(M1430-05-31) Development and Application of PBPK Models for Cariprazine and Its Active Metabolites to Predict CYP3A-Mediated Drug-Drug Interactions and Inform Dose Adjustment Strategies

Purpose: Cariprazine (CAR) is an oral dopamine D3/D2 receptor partial agonist approved by the US FDA for the treatment of schizophrenia, mania or mixed episodes associated with bipolar I disorder, depressive episodes associated with bipolar I disorder, and adjunctive therapy to antidepressant for the treatment of major depressive disorder in adults. CAR is extensively metabolized by CYP3A4 into two active metabolites—desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR)—which contribute to its clinical efficacy. Given the long half-life of DDCAR (approximately 1 to 3 weeks), short-term standard clinical drug-drug interaction (DDI) studies do not fully capture the extent of the DDI, especially with chronic co-administration of CYP3A4 inhibitors. This work aimed to develop and verify a physiologically-based pharmacokinetic (PBPK) model for CAR and its active metabolites, and to use these models to predict DDI outcomes and evaluate potential dose adjustments in patients receiving concomitant CYP3A4 inhibitor therapy.

Methods: PBPK models for CAR, DCAR, and DDCAR were developed using a combination of preclinical and clinical data, including physicochemical properties, passive permeability, in vitro metabolism, and human absorption, distribution, metabolism, and excretion (ADME) data from a radiolabeled study. Clinical pharmacokinetic (PK) data from healthy subjects (single doses of 1 mg and 2 mg; multiple doses of 0.5 mg) and from patients with schizophrenia (doses ranging from 0.5 mg to 18 mg/day) were incorporated. The parent and metabolites models were linked to reflect sequential metabolite formation and disposition. Model verification was conducted by comparing simulations to observed data from standalone DDI studies involving ketoconazole (a strong CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor). Simulations were then used to explore the effect of steady-state CYP3A4 inhibition on total CAR (the sum of CAR, DCAR and DDCAR) exposure at steady state and to evaluate dose reduction strategies using commercially available dose strengths.

Results: The PBPK models accurately captured the pharmacokinetics of CAR and its metabolites across dosing regimens in both healthy volunteers and patients. Model predictions of DDIs at steady state showed significant increases in total CAR exposure during co-administration with CYP3A4 inhibitors. Ketoconazole was predicted to increase steady-state Cmax and AUC of total CAR by approximately 5.5-fold and 6-fold, respectively, while fluconazole produced up to a 3-fold increase. These predictions at steady state exceeded the extent of DDIs observed in short-term clinical studies, highlighting the importance of steady-state modeling. Simulations suggested that lower doses than previously recommended in the USPI should be used to maintain target exposure levels and reduce the risk of adverse effects in patients co-administered strong or moderate CYP3A4 inhibitors.

Conclusion: Linked PBPK models for CAR, DCAR, and DDCAR were successfully developed and validated, providing a reliable tool for predicting drug exposure under monotherapy and DDI scenarios. These models support evidence-based dose adjustments for cariprazine during concomitant use with CYP3A4 inhibitors, especially for long-term therapy. PBPK modeling offers a valuable approach to optimize cariprazine treatment by enhancing safety and therapeutic consistency in complex clinical settings. This PBPK modeling successfully led to an update in the dose recommendation for cariprazine in concomitant use of strong or moderate CYP3A4 inhibitors in the USPI.

Acknowledgements: The cariprazine clinical trials and this analysis were funded by AbbVie Inc. and Gedeon Richter Plc. AbbVie played a role in model development and validation, data interpretation, manuscript development, and publication approval. All authors are employees of AbbVie and may hold stock or stock options in AbbVie.