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Pharmacokinetic mixed effects modelling of a new compound in rat - Combined analysis.

D. Martin , N. Frey , C. Laveille , H. Merdjan and R. Jochemsen

Servier Research and Development

Introduction and Objectives Several toxicokinetic (TK) and pharmacokinetic (PK) studies have been performed with a new drug composed of two stable ions, a natural endogenous compound, and an organic moiety. The combination of studies covered a variety of experimental conditions, including a broad range of doses. Pharmacokinetic information from TK studies was often limited to sparse sampling in only a few animals whereas PK studies generally provided more information. All PK and TK data were pooled in a combined population PK analysis, in an attempt to provide an overall description and/or better understanding of the PK properties of the stable ion (XX) in the rat.

Methods Data description Six studies used in this combined analysis covered a combination of single and multiple oral and single intravenous administration. Due to the difficulty in distinguishing between intra-individual, interindividual and residual variability and because of the increase of animal weight with time, rats with several days of treatment were considered to be different animals. After single intravenous administration, the unit doses of XX ranged from 1.7 to 9.3 mg. After oral administration, the unit doses of XX ranged from 4.6 to 198 mg and the duration of treatment ranged from one day to 26 weeks. The final database consisted of 858 data from 448 (112 male and 336 female) rats

Model The plasma concentrations were modelled using NONMEM. In each rat, there is a pre-existing endogenous level and this has to be taken into account in the model. The plasma concentration time data were fitted to a series of compartment disposition models, which were parameterised in terms of clearances and volumes of distribution. The absorption process was parameterised in terms of a rate constant and bioavailability (F1). The residual error model was proportional. The first order (FO) method was used to fit the data.

Results and conclusion The concentration-time data were best described by a four compartment model and significant relationships were found between bioavailability (F1) and Dose, and between endogenous level and gender. Furthermore, statistically significant different Ka and F1 were determined for a particular study, in relation to the age of animals (improved bioavailability in young animals). The rate of absorption was moderate, whatever the dose administered. The population bioavailability of this compound in rats decreased with increasing dose in agreement with the known saturable absorption. This compound is characterised by a very long terminal half-life of at least 80 days. In conclusion, this population model enabled determination of the time and dose effect, as well as identification of the important covariates on XX PK in the rat in the dose range studied during the development of this compound. In addition, it could be used to estimate individual XX PK parameters by bayesian feedback for studies using sparse sampling times in rats.