Document Detail


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.
MedLine Citation:
PMID:  16810714     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Xavière Panhard; Anne-Marie Taburet; Christophe Piketti; France Mentré
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Statistics in medicine     Volume:  26     ISSN:  0277-6715     ISO Abbreviation:  Stat Med     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-02-19     Completed Date:  2007-04-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8215016     Medline TA:  Stat Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  1268-84     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2006 John Wiley & Sons, Ltd.
Affiliation:
INSERM U738, Paris, France. xaviere.panhard@bch.aphp.fr
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MeSH Terms
Descriptor/Qualifier:
Adenine / 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:
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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