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We represent a community with a shared interest in data analysis using the population approach.

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Population pharmacokinetics of vinflunine from phase I data and evaluation of population sampling designs for further clinical development

L. Nguyen (1), S. Retout (2), F. Mentré (2), P. Variol (1) and C. Puozzo (1)

(1) Clinical Pharmacokinetic department, Institut de Recherche Pierre Fabre, Castres, France (2) Dpt of Biostatistics and Epidemiology, INSERM U436, University Hospital Bichat, Paris, France

Vinflunine (Javlor(r)) is a novel semi-synthetic vinca alkaloid under development. Vinflunine is administered by short IV infusion and in vitro has demonstrated a superior anti-tumor activity to other vincas from a panel of 11 human xenografts. Extensive blood sampling per patient was performed in three phase I studies (n=59 patients), allowing to develop a first population PK model. Data were analysed using the NONMEM program. The vinflunine concentration-time data were best described using a linear pharmacokinetic model with four mamillary compartments (ADVAN 6 subroutine). Eight pharmacokinetic parameters were estimated with a good precision for the fixed effects (SE < 15%) and an acceptable precision for the random effect parameters (SE < 47%). Vinflunine after IV infusion was characterized by a high clearance (39.2 l/h) and large volumes of distribution (V1=16.5 l, V2=105 l, V3=421 l and V4 = 669 l). Interindividual and inter-occasion (IOV) variabilities on the clearance were 25% and 11%, respectively. After completion of phase I trials, population sampling designs with limited number of samples per individual must be planned for further clinical development. Selection of informative data should be made carefully to ensure a successful population study, taking into account the constraints of phase II/III clinical studies for which outpatients are recruited. Indeed, only restricted admissible sampling times are allowed and they often vary in few specific sampling windows circumscribed by hospital visiting hours. Population designs for vinflunine were assessed using an extension of the PFIM S-plus function [1,2]. Based on the recent development of the Fisher information matrix for non linear mixed-effect model, PFIM offers a direct and easy evaluation of a large set of possible sampling designs for a given population analytical model. However, the four-compartment model of vinfluine was only described by differential equations which then required to extend PFIM to this case. Therefore, based on samples of 50 to 100 patients, several balanced designs with four samples per individual were evaluated. Thanks to this approach, some practicable sampling designs were defined to obtain acceptable precision for the parameters of interest. Despite that PFIM does not take into account of the covariates influence and IOV, it provides a guideline on the number of patients, the number of sampling times and their allocation to perform population analyses, avoiding thus cumbersome simulations.

[1] Retout S, Duffull S, Mentré F. Development and implementation of the population Fisher information matrix for evaluation of population pharmacokinetics designs. Comput Meth Prog Biomed, 2001, 65:141-51
[2] http://hermes.biomath.jussieu.fr/pfim.htm