ArticleClinical pharmacokinetics2023
Unraveling Complexities in the Absorption and Disposition Kinetics of Abiraterone via Iterative PBPK Model Development and Refinement.
Article in Clinical pharmacokinetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed, 6 citations in OpenAlex.
- Enhancing the pharmacokinetics of abiraterone acetate through lipid-based formulations: addressing solubility and food effect challenges.Drug delivery and translational research · 2025Article
- Enteric Coating Enhances the Biopharmaceutical Performance of a Silica-Lipid Formulation of Abiraterone Acetate.Pharmaceutics · 2025Article
- Multitarget Design of Steroidal Inhibitors Against Hormone-Dependent Breast Cancer: An Integrated In Silico Approach.International journal of molecular sciences · 2025Article
- Evaluation of exposure-response-safety relationship of model-informed low-dose 500 mg abiraterone acetate in prostate cancer patients.Cancer communications (London, England) · 2025Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
objectiveAbiraterone is a first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1), and its pharmacokinetic (PK) profile is susceptible to intrinsic and extrinsic variabilities. Potential associations between abiraterone concentrations and pharmacodynamic consequences in prostate cancer may demand further dosage optimization to balance therapeutic outcomes. Consequently, we aim to develop a physiologically based pharmacokinetic (PBPK) model for abiraterone via a middle-out approach to prospectively interrogate the untested, albeit clinically relevant, scenarios.
methodsTo characterize in vivo hydrolysis of prodrug abiraterone acetate (AA) and supersaturation of abiraterone, in vitro aqueous solubility data, biorelevant measurements, and supersaturation and precipitation parameters were utilized for mechanistic absorption simulation. CYP3A4-mediated N-oxidation and sulfotransferase 2A1-catalyzed sulfation of abiraterone were subsequently quantified in human liver subcellular systems. Iterative PBPK model refinement involved evaluation of potential organic anion transporting polypeptide (OATP)-mediated abiraterone uptake in transfected cells in the absence and presence of albumin.
resultsThe developed PBPK model recapitulated the duodenal concentration-time profile of both AA and abiraterone after simulated AA administration. Our findings established abiraterone as a substrate of hepatic OATP1B3 to recapitulate its unbound metabolic intrinsic clearance. Further consideration of a transporter-induced protein-binding shift established accurate translational scaling factors and extrapolated the sinusoidal uptake process. Subsequent simulations effectively predicted the PK of abiraterone upon single and multiple dosing.
conclusionOur systematic development of the abiraterone PBPK model has demonstrated its application for the prospective interrogation of the individual or combined influences of potential interindividual variabilities influencing the systemic exposure of abiraterone.
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