Phase i study of cabazitaxel plus cisplatin in patients with advanced solid tumors: Study to evaluate the impact of cytochrome P450 3A inhibitors (aprepitant, ketoconazole) or inducers (rifampin) on the pharmacokinetics of cabazitaxel

John Sarantopoulos, Alain C. Mita, James L. Wade, John C. Morris, Olivier Rixe, Monica M. Mita, Jean François Dedieu, Claudine Wack, Laurent Kassalow, A. Craig Lockhart

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Purpose: Cabazitaxel is primarily metabolized by CYP3A. This study evaluated the impact of moderate/strong CYP3A inhibitors [aprepitant (Study Part 2); ketoconazole (Study Part 3)] or strong CYP3A inducers [rifampin (Study Part 4)] on the pharmacokinetics of cabazitaxel. Methods: Adult patients received IV cabazitaxel/cisplatin 15/75 mg/m2 on Day 1 of 3-week cycles (5/75 mg/m2 in Cycles 1 and 2 of Part 3 to allow a safety margin to the cabazitaxel MTD). Patients received repeated oral doses of aprepitant, ketoconazole or rifampin before/during Cycle 2. Cabazitaxel clearance was the primary endpoint; clearance and area under the plasma concentration-time curve (AUC) were normalized to body surface area and dose, respectively. Results: The PK population included 13 (Part 2), 23 (Part 3) and 21 patients (Part 4). Repeated aprepitant administration did not affect cabazitaxel clearance [geometric mean ratio (GMR) 0.98; 90 % confidence interval (CI) 0.80-1.19]. Repeated ketoconazole administration resulted in 20 % decrease in cabazitaxel clearance (GMR 0.80; 90 % CI 0.55-1.15), associated with 25 % increase in AUC (GMR 1.25; 90 % CI 0.86-1.81). Repeated rifampin administration resulted in 21 % increase in cabazitaxel clearance (GMR 1.21; 90 % CI 0.95-1.53), associated with 17 % decrease in AUC (GMR 0.83; 90 % CI 0.65-1.05). The GMR of AUC0-24 with rifampin administration was 1.09 (90 % CI 0.9-1.33), suggesting that rifampin had a low impact during the initial phases of cabazitaxel elimination. Safety findings were consistent with previous results. Conclusions: Cabazitaxel pharmacokinetics are modified by drugs strongly affecting CYP3A. Co-administration of cabazitaxel with strong CYP3A inhibitors or inducers should be avoided.

Original languageEnglish (US)
Pages (from-to)1113-1124
Number of pages12
JournalCancer Chemotherapy And Pharmacology
Volume74
Issue number6
DOIs
StatePublished - Feb 5 2014

Keywords

  • Aprepitant
  • Cabazitaxel
  • Cytochrome P450 3A
  • Drug-drug interactions
  • Ketoconazole
  • Rifampin

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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