Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen

Toshimichi Nakamura, Kota Toshimoto, Wooin Lee, Chiyo Imamura, Yusuke Tanigawara, Yuichi Sugiyama

Research output: Contribution to journalArticle

Abstract

The Tamoxifen Response by CYP2D6 Genotype-based Treatment-1 (TARGET-1) study (n = 180) was conducted from 2012–2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET-1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0.469 on average. As the population size of this virtual clinical study (VCS) increased, the expected probability was substantially increased (0.674 for n = 260). Our analyses also informed that the probability to achieve the end point in the TARGET-1 study was negatively impacted by a large variability in endoxifen levels. Our current efforts demonstrate the promising utility of the PBPK modeling and VCS approaches in prospectively designing effective clinical trials.

Original languageEnglish
Pages (from-to)474-482
Number of pages9
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume7
Issue number7
DOIs
Publication statusPublished - 2018 Jul 1

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Cytochrome P-450 CYP2D6
Pharmacokinetics
Tamoxifen
Genotype
Predict
End point
Modeling
Efficacy
Dose
Metabolites
Population Size
Japan
Clinical Trials
Completion
Population Density
Clinical Studies
Cytochrome P-450 Enzyme System
Therapeutics
Demonstrate

ASJC Scopus subject areas

  • Modelling and Simulation
  • Pharmacology (medical)

Cite this

Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen. / Nakamura, Toshimichi; Toshimoto, Kota; Lee, Wooin; Imamura, Chiyo; Tanigawara, Yusuke; Sugiyama, Yuichi.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 7, No. 7, 01.07.2018, p. 474-482.

Research output: Contribution to journalArticle

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