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

Cancer Chemother Pharmacol. 2014 Dec;74(6):1113-24. doi: 10.1007/s00280-014-2572-z. Epub 2014 Oct 12.

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/m(2) on Day 1 of 3-week cycles (5/75 mg/m(2) 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.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Aprepitant
  • Area Under Curve
  • Cisplatin / administration & dosage
  • Cytochrome P-450 CYP3A / drug effects*
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology*
  • Cytochrome P-450 Enzyme Inducers / pharmacology*
  • Drug Interactions
  • Female
  • Humans
  • Ketoconazole / pharmacology
  • Male
  • Middle Aged
  • Morpholines / pharmacology
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Rifampin / pharmacology
  • Taxoids / administration & dosage
  • Taxoids / pharmacokinetics*

Substances

  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 Enzyme Inducers
  • Morpholines
  • Taxoids
  • Aprepitant
  • cabazitaxel
  • Cytochrome P-450 CYP3A
  • Cisplatin
  • Ketoconazole
  • Rifampin