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Article Dans Une Revue Journal of Pharmacokinetics and Pharmacodynamics Année : 2022

Impact of model misspecification on model-based tests in PK studies with parallel design: real case and simulation studies

Résumé

This article evaluates the performance of pharmacokinetic (PK) equivalence testing between two formulations of a drug through the Two-One Sided Tests (TOST) by a model-based approach (MB-TOST), as an alternative to the classical non-compartmental approach (NCA-TOST), for a sparse design with a few time points per subject. We focused on the impact of model misspecification and the relevance of model selection for the reference data. We first analysed PK data from phase I studies of gantenerumab, a monoclonal antibody for the treatment of Alzheimer's disease. Using the original rich sample data, we compared MB-TOST to NCA-TOST for validation. Then, the analysis was repeated on a sparse subset of the original data with MB-TOST. This analysis inspired a simulation study with rich and sparse designs. With rich designs, we compared NCA-TOST and MB-TOST in terms of type I error and study power. With both designs, we explored the impact of misspecifying the model on the performance of MB-TOST and adding a model selection step. Using the observed data, the results of both approaches were in general concordance. MB-TOST results were robust with sparse designs when the underlying PK structural model was correctly specified. Using the simulated data with a rich design, the type I error of NCA-TOST was close to the nominal level. When using the simulated model, the type I error of MB-TOST was controlled on rich and sparse designs, but using a misspecified model led to inflated type I errors. Adding a model selection step on the reference data reduced the inflation. MB-TOST appears as a robust alternative to NCA-TOST, provided that the PK model is correctly specified and the test drug has the same PK structural model as the reference drug.
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Dates et versions

hal-03789327 , version 1 (23-05-2023)

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Paternité - Pas d'utilisation commerciale

Identifiants

Citer

Mélanie Guhl, Francois Mercier, C Hofmann, Satish Sharan, M Donnelly, et al.. Impact of model misspecification on model-based tests in PK studies with parallel design: real case and simulation studies. Journal of Pharmacokinetics and Pharmacodynamics, 2022, 49, pp.557-577. ⟨10.1007/s10928-022-09821-z⟩. ⟨hal-03789327⟩
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