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Pharmacokinetic Mixed Effects Modelling of S16257 After Oral Administration in the Beagle Dog; Combined Analysis

L. Del Frari, F. Bouzom, B. Walther and R.Jochemsen

Technologie Servier (Orléans, France)

The objectives of the study were to build a population pharmacokinetic model for S 16257 after oral administration in dogs in order to "summarise" the pharmacokinetics of S 16257 in dogs, to identify factors causing interindividual variability in pharmacokinetics and to quantify the influence of these factors on pharmacokinetic parameters. Data used were taken from all pharmacokinetic and toxicokinetic studies including single and repeated oral administration with different treatment duration in the beagle dog. The database consisted of 2158 concentrations in 128 dogs (64 females and 64 males). The doses (expressed as base form) ranged from 0.225 to 41.8 mg/kg (from 1.60 to 376 mg) and were administered once or twice a day. The body weight ranged from 5.70 to 13.1 kg.

The S 16257 concentration-time data in the beagle dog were fitted by a two-compartment model with a first order absorption using the NONMEM computer program. This model was defined in terms of apparent clearance (CL/F), apparent volume of the central compartment (Vc/F), apparent intercompartment clearance (Q/F), apparent volume of the peripheral compartment (Vp/F) and absorption rate constant (ka). Inter-individual variabilities were estimated for all the parameters except for Vp/F. A same inter-occasion variability was attributed to the distribution and elimination parameters in order to estimate an inter-occasion variability on the bioavailability. An inter-occasion variability on ka was also estimated.

No time effect was observed for the pharmacokinetics of S 16257 in the dog and single and repeated administration could be fitted together.

Different ka and a relative bioavailability existed between the two administrations in the day. The dose, the duration of the treatment, the body weight and the sex did not influence CL/F and Vc/F and none of the covariates tested was found to influence significantly any other parameter. The influence of the time of the administration in the day could be summarized as follows: the absorption rate after the first administration was about 5-fold higher than after the second administration while the exposure after the first administration was only about 10 % higher than after the second administration. This difference was attributed to a food-interaction as the food was given between the 2 administrations (about 4 h after the first administration and about 4 h before the second administration in the day).

This population model allowed to clearly define the time and dose effect, as well as the important covariates on S 16257 pharmacokinetics in the dog in the dose range studied during the development of S 16257 and could be used to estimate individual S 16257 pharmacokinetic parameters by bayesian feedback for studies using sparse sampling times in dogs.