Single‐dose pharmacokinetic studies of abiraterone acetate in men with hepatic or renal impairment

Abstract

Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of abiraterone acetate was well-tolerated.

Population Pharmacokinetic Analysis of Abiraterone in Chemotherapy-Naïve and Docetaxel-Treated Patients with Metastatic Castration-Resistant Prostate Cancer

“…However, the influence of prednisone or prednisolone on the pharmacokinetics of abiraterone could not be formally tested since neither prednisone nor prednisolone was administered to any of the healthy subjects. Furthermore, though severe hepatic and renal impairment has been reported to alter drug pharmacokinetics [32,33], including abiraterone exposure [34], this was unlikely to affect abiraterone pharmacokinetics in this analysis owing to the population assessed. The molecular markers related to liver function (e.g., aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum albumin, total protein) as well as renal function (e.g., creatinine clearance) were explored using stepwise regression analysis.…”

Evaluation of Carbazeran 4-Oxidation and O6-Benzylguanine 8-Oxidation as Catalytic Markers of Human Aldehyde Oxidase: Impact of Cytosolic Contamination of Liver Microsomes

“…Control protein binding experiment was performed on human liver microsomes (100 mg) with drugs known to be highly bound to microsomal or plasma proteins; i.e., gefitinib (1 mM) (Burns et al, 2015) and abiraterone (1 mM). (Marbury et al, 2014). Initial experiments with buffer (no enzymes) and a drug (carbazeran, O 6 -benzylguanine, gefitinib, or abiraterone) were conducted to ensure that equilibrium was achieved after 4 hours.…”

Phase‐1 study of abiraterone acetate in chemotherapy‐naïve Japanese patients with castration‐resistant prostate cancer

“…The plasma was immediately stored at −20°C. Samples were analyzed using a validated liquid chromatography‐tandem mass spectrometry (LC/MS/MS) method used in previous studies . The lower limit of quantification (LLOQ) was 0.220 ng/mL for AA and abiraterone.…”

“…Samples were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC ⁄ MS ⁄ MS) method used in previous studies. (19) The lower limit of quantification (LLOQ) was 0.220 ng ⁄ mL for AA and abiraterone. Pharmacokinetic parameters, including area under the concentration-time curve (AUC), maximum concentration (C max ), time to C max (t max ) and elimination half-life (t 1/2 ) were evaluated for both analytes.…”