Jisoo Song1, Sungyeun Bae1, Kyung-Sang Yu1, In-Jin Jang1, SeungHwan Lee
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital
Objective Abiraterone acetate is an anti-androgen medication used for patients with prostate cancer not responsive to standard hormone therapy, converted into its active metabolite abiraterone in vivo [1]. As a biopharmaceutical classification system class IV compound, abiraterone acetate has low solubility and permeability, leading to poor oral bioavailability and highly variable absorption [2]. Some studies have reported a double-peak in plasma concentration of abiraterone due to pH-dependent solubility in the gastrointestinal tract [3, 4]. While several population pharmacokinetic (popPK) models of abiraterone have been developed, none have accounted for this double-peak phenomenon. This study aimed to develop a popPK model of abiraterone in healthy Korean, providing insights into its absorption characteristics. Methods A popPK analysis of abiraterone was conducted using nonlinear mixed-effects modeling in NONMEM (version 7.5.1). The dataset included 1,106 plasma abiraterone concentrations from 79 healthy subjects who participated in two clinical trials, each receiving a single 1000 mg oral dose of abiraterone acetate. The base model development involved evaluating one-, two-, and three-compartment models. Various absorption models with or without lag time were explored, including zero-order, first-order, Erlang-type, transit compartment, and mixed zero-order and first-order absorption. Inter-individual variability (IIV) was estimated using key PK parameters. Proportional, additive, and combination error models were tested for the residual error model, which accounted for unexplained variability. Covariate analysis included age, height, body weight, body mass index (BMI), aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), and serum creatinine. Parameter estimates were compared with previously published PK parameters of abiraterone and with non-compartmental analysis (NCA) results from the same dataset. The final model was evaluated based on the objective function value, goodness-of-fit (GOF) plots, visual predictive check (VPC), and bootstrap analysis. Results The PK of abiraterone following oral administration was well characterized by a two-compartment model. The double-peak phenomenon was successfully demonstrated using a mixed zero-order and first-order absorption model with lag time. The population estimates for apparent clearance (CL/F), apparent volume of distribution (Vd/F), absorption rate constant (Ka), duration of zero-order absorption (D2), and lag time (ALAG1) were 1610 L/h, 5030 L, 1.03/h, 22.1 h, and 0.245 h. These estimates were consistent with the NCA results and previous findings [5]. Residual variability was best described using a proportional error model. BMI for CL/F and serum GGT levels for both CL/F and Vd/F were covariates included in the final model. The GOF plots showed that the model-predicted concentrations were generally in agreement with the observed concentrations. Most of the observation values of abiraterone were within the 90% prediction interval of VPC, and the final model parameters were in accordance with the bootstrap results. Conclusions We developed a popPK model of abiraterone in healthy subjects using a two-compartment disposition with linear elimination. The model successfully captured the double peak phenomenon with a mixed zero-order and first-order absorption process, providing insights into abiraterone’s complex absorption. By enhancing plasma concentration predictions, this model can support dose optimization strategies effectively.
1. Harshman, L.C. and M.E. Taplin, Abiraterone acetate: targeting persistent androgen dependence in castration-resistant prostate cancer. Adv Ther, 2013. 30(8): p. 727-47. 2. Schultz, H.B., et al., Oral formulation strategies to improve the bioavailability and mitigate the food effect of abiraterone acetate. Int J Pharm, 2020. 577: p. 119069. 3. Liu, Y., et al., Development of Abiraterone Acetate Nanocrystal Tablets to Enhance Oral Bioavailability: Formulation Optimization, Characterization, In Vitro Dissolution and Pharmacokinetic Evaluation. Pharmaceutics, 2022. 14(6). 4. Papangelou, A., Olszanski, A.J., Stein, C.A. et al. , The Effect of Food on the Absorption of Abiraterone Acetate from a Fine Particle Dosage Form: A Randomized Crossover Trial in Healthy Volunteers. . Oncol Ther, 2017. 5(161–170). 5. Clinical Pharmacology Review, Zytiga. 2010, Center for Drug evaluation and Research.
Reference: PAGE 33 (2025) Abstr 11680 [www.page-meeting.org/?abstract=11680]
Poster: Drug/Disease Modelling - Other Topics