Population pharmacokinetic-based interspecies allometric scaling and prediction of first-in-human (FIH) pharmacokinetics of a new anticancer agent
Rubin Lubomirov (1), Ignacio Gonzalez Garcia (1), Carlos Fernández-Teruel (1), Pablo Avilés (2), Salvador Fudio (1)
(1) Department of Clinical Pharmacology, (2) Department of Research and Development (R&D), PharmaMar S.A., Colmenar Viejo (Madrid), Spain
Objectives: To develop a population pharmacokinetic model for simultaneous interspecies allometric scaling of individual preclinical pharmacokinetics and to predict the pharmacokinetic (PK) parameters and concentration-time profiles of a new anticancer agent in humans.
Methods: Preclinical PK studies conducted on mice, rats, dogs, mini-pigs and monkeys involving 122 animals with 387 plasma concentrations were available for interspecies scaling. In mice and in rats, each plasma concentration corresponds to a unique animal, whereas in the remaining species the individuals contributed with several plasma concentrations. The new anticancer compound was administered intravenously over wide range of doses (0.005 to 1.25 mg/kg) to animals with body weight ranging from 0.02 kg in mice to 20 kg in mini-pigs. Animal plasma concentrations were pooled and fitted in one step to a PK model using non-liner mixed-effects modelling implemented in NONMEM v7.3. Allometric equations were contained into the PK model to allow individual body weight PK parameters scaling. The incorporation into de model as covariates of gender, brain weight (BrW), maximum lifespan (MLS) and unbound plasma fraction (fu) was investigated.
Results: A three-compartment mammillary model with linear elimination from central compartment and additive residual error in log domain was shown to adequately describe four-species pooled concentration-time data. Including all five preclinical species resulted in a deficient fit, thus mini-pigs were excluded from the final model. Further model fit improvement was archived accounting for the presence of a small subpopulation of monkeys with low clearance and low central compartment volume of distribution. No other covariates (gender, BrW, MLS or fu) were retained in the final model. The final PK model allowed extrapolation of PK parameters from preclinical mammals to man. Subsequent simulations performed using an in-house dataset of phase I trials patients were used to inform the design of FIH dose-scaling clinical trial and to assist bioanalytical method development.
Conclusion: Population PK model for simultaneous interspecies allometric scaling was successfully used to describe plasma concentration-time profiles from four animal species administered intravenously over wide range of doses accounting for the presence of potential bimodal exposure. This approach provides valuable information that cannot be provided by “two-stage” allometric scaling methods.
