Abstract
Purpose
To assess the effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan HBr (CYP2D6 substrate) and theophylline (CYP1A2 substrate) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Methods
Men with progressive metastatic mCRPC who failed gonadotropin-releasing hormone therapy and ≥1 lines of chemotherapy were enrolled. Patients received two doses of dextromethorphan HBr-30 mg (n = 18; group A) or theophylline-100 mg (n = 16; group B) under fasting conditions; one dose on cycle 1, day −8, and the other dose on cycle 1, day 8. Only patients with extensive CYP2D6 metabolizing status were assigned to group A. All patients received continuous daily oral abiraterone acetate (1,000 mg) plus prednisone (10 mg) starting on cycle 1, day 1.
Results
Coadministration of abiraterone acetate plus prednisone increased the systemic exposure of dextromethorphan by approximately 100 %. Ratios of geometric means for maximum plasma concentration (C max) (275.36 %) and area under plasma concentration–time curves from time 0 to 24 h (AUC 24h) (268.14 %) of dextromethorphan were outside the bioequivalence limit. The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C max; 102.36 % and AUC 24h; 108.03 %] of theophylline exposure parameters were within the bioequivalence limit. The safety profile of abiraterone acetate was consistent with reported toxicities.
Conclusion
Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.
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Acknowledgments
Ananya Chikramane, PhD (SIRO Clinpharm Pvt. Ltd.), provided writing assistance, and Namit Ghildyal, PhD (Janssen Research and Development LLC), provided additional editorial assistance. The authors also thank the study participants, without whom this study would never have been accomplished. Drs. Molina, Jiao, Tran, and Acharya, and Ms. Bernard are employees of Janssen Research and Development LLC. Dr. Chi has served as a consultant to Janssen Research and Development LLC. Dr. Tolcher is a consultant for several pharmaceutical companies. Dr. Papadopoulos has received commercial research support from Cougar Biotechnology. Drs. Lee, Rosen, Kollmannsberger, and Patnaik, and Ms. Pankras and Kaiser have no conflict of interest. All authors met ICMJE criteria, and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, made the final decision about where to publish these data, and approved submission to this journal.
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Chi, K.N., Tolcher, A., Lee, P. et al. Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol 71, 237–244 (2013). https://doi.org/10.1007/s00280-012-2001-0
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DOI: https://doi.org/10.1007/s00280-012-2001-0