Development and comparison of model-integrated evidence approaches for bioequivalence studies with pharmacokinetic end points.

Autor: Chen X; Department of Pharmacy, Uppsala University, Uppsala, Sweden., Nyberg HB; Department of Pharmacy, Uppsala University, Uppsala, Sweden., Donnelly M; Division of Quantitative Methods and Modeling, Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA., Zhao L; Division of Quantitative Methods and Modeling, Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA., Fang L; Division of Quantitative Methods and Modeling, Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA., Karlsson MO; Department of Pharmacy, Uppsala University, Uppsala, Sweden., Hooker AC; Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2024 Oct; Vol. 13 (10), pp. 1734-1747. Date of Electronic Publication: 2024 Aug 23.
DOI: 10.1002/psp4.13216
Abstrakt: By applying nonlinear mixed-effect (NLME) models, model-integrated evidence (MIE) approaches are able to analyze bioequivalence (BE) data with pharmacokinetic end points that have sparse sampling, which is problematic for non-compartmental analysis (NCA). However, MIE approaches may suffer from inflation of type I error due to underestimation of parameter uncertainty and to the assumption of asymptotic normality. In this study, we developed a MIE BE analysis method that is based on a pre-defined model and consists of several steps including model fitting, uncertainty assessment, simulation, and BE determination. The presented MIE approach has several improvements compared with the previously reported model-integrated methods: (1) treatment, sequence, and period effects are only added to absorption parameters (such as relative bioavailability and rate of absorption) instead of all PK parameters; (2) a simulation step is performed to generate confidence intervals of the pharmacokinetic metrics for BE assessment; and (3) in an effort to maintain type I error, two more advanced parameter uncertainty evaluation approaches are explored, a nonparametric (case resampling) bootstrap, and sampling importance resampling (SIR). To evaluate the developed method and compare the uncertainty assessment methods, simulation experiments were performed for BE studies using a two-way crossover design with different amounts of information (sparse to rich designs) and levels of variability. Based on the simulation results, the method using SIR for parameter uncertainty quantification controls type I error at the nominal level of 0.05 (i.e., the significance level set for BE evaluation) even for studies with small sample size and/or sparse sampling. As expected, our MIE approach for BE assessment exhibited higher power than the NCA-based method, especially as the data becomes sparser and/or more variable.
(© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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