PBPK Modeling in Regulatory Review, Product Labeling and Safety Monitoring

Physiologically-based pharmacokinetic (PBPK) modeling can address various questions raised in drug development and regulatory review, and is used most extensively to predict and quantify the extent of drug-drug interactions (DDIs) from both in vitro and clinical data. This assists with dose selection and the design of clinical studies as well as informing decisions relating to product labeling. Here we present some recent examples of the role of PBPK modeling and how the Simcyp® Simulator has been used in the regulatory approvals process.

Modeling and simulation was used extensively by Janssen® Pharmaceuticals Inc, and FDA reviewers in the development of ibrutinib (Imbruvica™) – indicated for the treatment of patients with mantle cell lymphoma (MCL). Models built using in vitro data were validated using clinical data on the observed effects of both a strong CYP3A4 inhibitor and a strong inducer on ibrutinib exposure. Simulations then predicted the effects of a moderate CYP3A4 inducer and other CYP3A4 inhibitors (strong, moderate and weak) on ibrutinib exposure, as well as investigating the impact of dose staggering and dose adjustment.2