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

被引:2
作者
Brussee, Janneke M. [1 ]
Sidharta, Patricia N. [1 ]
Dingemanse, Jasper [1 ]
Krause, Andreas [1 ]
机构
[1] Idorsia Pharmaceut Ltd, Dept Clin Pharmacol, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
关键词
Pharmacokinetics; Hypertension; Resistant hypertension; Aprocitentan; Population modeling; SERUM CREATININE;
D O I
10.1007/s10928-024-09902-1
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 and 600 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 exposure 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.
引用
收藏
页码:243 / 252
页数:10
相关论文
共 28 条
  • [1] [Anonymous], 2020, R: A language and environment for statistical computing [Computer software manual]
  • [2] A novel method based on unbiased correlations tests for covariate selection in nonlinear mixed effects models: The COSSAC approach
    Ayral, Geraldine
    Si Abdallah, Jean-Francois
    Magnard, Claude
    Chauvin, Jonathan
    [J]. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, 2021, 10 (04): : 318 - 329
  • [3] Ways to fit a PK model with some data below the quantification limit
    Beal, SL
    [J]. JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 2001, 28 (05) : 481 - 504
  • [4] Aprocitentan and the endothelin system in resistant hypertension
    Clozel, Martine
    [J]. CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 2022, 100 (07) : 573 - 583
  • [5] A note on BIC in mixed-effects models
    Delattre, Maud
    Lavielle, Marc
    Poursat, Marie-Anne
    [J]. ELECTRONIC JOURNAL OF STATISTICS, 2014, 8 : 456 - 475
  • [6] Delyon B, 1999, ANN STAT, V27, P94
  • [7] Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment
    Fontes, Magda S. C.
    Dingemanse, Jasper
    Halabi, Atef
    Tomaszewska-Kiecana, Monika
    Sidharta, Patricia N.
    [J]. SCIENTIFIC REPORTS, 2022, 12 (01)
  • [8] Multiple-Dose Pharmacokinetics, Safety, and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Healthy Japanese and Caucasian Subjects
    Fontes, Magda S. C.
    Dingemanse, Jasper
    Sidharta, Patricia N.
    [J]. CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, 2021, 10 (07): : 718 - 725
  • [9] Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet
    Gueneau de Mussy, Pierre
    Sidharta, Patricia N.
    Wuerzner, Gregoire
    Maillard, Marc P.
    Guerard, Nicolas
    Iglarz, Marc
    Flamion, Bruno
    Dingemanse, Jasper
    Burnier, Michel
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2021, 109 (03) : 746 - 753
  • [10] Idorsia Pharmaceuticals Ltd, 2022, BIOEQ STUD DIFF APR