Einzeltreffer — DigiBib

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.

Titel:	Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension.
Autor/in / Beteiligte Person:	Brussee, JM ; Sidharta, PN ; Dingemanse, J ; Krause, A
Zeitschrift:	Journal of pharmacokinetics and pharmacodynamics, Jg. 51 (2024-06-01), Heft 3, S. 243-252
Veröffentlichung:	New York : Springer ; <i>Original Publication</i>: Bristol, England ; New York, N.Y. : Kluwer Academic/Plenum Publishers, c2001-, 2024
Medientyp:	academicJournal
ISSN:	1573-8744 (electronic)
DOI:	10.1007/s10928-024-09902-1
Schlagwort:	Adult Aged Aged, 80 and over Female Humans Male Middle Aged Young Adult Antihypertensive Agents pharmacokinetics Antihypertensive Agents administration & dosage Antihypertensive Agents therapeutic use Dose-Response Relationship, Drug Glomerular Filtration Rate drug effects Pyrimidines pharmacokinetics Pyrimidines administration & dosage Pyrimidines therapeutic use Sulfonamides Endothelin Receptor Antagonists pharmacokinetics Endothelin Receptor Antagonists administration & dosage Hypertension drug therapy Models, Biological
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [J Pharmacokinet Pharmacodyn] 2024 Jun; Vol. 51 (3), pp. 243-252. <i>Date of Electronic Publication: </i>2024 Feb 08. MeSH Terms: Endothelin Receptor Antagonists* / pharmacokinetics ; Endothelin Receptor Antagonists* / administration & dosage ; Hypertension* / drug therapy ; Models, Biological* ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Antihypertensive Agents / pharmacokinetics ; Antihypertensive Agents / administration & dosage ; Antihypertensive Agents / therapeutic use ; Dose-Response Relationship, Drug ; Glomerular Filtration Rate / drug effects ; Pyrimidines / pharmacokinetics ; Pyrimidines / administration & dosage ; Pyrimidines / therapeutic use ; Sulfonamides References: Schlaich MP, Bellet M, Weber MA et al (2022) Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet 400:1927–1937. https://doi.org/10.1016/S0140-6736(22)02034-7. (PMID: 10.1016/S0140-6736(22)02034-736356632) ; Clozel M (2022) Aprocitentan and the endothelin system in resistant hypertension. Can J Physiol Pharmacol 100:573–583. https://doi.org/10.1139/cjpp-2022-0010. (PMID: 10.1139/cjpp-2022-001035245103) ; Yanagisawa M, Kurihara H, Kimura S et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415. https://doi.org/10.1038/332411a0. (PMID: 10.1038/332411a02451132) ; Iglarz M, Clozel M (2010) At the heart of tissue: endothelin system and end-organ damage. Clin Sci 119:453–463. https://doi.org/10.1042/CS20100222. (PMID: 10.1042/CS20100222) ; Schiffrin EL (2001) Role of endothelin-1 in hypertension and vascular disease. Am J Hypertens 14. https://doi.org/10.1016/s0895-7061(01)02074-x . :83S-89S. ; Trensz F, Bortolamiol C, Kramberg M et al (2019) Pharmacological characterization of Aprocitentan, a dual endothelin receptor antagonist, alone and in combination with blockers of the Renin Angiotensin System, in two models of experimental hypertension. J Pharmacol Exp Ther 368:462–473. https://doi.org/10.1124/jpet.118.253864. (PMID: 10.1124/jpet.118.25386430622171) ; Verweij P, Danaietash P, Flamion B et al (2020) Randomized dose-response study of the new dual endothelin receptor antagonist aprocitentan in hypertension. Hypertension 75:956–965. (PMID: 10.1161/HYPERTENSIONAHA.119.1450432063059) ; Sidharta P, Melchior M, Kankam MK, Dingemanse J (2019) Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects. Drug Des Devel Ther Volume 13:949–964. https://doi.org/10.2147/DDDT.S199051. (PMID: 10.2147/DDDT.S199051) ; Sidharta PN, Fischer H, Dingemanse J (2021) Absorption, distribution, metabolism, and excretion of Aprocitentan, a dual endothelin receptor antagonist, in humans. Curr Drug Metab 22:399–410. https://doi.org/10.2174/1389200222666210204202815. (PMID: 10.2174/138920022266621020420281533563190) ; Sidharta PN, Ulč I, Dingemanse J (2019) Single-dose pharmacokinetics and tolerability of Aprocitentan, a dual endothelin receptor antagonist, in subjects with severe renal function impairment. Clin Drug Investig 39:1117–1123. https://doi.org/10.1007/s40261-019-00837-x. (PMID: 10.1007/s40261-019-00837-x31435905) ; Fontes MSC, Dingemanse J, Halabi A et al (2022) Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment. Sci Rep 12:19067. https://doi.org/10.1038/s41598-022-22470-z. (PMID: 10.1038/s41598-022-22470-z363520549645340) ; Sidharta PN, Dingemanse J (2020) Effect of multiple-dose Aprocitentan Administration on the pharmacokinetics of midazolam in healthy male subjects. Eur J Drug Metab Pharmacokinet 45:227–234. https://doi.org/10.1007/s13318-019-00590-8. (PMID: 10.1007/s13318-019-00590-831773427) ; Sidharta PN, Dingemanse J (2020) Effects of multiple-dose administration of Aprocitentan on the pharmacokinetics of Rosuvastatin. Clin Pharmacol Drug Dev 9:995–1002. https://doi.org/10.1002/cpdd.815. (PMID: 10.1002/cpdd.81532592633) ; Fontes MSC, Dingemanse J, Sidharta PN (2021) Multiple-dose pharmacokinetics, Safety, and tolerability of Aprocitentan, a dual endothelin receptor antagonist, in healthy Japanese and caucasian subjects. Clin Pharmacol Drug Dev 10:718–725. https://doi.org/10.1002/cpdd.881. (PMID: 10.1002/cpdd.88133063477) ; Raebel MA, Ellis JL, Carroll NM et al (2012) Characteristics of patients with primary non-adherence to medications for hypertension, diabetes, and lipid disorders. J Gen Intern Med 27:57–64. https://doi.org/10.1007/s11606-011-1829-z. (PMID: 10.1007/s11606-011-1829-z21879374) ; Gueneau de Mussy P, Sidharta PN, Wuerzner G et al (2021) Effects of the dual endothelin receptor antagonist Aprocitentan on Body Weight and Fluid Homeostasis in healthy subjects on a high Sodium Diet. Clin Pharmacol Ther 109:746–753. https://doi.org/10.1002/cpt.2043. (PMID: 10.1002/cpt.204332897570) ; Sidharta PN, Brussee JM, Schultz A et al (2022) ACCP Abstract Booklet. Clin Pharmacol Drug Dev 11:1–112. https://doi.org/10.1002/cpdd.1151. (PMID: 10.1002/cpdd.1151) ; Idorsia Pharmaceuticals Ltd (2022) Bioequivalence Study of Different Aprocitentan Tablet Formulations. In: ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT05196399 . Accessed 26 Jun 2023. ; Beal SL (2001) Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 28:481–504. https://doi.org/10.1023/A:1012299115260. (PMID: 10.1023/A:101229911526011768292) ; Lixoft (2021) Monolix documentation. ; Delyon B, Lavielle M, Moulines E (1999) Convergence of a stochastic approximation version of the EM algorithm. Ann Stat 27:94–128. (PMID: 10.1214/aos/1018031103) ; Levey AS, Bosch JP, Breyer Lewis J et al (1999) A more Accurate Method to Estimate glomerular filtration rate from serum creatinine: a New Prediction equation. Ann Intern Med 130:461. https://doi.org/10.7326/0003-4819-130-6-199903160-00002. (PMID: 10.7326/0003-4819-130-6-199903160-0000210075613) ; Levey AS, Coresh J, Greene T et al (2006) Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. https://doi.org/10.7326/0003-4819-145-4-200608150-00004. (PMID: 10.7326/0003-4819-145-4-200608150-0000416908915) ; Ayral G, Si Abdallah J, Magnard C, Chauvin J (2021) A novel method based on unbiased correlations tests for covariate selection in nonlinear mixed effects models: the COSSAC approach. CPT Pharmacometrics Syst Pharmacol 10:318–329. https://doi.org/10.1002/psp4.12612. (PMID: 10.1002/psp4.12612337553458099437) ; Delattre M, Lavielle M, Poursat MA (2014) A note on BIC in mixed-effects models. Electron J Stat 8:456–475. https://doi.org/10.1214/14-EJS890. (PMID: 10.1214/14-EJS890) ; Krause A, Lowe P (2014) Visualization and communication of pharmacometric models with Berkeley Madonna. CPT Pharmacometrics Syst Pharmacol 3:116. https://doi.org/10.1038/psp.2014.13. (PMID: 10.1038/psp.2014.13) ; Marcoline FV, Furth J, Nayak S et al (2022) Berkeley Madonna Version 10–A simulation package for solving mathematical models. CPT Pharmacometrics Syst Pharmacol 11:290–301. https://doi.org/10.1002/psp4.12757. (PMID: 10.1002/psp4.12757350649658923725) ; R (2020) R: a Language and Environment for Statistical Computing. Version 3.6.1 and 4.0.4, 2002, R Foundation for Statistical Computing. Contributed Indexing: Keywords: Aprocitentan; Hypertension; Pharmacokinetics; Population modeling; Resistant hypertension Substance Nomenclature: 0 (Antihypertensive Agents) ; MZI81HV01P (aprocitentan) ; 0 (Endothelin Receptor Antagonists) ; 0 (Pyrimidines) ; 0 (Sulfonamides) Entry Date(s): Date Created: 20240209 Date Completed: 20240529 Latest Revision: 20240607 Update Code: 20240607

Klicken Sie ein Format an und speichern Sie dann die Daten oder geben Sie eine Empfänger-Adresse ein und lassen Sie sich per Email zusenden.

BibTeX Citavi, JabRef, u.a.
(Literaturverwaltung)

PDF kein Volltext!
(Merkzettel, Notizen)

RIS Endnote, Citavi u.a.
(Literaturverwaltung)

MODS
(XML zur Weiterverarbeitung)

oder

Wählen Sie das für Sie passende Zitationsformat und kopieren Sie es dann in die Zwischenablage, lassen es sich per Mail zusenden oder speichern es als PDF-Datei.

Gewünschter Zitations-Stil:

oder

Bitte prüfen Sie, ob die Zitation formal korrekt ist, bevor Sie sie in einer Arbeit verwenden. Benutzen Sie gegebenenfalls den "Exportieren"-Dialog, wenn Sie ein Literaturverwaltungsprogramm verwenden und die Zitat-Angaben selbst formatieren wollen.

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