The PBPK model predicted that aficamten exposure is comparable between Chinese and Caucasian populations, that broad-spectrum CYP inhibitors (amiodarone, fluconazole) and strong inducers (carbamazepine, rifampicin) substantially change its exposure, and that CYP2D6 intermediate metabolizers receiving fluconazole or amiodarone are potentially sensitive scenarios requiring clinical confirmation.
A whole-body PBPK model of aficamten was developed from Caucasian clinical data and extrapolated to the Chinese population.
Key aficamten pharmacokinetic parameters were comparable between Caucasian and Chinese populations in ethnic sensitivity analysis.
Predicted DDI magnitudes in the Chinese population were generally consistent with the corresponding Caucasian DDI simulations.
Broad-spectrum CYP inhibitors were predicted to increase aficamten exposure, with fluconazole having a larger effect than amiodarone.
Strong CYP inducers were predicted to decrease aficamten exposure, with rifampicin having a larger effect than carbamazepine.
CYP2D6 intermediate metabolizers receiving fluconazole or amiodarone were predicted to have higher aficamten exposure than CYP2D6 normal metabolizers.
The model-based findings provide quantitative DDI risk information for Chinese subjects but require clinical confirmation.
Aficamten is a newer drug for obstructive hypertrophic cardiomyopathy, a condition in which the heart muscle thickens and obstructs blood flow. Most studies of how the body handles this drug have been done in Caucasian people. Because the drug is broken down by several liver enzymes (CYP enzymes), and these enzymes can work differently across ethnic groups, researchers wanted to know whether drug interactions might differ in Chinese patients. The researchers used a computer-based whole-body model, built from Caucasian clinical data and adapted to Chinese physiology. The model predicted that blood levels of aficamten would be similar in Chinese and Caucasian people, and that drug-interaction effects would be generally consistent between the groups. Drugs that block liver enzymes, such as amiodarone and fluconazole, were predicted to raise aficamten exposure by about 1.4-fold and 2.3-fold. Drugs that boost enzyme activity, such as carbamazepine and rifampicin, were predicted to lower exposure by 35% and 71%. The model also suggested that people who are intermediate metabolizers for the CYP2D6 enzyme, and who also take fluconazole or amiodarone, could have notably higher aficamten levels than normal metabolizers. This research suggests that these combinations may deserve particular attention. These are computer predictions only, and the authors note they must be confirmed in clinical studies.</br>
Wang Z, Wu X, Jia R, Wang H. (2026). Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions of Aficamten in the Chinese Population.. Drug design, development and therapy. https://doi.org/10.2147/DDDT.S637138