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


CONCLUSIONS
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.
British Columbia Cancer Agency, Vancouver, BC, Canada. kchi@bccancer.bc.ca
K N
KN
Chi
A
A
Tolcher
P
P
Lee
P J
PJ
Rosen
C K
CK
Kollmannsberger
K P
KP
Papadopoulos
A
A
Patnaik
A
A
Molina
J
J
Jiao
C
C
Pankras
B
B
Kaiser
A
A
Bernard
N
N
Tran
M
M
Acharya
D000069501:Abiraterone Acetate; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D019540:Area Under Curve; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000378:metabolism; D003915:Dextromethorphan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D011241:Prednisone / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000730:Androstadienes; D003915:Dextromethorphan; D013806:Theophylline; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D000069501:Abiraterone Acetate; D011241:Prednisone