Population Pharmacokinetics of Z-Endoxifen in Patients With Advanced Solid Tumors

Emily J. Koubek, Andrew T. Ralya, Thomas R. Larson, Renee M. McGovern, Sarah A. Buhrow, Joseph M. Covey, Alex A. Adjei, Naoko Takebe, Matthew M. Ames, Matthew P. Goetz, Joel M. Reid

Research output: Contribution to journalArticlepeer-review

Abstract

The purpose of this study was to develop and validate a population pharmacokinetic model for Z-endoxifen in patients with advanced solid tumors and to identify clinical variables that influence pharmacokinetic parameters. Z-endoxifen-HCl was administered orally once a day on a 28-day cycle (±3 days) over 11 dose levels ranging from 20 to 360 mg. A total of 1256 Z-endoxifen plasma concentration samples from 80 patients were analyzed using nonlinear mixed-effects modeling to develop a population pharmacokinetic model for Z-endoxifen. A 2-compartment model with oral depot and linear elimination adequately described the data. The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 4.89 L/h, 323 L, and 39.7 L, respectively, with weight-effect exponents of 0.75, 1, and 1, respectively. This model was used to explore the effects of clinical and demographic variables on Z-endoxifen pharmacokinetics. Weight, race on clearance, and aspartate aminotransferase on the absorption rate constant were identified as significant covariates in the final model. This novel population pharmacokinetic model provides insight regarding factors that may affect the pharmacokinetics of Z-endoxifen and may assist in the design of future clinical trials.

Original languageEnglish (US)
Pages (from-to)1121-1131
Number of pages11
JournalJournal of Clinical Pharmacology
Volume62
Issue number9
DOIs
StateAccepted/In press - 2022

Keywords

  • NONMEM
  • covariate
  • endoxifen
  • population pharmacokinetics
  • tamoxifen

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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