58 Background: Abiraterone acetate (AA) is an effective therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). AA is metabolized to abiraterone, an androgen biosynthesis inhibitor. We performed population pharmacokinetic (PK) analyses to estimate PK parameters after a 1,000 mg/d oral dose of AA in patients with mCRPC with and without prior chemotherapy and after a one-time 1,000 mg dose in healthy volunteers, to determine consistency between groups. Methods: Studies included in analysis: COU-AA-302 (pre-chemotherapy mCRPC); COU-AA-301 and COU-AA-006 (post-docetaxel mCRPC); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 360 subjects were analyzed using nonlinear mixed-effects modeling. Results: A two-compartment model with three-transit compartments following sequential zero-first order kinetics was used to characterize the systemic absorption of abiraterone. Absorption-related parameters were affected by food intake. Abiraterone PK was characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1505 L/h) compared with healthy subjects (2240 L/h), and by large apparent central (5630 L) and peripheral volumes of distribution (17,400 L). PK of abiraterone was similar in chemotherapy-naïve and chemotherapy-pretreated patients and was characterized by a relatively high between- and within-subject variability (eg, between-subject coefficient of variation [CV%] for relative bioavailability in the clinical studies was 61.1% and the CV% for within-subject variability was 71.3%). No factors other than food intake and patient-healthy volunteer status impacted PK. Conclusions: Based on this population PK model, the recommended 1,000 mg/d dose of AA results in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy status. The food effect on absorption-related parameters in this analysis confirms current dosing instructions for AA. Clinical trial information: NCT00638690, NCT00887198.
Mycotoxins such as aflatoxin B1 (AFB1) are secondary fungal metabolites present in food commodities and part of one's daily exposure, especially in certain regions, e.g., sub-Saharan Africa. AFB1 is mostly metabolised by cytochrome P450 (CYP) enzymes, namely, CYP1A2 and CYP3A4. As a consequence of chronic exposure, it is interesting to check for interactions with drugs taken concomitantly. A physiologically based pharmacokinetic (PBPK) model was developed based on the literature and in-house-generated in vitro data to characterise the pharmacokinetics (PK) of AFB1. The substrate file was used in different populations (Chinese, North European Caucasian and Black South African), provided by SimCYP® software (v21), to evaluate the impact of populations on AFB1 PK. The model's performance was verified against published human in vivo PK parameters, with AUC ratios and Cmax ratios being within the 0.5-2.0-fold range. Effects on AFB1 PK were observed with commonly prescribed drugs in South Africa, leading to clearance ratios of 0.54 to 4.13. The simulations revealed that CYP3A4/CYP1A2 inducer/inhibitor drugs might have an impact on AFB1 metabolism, altering exposure to carcinogenic metabolites. AFB1 did not have effects on the PK of drugs at representative exposure concentrations. Therefore, chronic AFB1 exposure is unlikely to impact the PK of drugs taken concomitantly.
