A phase I, open-label, single-dose, mass balance study of 14C-labeled abiraterone acetate in healthy male subjects

Abstract

1. Metabolic disposition of (14)C-abiraterone acetate (AA), a prodrug of abiraterone was assessed in a phase I, open-label, single-dose (1000 mg, approximately 100 μCi) study in healthy males (18-55 years, N = 8). Blood, urine, and faecal samples were obtained at specified timepoints for determination of abiraterone concentrations in the plasma, total radioactivity (TR), and the metabolite profile. 2. Most plasma AA concentrations were below the limit of quantification. The mean maximum plasma concentration (Cmax) of abiraterone was 10.4 ng/mL, mean area under the plasma concentration-time curve (AUC) from 0 to the last measurable plasma concentration (AUC0-last) was 74.8 ng·h/mL. The exposures for TR in plasma (Cmax = 3429 ng·eq/mL; AUC0-last = 26,683 ng eq·h/mL) and whole blood (Cmax = 1836 ng·eq/mL; AUC0-last = 12,162 ng·eq·h/mL) were >300-fold higher than abiraterone exposure in plasma. The majority of TR resided in the plasma compartment of blood. 3. Main circulating metabolites were abiraterone sulfate and N-oxide abiraterone sulfate. The main metabolite excreted in urine was N-oxide abiraterone sulfate (4.22% of TR). Major components of TR in faeces were unchanged AA (55.3% of TR) and abiraterone (22.3% of TR). Mean recovery of TR in faeces was 87.9%, indicating faeces as primary route of excretion.

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

“…In that study, repeated dosing of abiraterone acetate plus prednisone with high-fat meals resulted only in an approximately twofold higher abiraterone exposure than the modified fasting state and there was negligible change in abiraterone exposure with low-fat meals [36]. The difference between the outcomes of these two studies might be interpreted in terms of changes in the absorption characteristics between healthy subjects [1,13] and patients with mCRPC ( Table 3). The results of the PCR2008 study were, unfortunately, not available at the inception of this population pharmacokinetic analysis and therefore were not included in this study.…”

“…The pharmacokinetic properties of abiraterone have been studied in healthy subjects and in patients with mCRPC [1,5,7,13]. In studies of healthy volunteers, abiraterone plasma concentrations increase rapidly following administration of a single 1,000 mg oral dose of abiraterone acetate, and reach the maximum plasma concentration (C max ) in approximately 2 h [13].…”

“…The metabolism and elimination of abiraterone have been studied extensively in vitro in human liver microsomes and cryopreserved hepatocyte preparations [12] and in a mass balance study of radioactive abiraterone acetate in healthy subjects [1]. Shortly after administration, ester hydrolysis rapidly converts abiraterone acetate to its active metabolite abiraterone.…”

“…Therefore, treatment that suppresses androgen production at extragonadal sites remains valuable in the treatment of metastatic CRPC (mCRPC). Abiraterone acetate is the prodrug of abiraterone, a selective and irreversible inhibitor of 17a-hydroxylase/C17, 20-lyase [cytochrome P450 (CYP) 17], a key enzyme in the androgen-biosynthesis pathway [1][2][3]. Abiraterone acetate administration leads to inhibition of adrenal and intratumoral testosterone biosynthesis, inhibiting residual androgen signaling used to propagate prostate tumor progression [3][4][5][6][7].…”

In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity

“…The calculated R values (= 1 + [I] /K i ]) were greater than 1.1 for abiraterone and its metabolites, thus pointing toward the need for a clinical study to assess the interaction further. Although the concentrations of abiraterone acetate in blood were below the LLOQ of the assay in the vast majority of subjects (Acharya et al, 2012(Acharya et al, , 2013, the concentration in the liver is unknown, and therefore in vitro testing was conducted. The inhibition of CYP2C8 by abiraterone and its metabolites was reversible, as no evidence of time-dependent inhibition was seen.…”