Model-based bioequivalence approach for sparse pharmacokinetic bioequivalence studies: Model selection or model averaging?

Conventional pharmacokinetic (PK) bioequivalence (BE) studies aim to compare the rate and extent of drug absorption from a test (T) and reference (R) product using non-compartmental analysis (NCA) and the two one-sided test (TOST). Recently published regulatory guidance recommends alternative model-based (MB) approaches for BE assessment when NCA is challenging, as for long-acting injectables and products which require sparse PK sampling. However, our previous research on MB-TOST approaches showed that model misspecification can lead to inflated type I error.

Assessing Treatment Effects with Pharmacometric Models: A New Method that Addresses Problems with Standard Assessments.

Longitudinal pharmacometric models offer many advantages in the analysis of clinical trial data, but potentially inflated type I error and biased drug effect estimates, as a consequence of model misspecifications and multiple testing, are main drawbacks. In this work, we used real data to compare these aspects for a standard approach (STD) and a new one using mixture models, called individual model averaging (IMA). Placebo arm data sets were obtained from three clinical studies assessing ADAS-Cog scores, Likert pain scores, and seizure frequency.

CC30 Lineage and Absence of ,,-Harboring Plasmid Predict Embolism in Infective Endocarditis.

induces severe infective endocarditis (IE) where embolic complications are a major cause of death. Risk factors for embolism have been reported such as a younger age or larger IE vegetations, while methicillin resistance conferred by the gene appeared as a protective factor. It is unclear, however, whether embolism is influenced by other characteristics such as clonal complex (CC) or virulence pattern.

Genetics of Nevirapine Metabolic Pathways at Steady State in HIV-Infected Cambodians.

Nevirapine is metabolized by several hepatic cytochrome P450 (CYP) isoforms to generate four primary hydroxylated metabolites: 2-hydroxynevirapine, 3-hydroxynevirapine, 8-hydroxynevirapine, and 12-hydroxynevirapine. The present study characterized associations between genetic polymorphisms and metabolite ratios in HIV-infected Cambodians. We demonstrate associations between polymorphisms and metabolite ratios for both 3-hydroxynevirapine and 8-hydroxynevirapine, suggesting involvement of CYP2B6 in generating these metabolites.

Comparison of Nonlinear Mixed Effects Models and Noncompartmental Approaches in Detecting Pharmacogenetic Covariates.

Genetic data is now collected in many clinical trials, especially in population pharmacokinetic studies. There is no consensus on methods to test the association between pharmacokinetics and genetic covariates. We performed a simulation study inspired by real clinical trials, using the pharmacokinetics (PK) of a compound under development having a nonlinear bioavailability along with genotypes for 176 single nucleotide polymorphisms (SNPs).