| 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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MedLine Citation:
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PMID: 16810714 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Xavière Panhard; Anne-Marie Taburet; Christophe Piketti; France Mentré |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Statistics in medicine Volume: 26 ISSN: 0277-6715 ISO Abbreviation: Stat Med Publication Date: 2007 Mar |
Date Detail:
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Created Date: 2007-02-19 Completed Date: 2007-04-16 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8215016 Medline TA: Stat Med Country: England |
Other Details:
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Languages: eng Pagination: 1268-84 Citation Subset: IM |
Copyright Information:
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Copyright (c) 2006 John Wiley & Sons, Ltd. |
Affiliation:
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INSERM U738, Paris, France. xaviere.panhard@bch.aphp.fr |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenine
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analogs & derivatives*,
pharmacokinetics,
therapeutic use Anti-HIV Agents / pharmacokinetics*, therapeutic use Bias (Epidemiology)* Cross-Over Studies Drug Interactions France HIV Infections / drug therapy* Humans Likelihood Functions Nonlinear Dynamics* Oligopeptides / pharmacokinetics*, therapeutic use Phosphonic Acids / pharmacokinetics*, therapeutic use Pyridines / pharmacokinetics*, therapeutic use |
| Chemical | |
Reg. No./Substance:
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0/Anti-HIV Agents; 0/Oligopeptides; 0/Phosphonic Acids; 0/Pyridines; 107021-12-5/tenofovir; 198904-31-3/atazanavir; 73-24-5/Adenine |
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