Pharmacogenetic Dose Modeling Based on CYP2C19 Allelic Phenotypes

Pharmaceutics, vol. 14, pp. 2833

Abstract

Pharmacogenetic variability in drug metabolism leads to patient vulnerability to side effects and to therapeutic failure. Our purpose was to introduce a systematic statistical methodology to estimate quantitative dose adjustments based on pharmacokinetic differences in pharmacogenetic subgroups, addressing the concerns of sparse data, incomplete information on phenotypic groups, and heterogeneity of study design. Data on psychotropic drugs metabolized by the cytochrome P450 enzyme CYP2C19 were used as a case study. CYP2C19 activity scores were estimated, while statistically assessing the influence of methodological differences between studies, and used to estimate dose adjustments in genotypic groups. Modeling effects of activity scores in each substance as a population led to prudential predictions of adjustments when few data were available ('shrinkage'). The best results were obtained with the regularized horseshoe, an innovative Bayesian approach to estimate coefficients viewed as a sample from two populations. This approach was compared to modeling the population of substance as normally distributed, to a more traditional "fixed effects" approach, and to dose adjustments based on weighted means, as in current practice. Modeling strategies were able to assess the influence of study parameters and deliver adjustment levels when necessary, extrapolated to all phenotype groups, as well as their level of uncertainty. In addition, the horseshoe reacted sensitively to small study sizes, and provided conservative estimates of required adjustments.

Authors 4

1. Julia Stingl corresponding Aachen Institute of Clinical Pharmacology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Clinical Pharmacology, University Hospital of RWTH, 52074 Aachen, Germany

2. Jason Radermacher Aachen Institute of Clinical Pharmacology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Clinical Pharmacology, University Hospital of RWTH, 52074 Aachen, Germany

3. Justyna Wozniak Aachen Institute of Clinical Pharmacology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Clinical Pharmacology, University Hospital of RWTH, 52074 Aachen, Germany

4. Roberto Viviani

   Universität Innsbruck · Universität Ulm

   Affiliation as printed

   Institute of Psychology, University of Innsbruck, 6020 Innsbruck, Austria

   Psychiatry and Psychotherapy Clinic, University of Ulm, 89075 Ulm, Germany