title: Design optimisation for pharmacokinetic modeling of a cocktail of phenotyping drugs.
abstract: Our paper proposes a methodological strategy to select optimal sampling designs for phenotyping studies including a cocktail of drugs. A cocktail approach is of high interest to determine the simultaneous activity of enzymes responsible for drug metabolism and pharmacokinetics, therefore useful in anticipating drug-drug interactions and in personalized medicine. Phenotyping indexes, which are area under the concentration-time curves, can be derived from a few samples using nonlinear mixed effect models and maximum a posteriori estimation. Because of clinical constraints in phenotyping studies, the number of samples that can be collected in individuals is limited and the sampling times must be as flexible as possible. Therefore to optimize joint design for several drugs (i.e., to determine a compromise between informative times that best characterize each drug's kinetics), we proposed to use a compound optimality criterion based on the expected population Fisher information matrix in nonlinear mixed effect models. This criterion allows weighting different models, which might be useful to take into account the importance accorded to each target in a phenotyping test. We also computed windows around the optimal times based on recursive random sampling and Monte-Carlo simulation while maintaining a reasonable level of efficiency for parameter estimation. We illustrated this strategy for two drugs often included in phenotyping cocktails, midazolam (probe for CYP3A) and digoxin (P-glycoprotein), based on the data of a previous study, and were able to find a sparse and flexible design. The obtained design was evaluated by clinical trial simulations and shown to be efficient for the estimation of population and individual parameters.
authors.affiliation: CEA, LIST, Data Analysis and Systems Intelligence Laboratory, Gif-sur-Yvette, France.
authors.forename: Thu Thuy
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: CEA, DSV, iBiTecS, Gif-sur-Yvette, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Bénech
authors.affiliation: CEA, DSV, iBiTecS, Gif-sur-Yvette, France.
authors.forename: Marcel
authors.initials: M
authors.lastname: Delaforge
authors.affiliation: CEA, LIST, Data Analysis and Systems Intelligence Laboratory, Gif-sur-Yvette, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Lenuzza
mesh_terms: D017321:Clinical Trials, Phase I as Topic / Q000379:methods* / Q000706:statistics & numerical data; D004077:Digoxin / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D008874:Midazolam / Q000378:metabolism / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D010865:Pilot Projects; D011446:Prospective Studies
chemical_list: D004077:Digoxin; D008874:Midazolam
keywords: Fisher information matrix; design; nonlinear mixed effect models; pharmacokinetics; phenotyping cocktail