ORAL SESSION I Lewis Sheiner Student Session Non-linear mixed-effects models for tests of interaction or of lack of interaction in cross-over and parallel pharmacokinetic studies: application to the test of interaction between protease inhibitors and nucleoside analogs in HIV patients

Introduction: Pharmacokinetic (PK) interaction, or lack of interaction, of a drug B on a drug A, is usually tested by comparing the log AUC and the log Cmax of A given alone (or with placebo) versus A given with B. The standard method, recommended in guidelines, is the comparison of log AUC and log Cmax of A, using a Student test or a Schuirmann's two-one sided test (TOST) to test interaction or absence of interaction, respectively. In order to take benefit of the knowledge accumulated on the PK of the studied drugs and to decrease the number of samples per patient, tests based on nonlinear mixed effects models (NLMEM) are a good approach. Our objectives were to propose and evaluate tests based on NLMEM for evaluation of both PK interaction or absence of interaction, first in cross-over PK trials, which are designed to test such interactions, and second during usual population PK analyses, where interactions are usually tested a posteriori.