title: Design evaluation and optimisation in crossover pharmacokinetic studies analysed by nonlinear mixed effects models.
abstract: Bioequivalence or interaction trials are commonly studied in crossover design and can be analysed by nonlinear mixed effects models as an alternative to noncompartmental approach. We propose an extension of the population Fisher information matrix in nonlinear mixed effects models to design crossover pharmacokinetic trials, using a linearisation of the model around the random effect expectation, including within-subject variability and discrete covariates fixed or changing between periods. We use the expected standard errors of treatment effect to compute the power for the Wald test of comparison or equivalence and the number of subjects needed for a given power. We perform various simulations mimicking crossover two-period trials to show the relevance of these developments. We then apply these developments to design a crossover pharmacokinetic study of amoxicillin in piglets and implement them in the new version 3.2 of the r function PFIM.
authors.affiliation: UMR738 INSERM and University Paris Diderot, Paris, France. thu-thuy.nguyen@inserm.fr
authors.forename: Thu Thuy
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Caroline
authors.initials: C
authors.lastname: Bazzoli
authors.forename: France
authors.initials: F
authors.lastname: Mentré
mesh_terms: D000465:Algorithms; D000658:Amoxicillin / Q000493:pharmacokinetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation / Q000706:statistics & numerical data; D018592:Cross-Over Studies; D006801:Humans; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010599:Pharmacokinetics; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size; D013552:Swine; D013810:Therapeutic Equivalency
chemical_list: D000900:Anti-Bacterial Agents; D000658:Amoxicillin