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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

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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 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.

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Acknowledgments

This study was sponsored by Sanofi. The University of Texas Health Science Center San Antonio received a cancer center support grant from the National Cancer Institute (Cancer Center Support Grant P30CA054174). The authors received support in the form of medical writing services from Ben Caldwell of MediTech Media, funded by Sanofi.

Conflict of interest

JFD and CW are remunerated employees of Sanofi. JFD also holds Sanofi stock. LK is employed in a remunerated consultant/advisory role by Sanofi. ACL has received research funding from Sanofi. ACM, MMM, JCM, OR, JS and JW have no conflicts to disclose.

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Authors and Affiliations

  1. Institute for Drug Development, Cancer Therapy and Research Center at UTHSCSA, University of Texas Health Science Center San Antonio, 4th Floor, Zeller Building, 7979 Wurzbach Road, San Antonio, TX, 78229, USA

    John Sarantopoulos, Alain C. Mita & Monica M. Mita

  2. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Alain C. Mita & Monica M. Mita

  3. Cancer Care Center of Decatur, Decatur, IL, USA

    James L. Wade

  4. Division of Hematology-Oncology, Department of Medicine, University of Cincinnati Cancer Institute, Cincinnati, OH, USA

    John C. Morris

  5. Division of Hematology/Oncology, GRU Cancer Center, Georgia Regents University, Augusta, GA, USA

    Olivier Rixe

  6. Sanofi, Chilly-Mazarin, France

    Jean-François Dedieu & Claudine Wack

  7. Sanofi, Bridgewater, NJ, USA

    Laurent Kassalow

  8. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

    A. Craig Lockhart

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  1. John Sarantopoulos
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Correspondence to John Sarantopoulos.

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Sarantopoulos, J., Mita, A.C., Wade, J.L. et al. 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 74, 1113–1124 (2014). https://doi.org/10.1007/s00280-014-2572-z

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