Pharmacokinetics of serelaxin in patients with severe renal impairment or end‐stage renal disease requiring hemodialysis: A single‐dose, open‐label, parallel‐group study

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Abstract

Serelaxin, a recombinant human relaxin‐2 hormone, is in clinical development for treating acute heart failure. This open‐label, parallel‐group study investigated serelaxin pharmacokinetics (PK) after a single 4‐hour intravenous infusion (10 µg/kg) in patients with severe renal impairment (n = 6) or end‐stage renal disease (ESRD) requiring hemodialysis (PK on the day of dialysis [n = 6] or during dialysis‐free interval [n = 6]), compared with matched healthy subjects (n = 18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with mean terminal elimination half‐life of 6.5–8.8 hours. Compared with healthy subjects, a moderate decrease in serelaxin systemic clearance (37%–52%) and increase in its exposure (30%–115%) were observed in all patients. During the 4‐hour hemodialysis in ESRD patients, 30% serelaxin was removed, with hemodialysis clearance constituting approximately 52% of total systemic clearance. Serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE‐related discontinuations. Antiserelaxin antibodies were not detected in any participant. Given the shallow dose‐response relationship observed with serelaxin in clinical studies and its wide therapeutic window, the observed PK differences in patients with severe renal impairment compared with healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients.

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Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.

John R. Teerlink, Gad Cotter, Beth A Davison … (2013)

Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo. RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806. 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120-775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74-1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42-0·93; p=0·019). Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. Corthera, a Novartis affiliate company. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Renal impairment and outcomes in heart failure: systematic review and meta-analysis.

Grace Smith, Judith Lichtman, Michael B Bracken … (2006)

We estimated the prevalence of renal impairment in heart failure (HF) patients and the magnitude of associated mortality risk using a systematic review of published studies. Renal impairment in HF patients is associated with excess mortality, although precise risk estimates are unclear. A systematic search of MEDLINE (through May 2005) identified 16 studies characterizing the association between renal impairment and mortality in 80,098 hospitalized and non-hospitalized HF patients. All-cause mortality risks associated with any renal impairment (creatinine >1.0 mg/dl, creatinine clearance [CrCl] or estimated glomerular filtration rate [eGFR] 1.03 mg/dl) and moderate to severe impairment (creatinine > or =1.5, CrCl or eGFR or =1.56) were estimated using fixed-effects meta-analysis. A total of 63% of patients had any renal impairment, and 29% had moderate to severe impairment. After follow-up > or =1 year, 38% of patients with any renal impairment and 51% with moderate to severe impairment died versus 24% without impairment. Adjusted all-cause mortality was increased for patients with any impairment (hazard ratio [HR] = 1.56; 95% confidence interval [CI] 1.53 to 1.60, p < 0.001) and moderate to severe impairment (HR = 2.31; 95% CI 2.18 to 2.44, p < 0.001). Mortality worsened incrementally across the range of renal function, with 15% (95% CI 14% to 17%) increased risk for every 0.5 mg/dl increase in creatinine and 7% (95% CI 4% to 10%) increased risk for every 10 ml/min decrease in eGFR. Renal impairment is common among HF patients and confers excess mortality. Renal function should be considered in risk stratification and evaluation of therapeutic strategies for HF patients.

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High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database.

J HEYWOOD, Gregg C. Fonarow, Maria Costanzo … (2007)

The prevalence of renal dysfunction in patients hospitalized with acute decompensated heart failure remains poorly characterized. Data from 118,465 hospitalization episodes were evaluated. Glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease formula. At admission, 10,660 patients (9.0%) had normal renal function (GFR > or = 90 mL x min x 1.73 m2), 32,423 patients (27.4%) had mild renal dysfunction (GFR 60-89 mL x min x 1.73 m2), 51,553 patients (43.5%) had moderate renal dysfunction (GFR 30-59 mL.min.1.73 m2), 15,553 patients (13.1%) had severe renal dysfunction (GFR 15-29 mL x min x 1.73 m2), and 8276 patients (7.0%) had kidney failure (GFR < 15 mL x min x 1.73 m2 or chronic dialysis). Despite this, only 33.4% of men and 27.3% of women were diagnosed with renal insufficiency. Diuretic dose, inotrope use, and nesiritide use increased, whereas angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use decreased, with increasing renal dysfunction (all P < .0001 across stages). In-hospital mortality increased from 1.9% for patients with normal renal function to 7.6% and 6.5% for patients with severe dysfunction and kidney failure, respectively (P < .0001). The majority of patients admitted with acute decompensated heart failure have significant renal impairment, which influences treatment and outcomes.

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Pharmacol

Journal ID (iso-abbrev): J Clin Pharmacol

Journal ID (doi): 10.1002/(ISSN)1552-4604

Journal ID (publisher-id): JCPH

Title: Journal of Clinical Pharmacology

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0091-2700

ISSN (Electronic): 1552-4604

Publication date (Electronic): 04 November 2015

Publication date (Print): April 2016

Volume: 56

Issue: 4 ( doiID: 10.1002/jcph.v56.4 )

Pages: 474-483

Affiliations

[ ¹ ]Novartis Pharma AG BaselSwitzerland

[ ² ]Clinical Research Services GmbH KielGermany

[ ³ ]Novartis Healthcare Pvt Ltd HyderabadIndia

[ ⁴ ]Novartis Institutes for BioMedical Research Cambridge MAUSA

Author notes

[*] [* ] Corresponding Author

Yinuo Pang, PhD, Novartis Institutes for BioMedical Research, 200 Technology Square, Cambridge, MA 02139, USA

Email: yinuo.pang@ 123456novartis.com

Article

Publisher ID: JCPH607

DOI: 10.1002/jcph.607

PMC ID: 5063144

PubMed ID: 26239266

SO-VID: 3effefd4-64c0-41b0-9b3c-3aedf4c0a83c

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This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 11 June 2015

Date accepted : 31 July 2015

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Pages: 10

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source-schema-version-number 2.0

component-id jcph607

cover-date April 2016

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:13.10.2016

Keywords: serelaxin,pharmacokinetics,renal impairment,end‐stage renal disease

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Keywords: serelaxin, pharmacokinetics, renal impairment, end‐stage renal disease

Pharmacokinetics of serelaxin in patients with severe renal impairment or end‐stage renal disease requiring hemodialysis: A single‐dose, open‐label, parallel‐group study

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Most cited references 10

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.

Renal impairment and outcomes in heart failure: systematic review and meta-analysis.

High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database.

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