approach?8