Towards a Quantitative Understanding of Aficamten Clinical Pharmacology: Pharmacokinetic‐Cardiodynamic Modeling to Support Safety and Efficacy

. LVOT-G slope was ~10-fold steeper vs. LVEF, suggesting a relatively large therapeutic window. The commercial regimen allows for individualized flexible echocardiography-based dose titration (every 2-8 weeks) from 5 to 20 mg once daily and flexible maintenance dose monitoring. CTS demonstrated minimal differences in population progression of LVOT-G < 30 mmHg and LVEF < 50% between evaluated dose-titration frequencies (every 2, 4, 6, or 8 weeks) over the first 6 months of treatment, supporting a 2-8 week window for dose titration. With maintenance doses, the probability of maintaining LVOT-G < 30 mmHg (~60%) was high and the probability of occurrences of LVEF < 50% (~3%) was low. Therefore, this regimen should maintain safe and efficacious cardiodynamics while increasing convenience and access for patients with oHCM.