Mechanistic Physiologically Based Pharmacokinetic Modeling to Predict CYP3A4-Mediated Drug–Drug Interactions of Flumatinib as Both a Victim and a Perpetrator

Background: Flumatinib is an orally administered tyrosine kinase inhibitor (TKI) that selectively targets the BCR-ABL fusion protein and is approved in China for treating adult patients with chronic-phase chronic myeloid leukemia (CML-CP). It is mainly metabolized by CYP3A4 and CYP2C8 and exhibits time-dependent inhibition (TDI) of CYP3A4. However, its clinical drug–drug interaction (DDI) potential remains insufficiently characterized. Methods: A series of in vitro experiments were conducted using human liver microsomes and Caco-2 cells to characterize the pharmacokinetic properties of flumatinib, including CYP3A4 time-dependent inhibition and key physicochemical inputs relevant to systemic disposition. These data, together with in silico estimates and clinical pharmacokinetic profiles, were integrated into a mechanistic physiologically based pharmacokinetic (PBPK) model for Chinese subjects. Predictive performance was assessed by comparing simulated and clinically observed exposure ratios. Results: The PBPK model demonstrated robust performance, with predicted-to-observed exposure ratios predominantly within the 0.5– 2.0-fold range. DDI simulations indicated that, as a perpetrator, flumatinib exerted minimal impact on CYP3A4 substrate exposure. However, when acting as a victim, co-administration with strong CYP3A4 inhibitors (itraconazole, ketoconazole) increased flumatinib AUC 0-72h by approximately 12-fold (AUCR = 11.65– 12.96), whereas rifampicin decreased C max and AUC 0-72h by 2.4- and 4.7-fold (C max R = 0.41, AUCR = 0.21), respectively. Conclusion: Flumatinib shows negligible perpetrator potential but is highly sensitive to CYP3A4 modulation. PBPK-informed DDI assessment supports cautious co-administration with strong CYP3A4 inhibitors or inducers and guides its rational clinical use. Keywords: flumatinib, PBPK model, drug–drug interaction, CYP3A4 inhibitor, CYP3A4 inducer