PMID: identifiant
de la référence Pubmed : |
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 (16810714) |
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| titre : |
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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. |
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| auteur(s) : |
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Xavière Panhard ( ) 1, 2, Anne-Marie Taburet3, Christophe Piketti4, France Mentré1, 2 |
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| laboratoire : |
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| Équipe de recherche : |
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U738, INSERM |
| résumé : |
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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 type I error when intra-subject variability was not taken into account. Trials were simulated under H0 and several H1 and analysed with the NLME function. Different configurations of the number of subjects n and of the number of samples per subject J were evaluated for pharmacokinetic interaction and bioequivalence trials. Assuming intra-subject variability in the model dramatically improved the type I error of both interaction tests. For the Wald test, the type I error decreased from 22, 14 and 7.7 per cent for the original (n = 12, J = 10), intermediate (n = 24, J = 5) and sparse (n = 40, J = 3) designs, respectively, down to 7.5, 6.4 and 3.5 per cent when intra-subject variability was modelled. The LRT achieved very similar results. This improvement seemed mostly due to a better estimation of the standard error of the treatment effect. For J = 10, the type I error was found to be closer to 5 per cent when n increased when modelling intra-subject variability. Power was satisfactory for both tests. For bioequivalence trials, the type I error of the Wald test was 6.4, 5.7 and 4.2 per cent for the original, intermediate and sparse designs, respectively, when modelling intra-subject variability. We applied the Wald test to the pharmacokinetic interaction of tenofovir on atazanavir, a novel protease inhibitor. A significant decrease of the area under the curve of atazanavir was found when patients received tenofovir. |
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| domaine : |
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Sciences du Vivant/Bio-Informatique, Biostatistique
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langue du texte
intégral : |
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Anglais |
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| ISSN : |
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0277-6715 |
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| type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1002/sim.2622 |
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| journal : |
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| Statistics in Medicine (Stat Med) |
| Publisher |
John Wiley and Sons |
| ISSN |
0277-6715 (eISSN : 1097-0258) |
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| date de publication : |
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15/03/2007 |
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| volume : |
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26 |
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| numéro : |
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6 |
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| page, identifiant, ... : |
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1268-84 |
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| mots-clés auteur : |
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Nonlinear mixed effects models – Protease inhibitors – Intra-patient variability – cross-over trials – bioequivalence trials – PK interaction trials |
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| Descripteur(s) MeSH : |
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Adenine – Anti-HIV Agents – Bias (Epidemiology) – Cross-Over Studies – Drug Interactions – France – HIV Infections – Humans – Likelihood Functions – Nonlinear Dynamics – Oligopeptides – Phosphonic Acids – Pyridines |
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