Cancer Chemother Pharmacol DOI 10.1007/s00280-014-2616-4
ORIGINAL ARTICLE
Pharmacokinetics of abiraterone in healthy Japanese men: dose‑proportionality and effect of food timing Kouichi Inoue · Akira Shishido · Nicole Vaccaro · James Jiao · Hans Stieltjes · Apexa Bernard · Margaret Yu · Caly Chien
Received: 9 September 2014 / Accepted: 15 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men. Methods In the dose-proportionality study, subjects (n = 30 Japanese) were randomly assigned to receive single doses of 250, 500, and 1,000 mg AA, and in the foodtiming study, subjects (n = 22 Japanese and n = 23 Caucasian) randomly received single doses of 1,000 mg AA under fasted (overnight) and three different modified fasting conditions. Results Mean Cmax and AUC∞ for abiraterone increased dose-dependently in Japanese healthy men; however, 90 % confidential interval (CI) was outside the predefined doseproportionality criteria. Based on geometric mean ratios and 90 % CIs (versus overnight fasting condition), abiraterone exposure (AUC) increased significantly with dosing
The study PCR 1005 is registered at ClinicalTrials. gov: NCT01575587. K. Inoue · A. Shishido Janssen Pharmaceutical, KK, Tokyo, Japan N. Vaccaro · J. Jiao · A. Bernard · M. Yu · C. Chien (*) Janssen Research and Development, LLC, Titusville, USA e-mail: [email protected] H. Stieltjes Janssen Research and Development (a Division of Janssen Pharmaceutica), NV, Beerse, Belgium
1 h premeal, 2 h postmeal, or in between two meals 4 h apart by 57 %, 595 %, and 649 %, respectively. Conclusion No clinically meaningful difference was observed in the pharmacokinetics of abiraterone between Caucasian and Japanese subjects. Keywords Abiraterone acetate · Dose-proportionality · Food effect · Japanese · Pharmacokinetics
Introduction Prostate cancer is the most common cancer type in men with an annual estimate of approximately 238,590 cases and 29,720 deaths related to this malignancy in 2013 in the USA [1]. Prostate cancer incidence rate is increasing rapidly in Asian countries too (like China, Japan, Singapore, Korea), albeit at a lower proportion than in the USA [2]. In Japan, a 2.8-fold rise in prostate cancer-related deaths is expected by 2020 [3], and with growing burden of this disease in Japanese men, it will become the second most common type of cancer [4–6]. Targeting extra-gonadal androgen synthesis is an improved strategy for treating metastatic castration-resistant prostate cancer (mCRPC) as inhibition of adrenal, testicular, and intratumoral androgen synthesis results in reduced androgen levels in prostate tumor as well as in plasma. Abiraterone acetate (AA), a prodrug of abiraterone, irreversibly inhibits 17a-hydroxylase/C17, 20-lyase (CYP17), a key enzyme for de novo androgen synthesis. The combination of AA and prednisone (P) is approved in Japan and more than 70 other countries for treating mCRPC patients who have received prior docetaxel therapy [7] and in chemotherapy-naïve mCRPC patients. Treatment with AA + P improves progression-free survival (median 16.5 months)
13
in chemotherapy-naïve mCRPC patients compared with the control of P alone (median 8.3 months) [8]. Since the administration of AA in fed conditions substantially increases systemic exposure to abiraterone versus the fasted condition [9], AA is recommended to be taken on an empty stomach, with no food consumption for at least 2 h before and 1 h after the dosing. To date, there is no dedicated clinical PK study evaluating the impact of variations in food timings on abiraterone pharmacokinetics. Food effect on PK is assumed to be the same regardless of race or ethnicity, but data generated from a well-controlled study to verify this assumption are lacking. This report presents the pharmacokinetics of abiraterone after single-dose administration of AA (250, 500, and 1,000 mg) in healthy Japanese men (study 1). Additionally, we evaluated the effects of food timing in relation to single doses of AA (1,000 mg) on the pharmacokinetics of abiraterone in Japanese and Caucasian healthy men (study 2).
Methods Study populations Study 1 recruited healthy men (20–55 years of age) from Japan. Study 2 recruited healthy men (25–35 years of age) either of Japanese descent who resided outside of Japan for ≤5 years and whose parents and grandparents (both maternal and paternal) were Japanese, or non-Hispanic Caucasians having Caucasian parents. Subjects in both studies had BMI of 18–30 kg/m2 and were required to be in good health as determined by the medical history and physical examinations at screening, who refrained from the use of nicotine-containing products (including tobacco) and were in agreement to use medically accepted contraceptive throughout the study duration. The exclusion criteria for both studies were as follows: serum testosterone level
ORIGINAL ARTICLE
Pharmacokinetics of abiraterone in healthy Japanese men: dose‑proportionality and effect of food timing Kouichi Inoue · Akira Shishido · Nicole Vaccaro · James Jiao · Hans Stieltjes · Apexa Bernard · Margaret Yu · Caly Chien
Received: 9 September 2014 / Accepted: 15 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men. Methods In the dose-proportionality study, subjects (n = 30 Japanese) were randomly assigned to receive single doses of 250, 500, and 1,000 mg AA, and in the foodtiming study, subjects (n = 22 Japanese and n = 23 Caucasian) randomly received single doses of 1,000 mg AA under fasted (overnight) and three different modified fasting conditions. Results Mean Cmax and AUC∞ for abiraterone increased dose-dependently in Japanese healthy men; however, 90 % confidential interval (CI) was outside the predefined doseproportionality criteria. Based on geometric mean ratios and 90 % CIs (versus overnight fasting condition), abiraterone exposure (AUC) increased significantly with dosing
The study PCR 1005 is registered at ClinicalTrials. gov: NCT01575587. K. Inoue · A. Shishido Janssen Pharmaceutical, KK, Tokyo, Japan N. Vaccaro · J. Jiao · A. Bernard · M. Yu · C. Chien (*) Janssen Research and Development, LLC, Titusville, USA e-mail: [email protected] H. Stieltjes Janssen Research and Development (a Division of Janssen Pharmaceutica), NV, Beerse, Belgium
1 h premeal, 2 h postmeal, or in between two meals 4 h apart by 57 %, 595 %, and 649 %, respectively. Conclusion No clinically meaningful difference was observed in the pharmacokinetics of abiraterone between Caucasian and Japanese subjects. Keywords Abiraterone acetate · Dose-proportionality · Food effect · Japanese · Pharmacokinetics
Introduction Prostate cancer is the most common cancer type in men with an annual estimate of approximately 238,590 cases and 29,720 deaths related to this malignancy in 2013 in the USA [1]. Prostate cancer incidence rate is increasing rapidly in Asian countries too (like China, Japan, Singapore, Korea), albeit at a lower proportion than in the USA [2]. In Japan, a 2.8-fold rise in prostate cancer-related deaths is expected by 2020 [3], and with growing burden of this disease in Japanese men, it will become the second most common type of cancer [4–6]. Targeting extra-gonadal androgen synthesis is an improved strategy for treating metastatic castration-resistant prostate cancer (mCRPC) as inhibition of adrenal, testicular, and intratumoral androgen synthesis results in reduced androgen levels in prostate tumor as well as in plasma. Abiraterone acetate (AA), a prodrug of abiraterone, irreversibly inhibits 17a-hydroxylase/C17, 20-lyase (CYP17), a key enzyme for de novo androgen synthesis. The combination of AA and prednisone (P) is approved in Japan and more than 70 other countries for treating mCRPC patients who have received prior docetaxel therapy [7] and in chemotherapy-naïve mCRPC patients. Treatment with AA + P improves progression-free survival (median 16.5 months)
13
in chemotherapy-naïve mCRPC patients compared with the control of P alone (median 8.3 months) [8]. Since the administration of AA in fed conditions substantially increases systemic exposure to abiraterone versus the fasted condition [9], AA is recommended to be taken on an empty stomach, with no food consumption for at least 2 h before and 1 h after the dosing. To date, there is no dedicated clinical PK study evaluating the impact of variations in food timings on abiraterone pharmacokinetics. Food effect on PK is assumed to be the same regardless of race or ethnicity, but data generated from a well-controlled study to verify this assumption are lacking. This report presents the pharmacokinetics of abiraterone after single-dose administration of AA (250, 500, and 1,000 mg) in healthy Japanese men (study 1). Additionally, we evaluated the effects of food timing in relation to single doses of AA (1,000 mg) on the pharmacokinetics of abiraterone in Japanese and Caucasian healthy men (study 2).
Methods Study populations Study 1 recruited healthy men (20–55 years of age) from Japan. Study 2 recruited healthy men (25–35 years of age) either of Japanese descent who resided outside of Japan for ≤5 years and whose parents and grandparents (both maternal and paternal) were Japanese, or non-Hispanic Caucasians having Caucasian parents. Subjects in both studies had BMI of 18–30 kg/m2 and were required to be in good health as determined by the medical history and physical examinations at screening, who refrained from the use of nicotine-containing products (including tobacco) and were in agreement to use medically accepted contraceptive throughout the study duration. The exclusion criteria for both studies were as follows: serum testosterone level
