Population pharmacokinetic/pharmacodynamic modeling of NH600001 reveals age-related differences in sedation response and supports individualized dosing in elderly patients

BACKGROUND: NH600001 is a novel intravenous anesthetic developed as a safer alternative to etomidate. Its pharmacokinetic/pharmacodynamic (PK/PD) profile and optimal dosing in elderly patients remain insufficiently characterized. This study aimed to develop a population PK/PD model of NH600001 and evaluate age‑related differences in disposition and sedation response. RESEARCH DESIGN AND METHODS: Data from seven clinical studies involving 457 subjects were pooled. Plasma concentrations, bispectral index (BIS), and modified observer's assessment of alertness/sedation (MOAA/S) were analyzed using nonlinear mixed‑effects modeling. A three‑compartment model with allometric scaling and effect‑compartment PD models were developed, followed by covariate analysis, bootstrap validation, visual predictive checks, exposure-response evaluation, and clinical simulations. RESULTS: Age category, concomitant alfentanil, population category, and sex significantly affected PK parameters. BIS and MOAA/S models adequately described NH600001‑induced sedation. Simulations showed that elderly subjects achieved BIS ≤ 60 more rapidly and maintained sedation longer than non‑elderly subjects at identical doses, with flat exposure-response relationships for recovery and safety endpoints. CONCLUSIONS: The PopPK/PD model characterizes age‑related variability in NH600001 and supports age‑tailored dosing strategies for precision anesthesia in elderly patients.