title: Population pharmacokinetic analysis of abiraterone in chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer.
abstract: OBJECTIVE
  Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence abiraterone pharmacokinetics.
  
  
  METHODS
  Studies in this analysis included COU-AA-302 (chemotherapy naïve); COU-AA-301 and COU-AA-006 (chemotherapy pretreated); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 359 subjects (62 healthy volunteers, 297 patients) were analyzed using non-linear mixed-effects modeling.
  
  
  RESULTS
  An Erlang-type absorption model with first-order elimination and three-transit compartments following sequential zero- and first-order processes was used to characterize abiraterone pharmacokinetics. Absorption-related parameters were affected by food intake. Abiraterone pharmacokinetics were characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1,550 L/h) versus healthy subjects (2,240 L/h), and by large apparent central (5,620 L) and peripheral (17,400 L) volumes of distribution. Abiraterone pharmacokinetics were similar in chemotherapy-pretreated and -naïve patients and were characterized by a high between- and within-subject variability [e.g., between-subject coefficient of variation (CV%) for relative bioavailability for the modified fasting state was 61.1% and the CV% for within-subject variability was 71.3%]. The fat content of food taken with abiraterone acetate affected the bioavailability of abiraterone. No factors beyond food intake and health status (healthy vs. mCRPC) impacted abiraterone pharmacokinetics.
  
  
  CONCLUSIONS
  Based on the pharmacokinetics model, the recommended 1,000 mg/day of abiraterone acetate resulted in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy. The fat content of food affected relative bioavailability of abiraterone, though the extent of this effect is dependent on health status.
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, Beerse, B-2340, Belgium, kstuyck1@its.jnj.com.
authors.forename: Kim
authors.initials: K
authors.lastname: Stuyckens
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Xu Steven
authors.initials: XS
authors.lastname: Xu
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Griffin
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Yu
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.forename: Partha
authors.initials: P
authors.lastname: Nandy
authors.forename: Italo
authors.initials: I
authors.lastname: Poggesi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001682:Biological Availability; D018592:Cross-Over Studies; D004041:Dietary Fats / Q000008:administration & dosage; D000077143:Docetaxel; D004311:Double-Blind Method; D005215:Fasting / Q000378:metabolism; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000736:Androstenes; D000970:Antineoplastic Agents; D004041:Dietary Fats; D043823:Taxoids; D000077143:Docetaxel; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone