Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions

Abstract

Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin‐only pill (PoP). Acceptance of COC drug‐drug interaction (DDI) assessment using PBPK is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE) DDI potential with COCs. Guidance recommends a clinical interaction study to be considered if, an investigational drug is a weak or moderate inducer, or a moderate/strong inhibitor, of CYP3A4. Therefore, availability of validated OC PBPK models within one software platform, will be useful in predicting the DDI potential with NCEs earlier in the clinical development. Thus, this work was focused on developing and validating PBPK models for progestins, DNG, DRSP, LNG and NET, within Simcyp®, and assessing the DDI potential with known CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampicin) with published clinical data. In addition, this work demonstrated confidence in the Simcyp® EE model for regulatory and clinical applications by extensive verification in 70+ clinical PK and CYP3A4 interaction studies. The results provide greater capability to prospectively model clinical CYP3A4 DDI with COCs using Simcyp® PBPK to interrogate the regulatory decision‐tree to contextualise the potential interaction by known perpetrators and NCEs, enabling model‐informed decision making, clinical study designs and delivering potential alternative COC options for women of childbearing potential.

Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically Based Pharmacokinetic, and First-Principal Models

“…It has been used to justify a biowaiver for a selected BCS 2 compounds [124] and determine the impact of different formulation factors such as solubility, particle size, size distribution, and food on the absorption of drugs [125][126][127][128][129][130][131]. The ADAM model is also available commercially, Symcyp®, and is used to predict the effect of drug release rate on the absorption [120,[132][133][134], to allow the optimization of paediatric drug [135,136], and to investigate drug-drug interactions [137]. Additional compartmental models are reviewed in Huang et al [4].…”