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01.12.2014 | Original Article

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2014

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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 AUC_0–24 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.

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Titel: 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
verfasst von: 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
Publikationsdatum: 01.12.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2014
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2572-z

Springer Medizin

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