Physiologically‐Based Pharmacokinetic Model‐Informed Labeling for Cariprazine Drug Interactions With CYP3A Inhibitors

receptor antagonist approved for the treatment of a variety of psychiatric disorders. A clinical study examining short-term (4 days) drug-drug interactions (DDIs) between cariprazine and ketoconazole, a strong CYP3A4 inhibitor, guided cariprazine dosing adjustment recommendations in concomitant use with CYP3A4 inhibitors in the original US FDA marketing approval. However, didesmethyl-cariprazine (DDCAR), a major active metabolite of cariprazine, takes 4-8 weeks to reach steady-state plasma concentration. Therefore, longer term clinical DDI studies would be needed to fully understand cariprazine DDIs but are greatly challenging. Regulatory agencies are increasingly encouraging the use of physiologically based pharmacokinetic (PBPK) modeling to evaluate DDIs. Here, we developed PBPK models of cariprazine, DCAR, and DDCAR that adequately described their plasma exposures across multiple Phase 1 or 2 clinical studies with cariprazine treatment alone or in combination with CYP3A inhibitors ketoconazole or erythromycin. The validated models predicted up to 6.0-fold, 2.9-fold, and 1.1-fold increases in total cariprazine (cariprazine + DCAR + DDCAR) exposure at steady state upon prolonged coadministration of strong, moderate, and weak CYP3A4 inhibitors, respectively. The PBPK models allowed for more optimal cariprazine dose adjustments with short-term and long-term concomitant use of strong and moderate CYP3A4 inhibitors. Model predictions led to an update in US prescribing information in November 2024 to inform on optimal cariprazine dose adjustment with concomitant use of CYP3A inhibitors. Updated recommendations had the objective of maintaining treatment efficacy while minimizing drug adverse effect risk.