Predicting human from animal PBPK simulation combined with in vitro data
Mathilde Marchand (1, 2), Eliane Fuseau (1)
(1) EMF consulting, Aix en Provence, France (2) EA3286 Laboratoire de Toxicocinétique et Pharmacocinétique, Marseille, France
Objectives: Scientific rationale should guide the selection of the first dose to administer to human. This work compares the use of allometric scaling and animal PKPB simulations based on animal data and physicochemical data to investigate drug X pharmacokinetics and predict concentration-time profile in healthy subjects. The predictivity of these methods is compared to empirical dose selection methods base on toxicology and toxicokinetic findings.
Methods: TAfter single oral dose administered to healthy subjects, drug X concentration-time profile displays multiple peaks. Several hypotheses were tested to explore this potential recycling. Preclinical data were available in different species: rat, dog and monkey, treated with a range of oral and intravenous dose of drug X. In vitro protein binding and in vitro metabolism were explored. Available physicochemical data include: molecular weight, pKa, logP, solubility. Hypotheses assessed were an enterohepatic recycling, various sites of metabolism and active transport on absorption and distribution processes. PK Sim , version 3.0 software (Bayer technology service) was used for the simulations.
Results/Conclusions: The preclinical PBPK in addition to physicochemical properties and in vitro data allowed a retrospective prediction of the pharmacokinetics in human. Factors influencing human pharmacokinetics were determined. Then PBPK simulations and allometric scaling were compared for the prediction of human clearance. The simulated profiles obtained after several doses in a population were compared to clinical data collected in healthy subjects.
Since in vitro and in vivo preclinical data as well as physicochemical properties are available early in the drug development, the use of PBPK simulation should be applied at this early stage to help building a rationale for the selection of the first dose to administer to humans.