Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension

Publication: J Pharmacokinet Pharmacodyn


Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors(covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and600 mg. The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance. The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence expo-sure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.

By Janneke M. Brussee, Patricia N. Sidharta, Jasper Dingemanse, Andreas Krause