Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 1, pp 237–244

Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer

  • K. N. Chi
  • A. Tolcher
  • P. Lee
  • P. J. Rosen
  • C. K. Kollmannsberger
  • K. P. Papadopoulos
  • A. Patnaik
  • A. Molina
  • J. Jiao
  • C. Pankras
  • B. Kaiser
  • A. Bernard
  • N. Tran
  • M. Acharya
Original Article

DOI: 10.1007/s00280-012-2001-0

Cite this article as:
Chi, K.N., Tolcher, A., Lee, P. et al. Cancer Chemother Pharmacol (2013) 71: 237. doi:10.1007/s00280-012-2001-0

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 (Cmax) (275.36 %) and area under plasma concentration–time curves from time 0 to 24 h (AUC24h) (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 [Cmax; 102.36 % and AUC24h; 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.

Keywords

Abiraterone acetate CYP2D6 CYP1A2 Drug–drug interaction Metastatic castration-resistant prostate cancer 

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • K. N. Chi
    • 1
  • A. Tolcher
    • 2
  • P. Lee
    • 3
  • P. J. Rosen
    • 4
  • C. K. Kollmannsberger
    • 1
  • K. P. Papadopoulos
    • 2
  • A. Patnaik
    • 2
  • A. Molina
    • 5
  • J. Jiao
    • 6
  • C. Pankras
    • 1
  • B. Kaiser
    • 2
  • A. Bernard
    • 6
  • N. Tran
    • 5
  • M. Acharya
    • 6
  1. 1.British Columbia Cancer AgencyVancouverCanada
  2. 2.South Texas Accelerated Research Therapeutics, START Center for Cancer CareSan AntonioUSA
  3. 3.Tower Cancer Research FoundationBeverly HillsUSA
  4. 4.Providence Saint Joseph Medical CenterBurbankUSA
  5. 5.Janssen Research and Development LLCLos AngelesUSA
  6. 6.Janssen Research and Development LLCRaritanUSA