Addressing Adherence Using Genotype-Specific PBPK Modeling—Impact of Drug Holidays on Tamoxifen and Endoxifen Plasma Levels

Abstract

Introduction: Tamoxifen is one of the most common treatment opportunities for hormonal positive breast cancer. Despite its good tolerability, patients demonstrate decreasing adherence over years impacting on therapeutic success. PBPK modeling was applied to demonstrate the impact of drug holidays on plasma levels of tamoxifen and its active metabolite endoxifen for different CYP2D6 genotypes.Materials and Methods: A virtual study with 24,000 patients was conducted in order to investigate the development of tamoxifen steady-state kinetics in patient groups of different CYP2D6 genotypes. The impact of drug holidays on steady-state kinetics was investigated assuming changing drug holiday scenarios.Results: Drug holidays in CYP2D6 extensive and intermediate metabolizers (EMs, IMs) exceeding 1 month lead to a decrease of endoxifen steady-state trough levels below the 5th percentile of the control group. Assuming drug holidays of 1, 2, or 3 months and administering a fixed-dose combination of 20 mg tamoxifen and 3 mg endoxifen EMs demonstrated re-established endoxifen steady-state trough levels after 5, 8, and 9 days. IMs receiving the same fixed-dose combination demonstrated re-established endoxifen steady-state trough levels after 7, 10, and 11 days.Discussion: The PBPK model impressively demonstrates the impact of drug holidays in different CYP2D6 genotypes on PK. Population simulation results indicate that drug holidays of more than 2 weeks cause a tremendous decrease of plasma levels despite the long half-life of tamoxifen. To improve therapeutic success, PBPK modeling allows identifying genotype-specific differences in PK following drug holidays and adequate treatment with loading doses.

Utilization of Physiologically Based Pharmacokinetic Modeling in Clinical Pharmacology and Therapeutics: an Overview

“…Similarly, a VCS with 24,000 patients by Dickschen et al emphasized the impact of drug holidays of different lengths on steady-state kinetics and plasma levels of tamoxifen and its active metabolite, endoxifen, in patients with different CYP2D6 genotypes (i.e., extensive, intermediate, and poor metabolizers) [33]. The VCS explores the impact of patient adherence, which is difficult and nearly impossible to assess prospectively in vivo as patients tend to declare their compliance greater than what is reality.…”

Physiologically based pharmacokinetic modeling to predict the pharmacokinetics of codeine in different CYP2D6 phenotypes

“…With the development of PBPK software and human genomics in recent years, pharmacogenomics has provided new ideas for personalized medicine with the help of PBPK modeling. Previous studies have developed CYP2D6 phenotype-related PBPK models to explore the effect of CYP2D6 gene polymorphisms on pharmacokinetics ( Grzegorzewski et al, 2022 ) and elucidate the extent of CYP2D6-mediated drug–drug interactions (DDIs) ( Dickschen et al, 2017 ; Xu et al, 2021 ). PBPK modeling can reduce unnecessary clinical trials and maximize existing data.…”