Loading…

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 pharmacokinet...

Full description

Saved in:
Bibliographic Details
Published in:The AAPS journal 2015-05, Vol.17 (3), p.597-608
Main Authors: Tessier, Adrien, Bertrand, Julie, Chenel, Marylore, Comets, Emmanuelle
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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). Scenarios included 78 subjects extensively sampled (16 observations per subject) to simulate a phase I study, or 384 subjects with the same rich design. Under the alternative hypothesis (H 1 ), six SNPs were drawn randomly to affect the log-clearance under an additive linear model. For each scenario, 200 PK data sets were simulated under the null hypothesis (no gene effect) and H 1 . We compared 16 combinations of four association tests, a stepwise procedure and three penalised regressions (ridge regression, Lasso, HyperLasso), applied to four pharmacokinetic phenotypes, two observed concentrations, area under the curve estimated by noncompartmental analysis and model-based clearance. The different combinations were compared in terms of true and false positives and probability to detect the genetic effects. In presence of nonlinearity and/or variability in bioavailability, model-based phenotype allowed a higher probability to detect the SNPs than other phenotypes. In a realistic setting with a limited number of subjects, all methods showed a low ability to detect genetic effects. Ridge regression had the best probability to detect SNPs, but also a higher number of false positives. No association test showed a much higher power than the others.
ISSN:1550-7416
1550-7416
DOI:10.1208/s12248-015-9726-8