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Pharmacokinetics of Serelaxin in Patients with Severe Renal

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Pharmacokinetics of Serelaxin in Patients with Severe Renal Special Populations The Journal of Clinical Pharmacology Pharmacokinetics of Serelaxin in Patients With 2016, 56(4) 474–483 © 2015 The Authors. The Journal of Severe Renal Impairment or End-Stage Renal Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Disease Requiring Hemodialysis: A Single-Dose, Pharmacology Open-Label, Parallel-Group Study DOI: 10.1002/jcph.607 Marion Dahlke, MD, PhD1, Atef Halabi, MD, PhD2, Jasna Canadi, PhD1, Chiaki Tsubouchi, PhD1, Surendra Machineni, MSc3, and Yinuo Pang, PhD4 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 mg/kg) in patients with severe renal impairment (n 6) or ¼ end-stage renal disease (ESRD) requiring hemodialysis (PK on the day of dialysis [n 6] or during dialysis-free interval [n 6]), compared with ¼ ¼ matched healthy subjects (n 18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with mean ¼ 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. Keywords serelaxin, pharmacokinetics, renal impairment, end-stage renal disease Serelaxin, currently in clinical development for the treatment of acute heart failure (AHF), is a recombinant peptide identical in structure to human relaxin-2, a naturally occurring hormone that is believed to mediate hemodynamic and vascular changes during pregnancy.1 Serelaxin stimulates the vascular signaling pathways with Abbreviations: AE, adverse events; AHF, acute heart failure; AUC, short- and long-term effects on hemodynamics.1,2 Data area under the serum concentration-time curve; BMI, body mass fi are available on the efficacy and safety of serelaxin in index; Cmax, maximum serum concentration; CI, con dence interval; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated patients with AHF from 2 randomized, double-blind, glomerular filtration rate; ELISA, enzyme-linked immunosorbent placebo-controlled, parallel-group, multinational clinical assay; ESRD, end-stage renal disease; GMR, geometric mean ratios; trials—the phase 2 Pre-RELAX-AHF and the pivotal HF, heart failure; IV, intravenous; PK, pharmacokinetics; PR, pulse phase 3 RELAX-AHF.3,4 In these studies, a 48-hour rate; RELAX-AHF, RELAXin in Acute Heart Failure; SAE, serious intravenous (IV) infusion of serelaxin, 30 mg/kg/day adverse event; SBP, systolic blood pressure; SD, standard deviation. significantly improved dyspnea and was well tolerated 1Novartis Pharma AG, Basel, Switzerland with favorable effects on long-term clinical outcomes.3,4 In 2Clinical Research Services GmbH, Kiel, Germany 3 addition, the RELAX-AHF trial demonstrated that ser- Novartis Healthcare Pvt Ltd, Hyderabad, India 4Novartis Institutes for BioMedical Research, Cambridge, MA, USA elaxin, along with standard therapy, significantly reduced the incidences of in-hospital worsening heart failure (WHF) This is an open access article under the terms of the Creative through day 5 and all-cause and cardiovascular (CV) Commons Attribution-NonCommercial License, which permits use, mortality through day 180; however, no significant effects distribution and reproduction in any medium, provided the original were observed for days alive and out of hospital and CV work is properly cited and is not used for commercial purposes. death or readmission for heart failure (HF) or renal failure Submitted for publication 11 June 2015; accepted 31 July 2015. up to day 60.3 An ongoing phase 3 trial, RELAX-AHF-2, fi Corresponding Author will con rm the effects of serelaxin on reducing CV death Yinuo Pang, PhD, Novartis Institutes for BioMedical Research, 200 over 180 days after treatment and in-hospital WHF through Technology Square, Cambridge, MA 02139, USA day 5 (primary endpoints), and to assess several important Email: [email protected] 2Dahlke et al. The Journal of Clinical Pharmacology / Vol XX No XX 20154753 clinicalcreatinine outcomes clearance (secondary levels calculated endpoints) according in a large patient to the toused assess were the Fresenius safety, 4008s tolerability, (Dialysator and immunogenicity FX80, surface area of populationsimplified Modi of approximatelyfication of Diet 6800 in Renal patients Disease with formula AHF serelaxin1.8 m2), Fresenius in all the participants.5008s (Dialysator FX80, surface area (ClinicalTrials.gov(15 mL/[min 1.73 midenti2] fierestimated NCT01870778). glomerular filtration 1.8 m2), Fresenius 5008s (Dialysator FX1000, surface ratePatients [eGFR] with<� 30 mL/[min AHF� are1.73 often m2 diagnosed]). Patients inwith groups renal 2 area 2.2 m2), and Gambro AK 200 ultra (Dialysator insufandfi 3ciency were or included experience if� worseningthey had ofESRD renal requiring function MethodsPolyflux P210H). For ESRD patients with PK assess- duringhemodialysis. hospitalization. The vital A signs meta-analysis for patients of in groupsHF studies 1 to Studyments Design performed and Participants during the dialysis-free interval, showed3, at screening that 63% and baseline of patients visits, had were some required degree to ofhave renal the Theserelaxin study infusion protocol was was started reviewed after an and interval approved of at least by dysfunction,following: systolic with 29% blood having pressure moderate (SBP) ranging to severe from renal 110 the12 hours Research following Ethics the Committee previous hemodialysis at Ethikkommission with PK dysfunction.to 170 mm Hg,5 An diastolic analysis blood of the pressure Acute Decompensated (DBP) ranging Schleswig-Holstein,sample collection and Germany. safety/tolerability The study was assessments designed, Heartfrom 60 Failure to 105 National mm Hg, andRegistry pulse (ADHERE) rate (PR) between data base 45 and of conducted,being performed and reported over the in following accordance 48 with hours the (until ICH 118,465100 bpm. patients The corresponding hospitalized inclusionwith AHF criteria showed for that healthy 91% Harmonizedday 3) and prior Tripartite to the Guidelines subsequent for hemodialysis. Good Clinical All ofsubjects patients were had eGFR some degree90 mL/(min of renal dysfunction,1.73 m2); matching of whom in Practice,participants the were applicable required local to remain regulations, at the study and site the 64%terms had of race, at least age a ( � moderate10 years), renal sex,� anddysfunction. BMI ( 615%)In the to Declarationfor approximately of Helsinki. 3 days All to facilitate participants baseline, provided PK, Pre-RELAX-AHFan individual patient and� with RELAX-AHF renal impairment trials, in the groups� analyses 1, 2, writtenand safety/tolerability informed consent assessments, before any with study an procedures additional ofor 3; serelaxin SBP ranging systemic from clearance 100 to 150 in mm patients Hg; DBP with ranging renal wereambulatory conducted. end-of-study visit on day 15. dysfunctionfrom 60 to 95 indicated mm Hg; andno clinically PR between relevant 50 and impact 100 bpm. of This was a phase 1, open-label, parallel-group study impairedThe keyrenal function exclusion on thecriteria pharmacokinetics were as follows: (PK) of conductedPharmacokinetic in patients Assessments with severe and renal Analyses impairment and serelaxin.(1) clinically However, significant these electrocardiogram were mostly patients abnormalities; with mild thoseSerum with samples ESRD for PKrequiring analysis hemodialysis. were collected The during control the to(2) moderate history of renal hypersensitivity dysfunction to and the a study relatively drug small or to grouptreatment comprised and follow-up demographically periods (time matched points: pretreat- healthy numberdrugs of of a patients similar withclass; severe (3) use renal of impairmentother investigational (n 12). subjectsment, 15 with minutes, normal and renal 1, 2, 3,function. 4, 4.25, As 5, 6, shown 7, 8, 9, in 10, Figure 11, 12, 1, Indrugs addition, at the time the available of study enrollment; serelaxin PK (4) data presence in these¼ of any 12 the16, 24, study 28, participants 36, and 48 hours were after grouped the start according of infusion) to their and patientsnoncontrolled were limitedand clinically to the signi steady-stateficant disease, serum surgical, concen- renalon day function 15 (end status of study). as follows: Specifi patientscally for with group severe 2 patients, renal trationsor medical at condition 12 hours that during could infusion have affected (data the on studyfile). impairmentwho had hemodialysis (group 1), performed patients from with 6 ESRD to 10 hours requiring post– Therefore,outcome or itthat was would deemed have placed
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