Optimizing aprocitentan dosing in elderly Chinese patients with resistant hypertension: a PBPK/PD-circadian rhythm modeling study.
Jia Mengqi M, Xu Zihan Z, Qian Fangyi F, Zhang Lesheng L et al.
Aprocitentan is a dual endothelin receptor antagonist for resistant hypertension (RH), but its optimal use in elderly Chinese patients remains unclear. This study aimed to develop an integrated physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD)-circadian rhythm model to suggest precision dosing and administration-time optimization in this special population. A PBPK model was developed using published clinical pharmacokinetic data and linked to a direct-effect sigmoid maximal effect model. Circadian blood pressure (BP) variation was described by a triple-harmonic cosine function. After validation against independent pharmacokinetic (PK) and PD datasets, the model was extrapolated to elderly Chinese patients by incorporating age-related physiology, uridine 5'-diphospho-glucuronosyltransferase 1A1 activity variability, and mild hepatic impairment. Sensitivity analyses and simulations were performed to evaluate exposure, BP response, and dosing time. The model showed acceptable predictive performance. Sensitivity analyses indicated that aprocitentan exposure was mainly influenced by ionization-, binding-, and distribution-related parameters. Plasma unbound fraction and liver volume were the major determinants of cumulative and steady-state area under the curve (AUC), while lipophilicity predominantly affected early exposure, mean residence time, and terminal half-life. Compared with healthy elderly Caucasian subjects, simulated steady-state AUC increased by 20.6% in elderly Chinese patients and by 52.5% in those with mild hepatic impairment. Among the simulated regimens, 6.25 mg once daily provided the most balanced exposure profile and maintained AUC and maximum plasma concentration within the prespecified reference range in both populations. The model identified 12:00-13:00 as an alternative administration window associated with a favorable simulated 24-hour BP profile. Under the model-predicted regimen, simulated reductions in systolic BP/diastolic BP were 13.04/8.97 mmHg in elderly Chinese RH patients and 13.63/9.37 mmHg in those with mild hepatic impairment, with 24-hour BP remaining mainly within the Grade 1 hypertension range. This study established an integrated PBPK/PD-circadian rhythm model for aprocitentan in elderly Chinese patients with RH. The simulations identified 6.25 mg once daily and midday administration as candidate strategies for further clinical evaluation. These findings are hypothesis-generating and require prospective PK/PD, ambulatory BP, safety, adherence, and clinical validation before implementation in clinical practice.