Abstract
PurposeTo evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men.MethodsTwo phase I studies (dose-escalation study and dose-proportionality study) were conducted in healthy men aged 18–55 years. All subjects received 4 consecutive single doses of AA (250, 500, 750 and 1,000 mg). The dose-escalation study subjects (N = 33) received AA doses in a sequential manner, starting with the lowest dose. The dose-proportionality study subjects (N = 32) were randomly allocated (1:1:1:1) to receive each of the 4 doses in a four-way crossover design.ResultsA dose-related increase in abiraterone exposure was observed in both studies. Over the evaluated dose range, the mean abiraterone maximum plasma concentrations increased from 26 to 112 ng/mL in dose-escalation study and from 40 to 125 ng/mL in dose-proportionality study; the mean area under the plasma concentration–time curve from 0 to the last measurable plasma concentration increased from 155 to 610 ng.h/mL in dose-escalation study, and from 195 to 607 ng.h/mL in dose-proportionality study. In the dose-proportionality study, abiraterone exposure was dose proportional between 1,000 and 750 mg doses; however, the exposure was slightly greater than dose proportional when exposures at 500 and 250 mg doses were compared with the exposure at 1,000 mg. Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients.ConclusionSystemic exposure to abiraterone increased with increasing doses of AA (250–1,000 mg) in healthy men; AA was well tolerated in this population.
Highlights
Prostate cancer is the second leading cause of cancer deaths, accounting for 9 % of all cancer-related death in men [1]
Abiraterone exposure was dose proportional between 1,000 and 750 mg doses; the exposure was slightly greater than dose proportional when exposures at 500 and 250 mg doses were compared with the exposure at 1,000 mg
The PK analysis was not performed for AA as the majority of plasma concentrations for AA were below the limit of quantification in both studies
Summary
Prostate cancer is the second leading cause of cancer deaths, accounting for 9 % of all cancer-related death in men [1]. Androgen deprivation therapy (ADT) is a standard treatment for advanced, adjuvant, and non-adjuvant stages of the disease and involves surgical (orchiectomy) or medical (luteinizing hormone (LH)-releasing hormone agonists, or antiandrogens) intervention [2, 3]. ADT induces a remission in 80–90 % of patients with advanced disease [4], majority of patients eventually develop castration-resistant prostate cancer (CRPC), an androgen-independent phenotype and the lethal form of the disease, in which \20 % of patients survive beyond 3 years [5]. Ketoconazole, the non-selective inhibitor of CYP17 enzyme, presents modest antitumor activity and is associated with an increase in androgenic steroids at disease progression, indicating incomplete target blockade [7]. Abiraterone is a selective and irreversible inhibitor of CYP17 enzyme and is 10–30-fold more potent than ketoconazole [8].
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