{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T21:30:40Z","timestamp":1761514240869,"version":"3.37.3"},"reference-count":27,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T00:00:00Z","timestamp":1534982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Serelaxin is a recombinant human relaxin\u20102 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Serum concentration\u2013time data for 613 subjects from nine phase I and II studies were analysed using a nonlinear mixed\u2010effects model to estimate population pharmacokinetics and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from a phase III study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A three\u2010compartment disposition model was established to describe serelaxin pharmacokinetics. Three out of 23 covariates, including baseline body mass index (BMI) and estimated glomerular filtration rate (eGFR) and study A1201, were identified as significant covariates for clearance but with a moderate impact on steady\u2010state concentration, reducing the intersubject variability from 44% in the base model to 41% in the final model with covariates. The steady\u2010state volume of distribution (Vss) was higher in patients with AHF (544\u00a0ml kg<jats:sup>\u20131<\/jats:sup>) or chronic heart failure (434\u00a0ml kg<jats:sup>\u20131<\/jats:sup>), compared with typical nonheart failure subjects (347\u00a0ml kg<jats:sup>\u20131<\/jats:sup>). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased serelaxin clearance by 9.2% or 5.2%, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Patients with HF showed higher Vss but similar clearance (and therefore steady\u2010state exposure) <jats:italic>vs<\/jats:italic>. non nonheart failure subjects. BMI and eGFR were identified as the main covariates explaining intersubject variability in clearance; however, the impact of these covariates on steady\u2010state concentration was moderate and therefore unlikely to be clinically relevant.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13714","type":"journal-article","created":{"date-parts":[[2018,7,17]],"date-time":"2018-07-17T03:08:02Z","timestamp":1531796882000},"page":"2572-2585","source":"Crossref","is-referenced-by-count":4,"title":["Population pharmacokinetics of serelaxin in patients with acute or chronic heart failure, hepatic or renal impairment, or portal hypertension and in healthy subjects"],"prefix":"10.1111","volume":"84","author":[{"given":"Antoine","family":"Soubret","sequence":"first","affiliation":[{"name":"Disease Modeling \u2013 Clinical Pharmacology, Roche Pharma Research and Early Development F. Hoffmann\u2010La Roche Ltd  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinuo","family":"Pang","sequence":"additional","affiliation":[{"name":"AbbVie Clinical Pharmacology and Pharmacometrics AbbVie Inc.  Chicago IL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1789-2602","authenticated-orcid":false,"given":"Jing","family":"Yu","sequence":"additional","affiliation":[{"name":"Pharmacometrics Novartis Institutes for BioMedical Research  Cambridge MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Dahlke","sequence":"additional","affiliation":[{"name":"Translational Medicine Novartis Pharma A.G.  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