Impact of modelling intra-subject variability on tests based on non-linear mixed-effects models in cross-over pharmacokinetic trials with application to the interaction of tenofovir on atazanavir in HIV patients

• Published in: Statistics in medicine Vol. 26; no. 6; pp. 1268 - 1284
• Main Authors: Panhard, Xavière, Taburet, Anne-Marie, Piketti, Christophe, Mentré, France
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 15.03.2007; Wiley Subscription Services, Inc; Wiley-Blackwell
• Subjects: Adenine; Adenine - analogs & derivatives; Adenine - pharmacokinetics; Adenine - therapeutic use; Anti-HIV Agents; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - therapeutic use; Atazanavir Sulfate; Bias; Bias (Epidemiology); bioequivalence; Biostatistics; Clinical trials; cross-over pharmacokinetic trials; Cross-Over Studies; Drug Interactions; Drug therapy; drug-drug interactions; France; HIV Infections; HIV Infections - drug therapy; Humans; Life Sciences; Likelihood Functions; non-linear mixed effects models; Nonlinear Dynamics; Oligopeptides; Oligopeptides - pharmacokinetics; Oligopeptides - therapeutic use; Organophosphonates - pharmacokinetics; Organophosphonates - therapeutic use; Phosphonic Acids; Pyridines; Pyridines - pharmacokinetics; Pyridines - therapeutic use; Quantitative Methods; Ratio analysis; Tenofovir; Variances; bioequivalence trials; PK interaction trials; Nonlinear mixed effects models; Protease inhibitors; Intra-patient variability; cross-over trials

We evaluated the impact of modelling intra‐subject variability on the likelihood ratio test (LRT) and the Wald test based on non‐linear mixed effects models in pharmacokinetic interaction and bioequivalence cross‐over trials. These tests were previously found to achieve a good power but an inflated...