Pooled PK analysis of a new CNS drug, in healthy subjects.
M. Vernaz-Gris (1), E. Fuseau (1), L. Del Frari (2), V. Brunner (2), P. Hermann (2)
(1) EMF Consulting, France ; (2) IRPF, France
Objectives: The objectives of the pooled data analysis were to describe the PK of a new drug developed in the CNS area, to evaluate variability in a population of healthy subjects and to provide a simulation model for optimising study design in patients.
Methods: The population PK analysis was performed on a pooled database, including 121 healthy subjects in 6 phase I studies. Subjects received single or repeated oral dose as a solution (0.075 to 2.5 mg) or as a capsule (1 to 2.25 mg). 2490 plasma concentrations were available. The structural PK model was chosen through individual PK modelling on a subset of subjects. Thereafter, population PK modelling on the complete database was used to estimate the parameters (FOCE interaction estimation method).
Results and Conclusion: A two compartment disposition model with first order elimination and a proportional residual error model were used. The drug often displayed either a large peak or two main peaks of plasma concentrations following single and repeated oral dose administration. The absorption was best described by two different processes separated by a lag time: one fraction of the dose is absorbed into the central compartment by a zero order process; the remaining fraction of the dose is absorbed through a first order process. The structural model includes various covariates, including the effect of the dose, food, formulation and time on apparent volumes of distribution (V2/F, V3/F), apparent inter-compartmental clearance (Q/F), duration of zero order absorption process (D2). The absorption was rapid although D2 was increased with administration of a capsule and with food intake. Inter individual variability (IIV) was evaluated for apparent clearance (CL/F), V2/F, V3/F, Q/F and D2. The magnitude of IIV was estimated between 30 and 47 CV% with exponential error models. Based on these results, simulations will be performed for optimising study design in patients.