Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam

Lisa T. van der Heijden*, Claire A. Ribbers, Marit A.C. Vermunt, Dick Pluim, Manon Acda, Matthijs Tibben, Hilde Rosing, Joeri A.J. Douma, Kishan Naipal, Andre M. Bergman, Jos H. Beijnen, Alwin D.R. Huitema, Frans L. Opdam

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Patients with prostate cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8-fold) and oral administration (2.4-fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study, CYP3A activity defined by midazolam clearance (CL) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A-modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously on 2 consecutive days. Plasma concentrations were measured with a validated liquid chromatography–tandem mass spectrometry method. Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam CL was 1.26-fold higher in patients with PCa compared to patients with other solid tumors (geometric mean [coefficient of variation], 94.1 [33.5%] L/h vs 74.4 [39.1%] L/h, respectively; P =.08). Intravenous midazolam CL did not significantly differ between the 2 groups (P =.93). Moreover, the metabolic ratio of midazolam to 1′-hydroxy midazolam did not differ between the 2 groups for both oral administration (P =.67) and intravenous administration (P =.26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be explained neither by a difference in midazolam CL nor by a difference in metabolic conversion rate of midazolam.

Original languageEnglish
Pages (from-to)155-163
Number of pages9
JournalJournal of Clinical Pharmacology
Volume64
Issue number2
DOIs
Publication statusPublished - Feb 2024

Keywords

  • cytochrome P450 3A
  • in vivo phenotyping
  • midazolam
  • pharmacokinetics
  • prostate cancer

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