Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions of Aficamten in the Chinese Population

Q: What is the clinical evidence from this study?

Population: Obstructive hypertrophic cardiomyopathy (oHCM). Intervention: Aficamten co-administered with CYP inhibitors (itraconazole, verapamil, paroxetine, fluoxetine, amiodarone, fluconazole) or CYP inducers (carbamazepine, rifampicin) vs. Aficamten 10 mg oral alone (and comparison between Chinese and Caucasian populations, as well as CYP2D6 intermediate vs normal metabolizers). Primary outcome: Predicted pharmacokinetic exposure parameters of aficamten (AUC0-infinity, Cmax, and geometric mean ratios [GMR] under DDI scenarios).

Q: What does this research mean for the field?

Aficamten pharmacokinetic exposure is comparable between Chinese and Caucasian populations, with drug-drug interaction magnitudes showing similar sensitivity to broad-spectrum CYP inhibitors and inducers, particularly elevating exposure in CYP2D6 intermediate metabolizers. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Ziyang Wang; Xiaofei Wu; Ranran Jia; Hongyun Wang

doi:10.2147/dddt.s637138

October 1, 2026Drug Design Development and TherapyOpen Access

Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions of Aficamten in the Chinese Population

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Key result

Amiodarone increases aficamten exposure ~43%, while rifampicin substantially reduces it.

Why the study?

Although extensive clinical pharmacology studies of aficamten for obstructive hypertrophic cardiomyopathy exist in Caucasian populations, data on drug-drug interaction risks in Chinese populations were limited despite known inter-ethnic differences in cytochrome P450-mediated metabolism.

Does co-administration with CYP inhibitors or inducers, or inter-ethnic differences between Chinese and Caucasian populations, alter the pharmacokinetic exposure of aficamten?

Key Points

To evaluate potential drug-drug interaction risks and changes in aficamten systemic exposure in the Chinese population using a physiologically based pharmacokinetic model.
A whole-body physiologically based pharmacokinetic (PBPK) model of aficamten was constructed using Caucasian clinical data across single doses (10, 25, 40, 50, and 75 mg) and extrapolated to the Chinese population using population-specific physiological parameters and CYP abundances.
Model predictions were validated against observed clinical datasets from Chinese subjects receiving 10 mg and 20 mg doses, targeting predicted-to-observed ratios within a 0.5- to 2.0-fold acceptance range.
Simulations assessed inter-ethnic pharmacokinetic differences and quantified drug-drug interactions with CYP inhibitors (amiodarone, fluconazole) and inducers (carbamazepine, rifampicin), including stratification by CYP2D6 metabolizer status.
Predicted Chinese-to-Caucasian exposure ratios were 1.13 for Cmax and 1.07 for AUC0-∞ at both 10 mg and 40 mg doses, falling entirely within the 0.80–1.25 equivalence window.
Co-administration with the broad-spectrum CYP inhibitors amiodarone and fluconazole increased aficamten AUC0-∞ by 1.43- and 2.27-fold, respectively, whereas strong inducers carbamazepine and rifampicin decreased exposure by 35% and 71%, respectively.
Under simulated fluconazole or amiodarone co-administration, aficamten AUC0-∞ in CYP2D6 intermediate metabolizers was 2.22-fold and 1.50-fold higher than in CYP2D6 normal metabolizers, respectively.

Structured PICO

Does co-administration with CYP inhibitors or inducers, or inter-ethnic differences between Chinese and Caucasian populations, alter the pharmacokinetic exposure of aficamten?

P

Population

Physiologically based pharmacokinetic (PBPK) modeling study using virtual Chinese and Caucasian populations (100 simulated individuals per cohort) calibrated against Phase I clinical data from healthy Caucasian (n=57) and Chinese (n=16) subjects.

I

Intervention

Oral aficamten (single ascending doses of 10, 20, 25, 40, 50, and 75 mg) evaluated alone and in simulated co-administration scenarios with CYP inhibitors (itraconazole 200 mg qd, verapamil 80 mg tid, paroxetine 40 mg qd, fluoxetine 40 mg qd, amiodarone 200 mg qd, fluconazole 400 mg qd) and CYP inducers (carbamazepine, rifampicin).

C

Comparator

Aficamten administered alone (for DDI comparisons), Caucasian virtual population (for inter-ethnic comparisons), and CYP2D6 normal metabolizers (for phenotype comparisons).

O

Outcome

Pharmacokinetic exposure parameters of aficamten, specifically area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) and maximum plasma concentration (Cmax), quantified as predicted-to-observed ratios and geometric mean ratios (GMR) under co-administration or between populations.surrogate

PBPK modeling demonstrates that while baseline aficamten exposure is comparable between Chinese and Caucasian individuals, co-administration with broad-spectrum CYP inhibitors (fluconazole, amiodarone) or strong CYP inducers (carbamazepine, rifampicin) substantially alters aficamten exposure in Chinese subjects, especially in CYP2D6 intermediate metabolizers.

Limitations

Model-based findings require clinical confirmation
A dedicated Chinese population database was not available in PK-Sim, requiring use of the built-in Japanese population database as the starting physiological framework
Isolated deviation in Cmax prediction for the 75 mg Caucasian cohort likely due to limited sample size (n=1) and intra-subject variability
Dedicated Chinese population database was not available in PK-Sim, requiring use of the built-in Japanese population database as the starting physiological framework
Only one subject (n=1) was enrolled in the 75 mg Caucasian cohort, resulting in a discrepancy between simulated and observed Cmax likely attributable to limited sample size and intra-subject variability
Model-based findings and scenario-based uncertainty ranges require clinical confirmation

Implication

Predicted DDI effects may warrant exposure monitoring with CYP modulators in Chinese patients; leaves open prospective validation of these PBPK predictions.

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 (AUC 0-∞ , C max , and T 1/2 ) 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 AUC 0-∞ 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 AUC 0-∞ 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.

Discussion

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Cite This Study

Wang et al. (2026) studied Obstructive hypertrophic cardiomyopathy (oHCM). Aficamten co-administered with CYP inhibitors (itraconazole, verapamil, paroxetine, fluoxetine, amiodarone, fluconazole) or CYP inducers (carbamazepine, rifampicin) vs. Aficamten 10 mg oral alone (and comparison between Chinese and Caucasian populations, as well as CYP2D6 intermediate vs normal metabolizers) was evaluated on Predicted pharmacokinetic exposure parameters of aficamten (AUC0-infinity, Cmax, and geometric mean ratios [GMR] under DDI scenarios). Co-administration of aficamten with amiodarone and fluconazole increased predicted AUC0-∞ by 1.43- and 2.27-fold in Chinese subjects, while carbamazepine and rifampicin reduced exposure by 35% and 71%.

synapsesocial.com/papers/6adaa50c59c5e832a62b4a89 https://doi.org/10.2147/dddt.s637138

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Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions of Aficamten in the Chinese Population

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions of Aficamten in the Chinese Population

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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