DEVELOPMENT OF A POPULATION PHARMACOKINETIC DATABASE FOR TIANEPTINE

Two thousand three hundred and thirty five plasma concentrations of ti aneptine from 112 patients enrolled in nine studies of tianeptine phar macokinetics performed prior to the marketing of the drug were pooled for analysis using mixed-effect modeling. Studies represented a combin ation of single dose and multiple dosing at steady-state. Tianeptine p lasma concentration time data were fit to a two compartment model with first order absorption using the NONMEM computer program. The results of this analysis suggested that alcoholism is associated with signifi cant increase in clearance (124 % increase) and volume of the central compartment (161 % increase). The volume of the peripheral compartment is significantly lower in women (31 % decrease) and in depressed pati ents (59 % decrease).The population mean (interindividual variability) clearance was equal to 0.171 . h-1 . kg-1 (28.6 %), the volume of cen tral compartment was 0.131 . kg-1 (60.4 %), intercompartmental clearan ce was 0.071. h-l . kg-1 (30.1 %), volume of the tissue compartment wa s 1.171 . kg-1 (28.3 %), and the absorption rate constant was 0.63 h-1 (21.8 %). The residual variability was approximately 30 % at concentr ations expected during clinical use of the drug. Because of the increa sed clearance, alcoholic patients would be expected to have significan tly reduced concentrations during steady-state dosing. These populatio n parameters provide a basis for developing initial dosing recommendat ions and for performing bayesian evaluations of drug concentrations ob tained in post-marketing studies.