Drug Des Devel Ther. 2026 Oct 21;20:637138. doi: 10.2147/DDDT.S637138. eCollection 2026.
ABSTRACT
BACKGROUND: Aficamten is a next-generation cardiac myosin inhibitor (CMI) developed for the treatment of obstructive hypertrophic cardiomyopathy (oHCM). Although extensive clinical pharmacology studies have been conducted in Caucasian populations, limited information is available regarding drug-drug interaction (DDI) risks in the Chinese population. Given the contribution of multiple cytochrome P450 (CYP) enzymes to aficamten metabolism and inter-ethnic differences in CYP-mediated metabolic capacity, it is important to characterize DDI risks and associated changes in aficamten exposure in Chinese subjects.
METHODS: A whole-body physiologically-based pharmacokinetic (PBPK) model of aficamten was developed using clinical data from Caucasian subjects and extrapolated to the Chinese population. The PBPK model was subsequently applied to compare aficamten exposure between Chinese and Caucasian populations and to predict DDIs in Chinese subjects.
RESULTS: Ethnic sensitivity analysis indicated that the key PK parameters of aficamten (AUC0-∞, Cmax, and T1/2) were comparable between Caucasian and Chinese populations. Overall, the predicted DDI magnitudes in the Chinese population were generally consistent with the corresponding Caucasian DDI simulations. Specifically, the model predicted that co-administration with the broad-spectrum CYP inhibitors amiodarone and fluconazole increased the AUC0-∞ of aficamten by 1.43- and 2.27-fold, respectively, whereas the strong inducers carbamazepine and rifampicin decreased its exposure by 35% and 71%, respectively. Notably, under the simulated fluconazole or amiodarone co-administration scenarios, the predicted AUC0-∞ of CYP2D6 intermediate metabolizers (IMs) was 2.22-fold and 1.50-fold higher than that in CYP2D6 normal metabolizers (NMs), respectively.
CONCLUSION: The PBPK model predicted substantial changes in aficamten exposure with broad-spectrum CYP inhibitors (eg, amiodarone, fluconazole) and strong CYP inducers (eg, carbamazepine, rifampicin), and identified CYP2D6 IMs receiving fluconazole or amiodarone as potentially sensitive scenarios. These model-based findings provide quantitative information for DDI risk assessment in Chinese subjects but require clinical confirmation.
PMID:42928782 | PMC:PMC13695942 | DOI:10.2147/DDDT.S637138