Pharmacokinetics of Serelaxin in Patients With

British Journal of Clinical DOI:10.1111/bcp.12572 Pharmacology Correspondence Dr Marion Dahlke, Novartis Pharma AG, Pharmacokinetics of serelaxin CH-4056 Basel, Switzerland. Tel.: +41 79 5590130 Fax: +41 61 3246623 in patients with hepatic E-mail: [email protected] ----------------------------------------------------------------------- impairment: a single-dose, Keywords cardiovascular disease, healthy subjects, hepatic, pharmacokinetics, therapeutics open-label, parallel ----------------------------------------------------------------------- Received 4 September 2014 group study Accepted 9 December 2014 Zhanna Kobalava,1 Svetlana Villevalde,1 Yulia Kotovskaya,1 Accepted Article 2 3 4 Published Online Holger Hinrichsen, Marc Petersen-Sylla, Andreas Zaehringer, 16 December 2014 Yinuo Pang,5 Iris Rajman,4 Jasna Canadi,4 Marion Dahlke,4 Peter Lloyd6 & Atef Halabi3 1Peoples Friendship University of Russia, Moscow, Russia, 2Gastroenterologisch-Hepatologisches Zentrum Kiel, Kiel, 3Clinical Research Services, Kiel, Germany, 4Novartis Institutes for BioMedical Research, Basel, Switzerland, 5Novartis Institutes for BioMedical Research, Cambridge, MA, USA and 6KinDyn Consulting Ltd, Horsham, UK WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Data available from completed clinical studies of serelaxin, a recombinant form of AIMS human relaxin-2 currently in clinical Serelaxin is a recombinant form of human relaxin-2 in development for treatment of development for the treatment of acute acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of heart failure, have supported its clinical serelaxin in patients with hepatic impairment. Secondary objectives included dosing at 30 μgkg−1 day−1 as a 48 h i.v. evaluation of immunogenicity, safety and tolerability of serelaxin. infusion. METHODS • Hepatic impairment, relatively common in a This was an open-label, parallel group study (NCT01433458) comparing the PK of −1 −1 typically aged population of patients with serelaxin following a single 24 h intravenous (i.v.) infusion (30 μgkg day ) between patients with mild, moderate or severe hepatic impairment (Child–Pugh class A, B, C) heart failure, may significantly affect the and healthy matched controls. Blood sampling and standard safety assessments were pharmacokinetics of a drug to the extent conducted. Primary non-compartmental PK parameters [including area under the that dosage adjustment is warranted. serum concentration–time curve AUC(0–48 h) and AUC(0–∞) and serum concentration at 24 h post-dose (C24h)] were compared between each hepatic impairment group and healthy controls. RESULTS WHAT THIS STUDY ADDS A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, • This study investigated the of which 48 subjects completed the study. In all groups, the serum concentration of pharmacokinetics of serelaxin in patients serelaxin increased over the first few hours of infusion, reached steady-state at 12–24 h and then declined following completion of infusion, with a mean terminal with varying degrees of hepatic impairment, half-life of 7–8 h. All PK parameter estimates were comparable between each group to help inform potential dosing adjustments of patients with hepatic impairment and healthy controls. No serious adverse events, for serelaxin in this patient population. discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. • This study revealed that the pharmacokinetics of serelaxin is not affected CONCLUSIONS by hepatic impairment, and hence dose The PK and safety profile of serelaxin were not affected by hepatic impairment. No adjustments are unlikely to be required. dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment. © 2014 The British Pharmacological Society Br J Clin Pharmacol / 79:6 / 937–945 / 937 Z. Kobalava et al. Introduction vided there were no safety or tolerability concerns, as judged by the investigator. The study was initiated on 29 Heart failure (HF) is a growing public health issue world- July 2011 and completed on 16 December 2011. wide due to an ageing population and improvement in The study protocol was reviewed by the Independent myocardial infarction survival [1, 2]. Globally, more than 23 Ethics Committee or Institutional Review Board for each million people suffer from HF [3] and in the United States centre, and the study was conducted according to the alone, each year over 1 million patients with HF are hospi- ethical principles of the Declaration of Helsinki. All subjects talized [4]. Indeed, acute heart failure (AHF) is the most provided written informed consent before any study- common cause of hospitalization in patients over 65 years specific procedures were conducted. of age [5]. Serelaxin is a recombinant form of human relaxin-2, a Inclusion and exclusion criteria naturally occurring peptide hormone [6], and is in clinical Inclusion criteria for all subjects (male or female) included development for the treatment of AHF [7, 8]. In the phase age 18–70 years, weight ≥50 kg and body mass index − III RELAX-AHF study, patients with AHF receiving serelaxin 18–35 kg m 2. For patients with hepatic impairment, inclu- (30 μgkg−1 day−1) on top of standard of care reported sig- sion required sitting vital signs as follows: systolic blood nificantly greater improvement in dyspnoea [as measured pressure (SBP), 100 to 159 mmHg; diastolic blood pressure by the visual analogue scale area under the curve (AUC) (DBP), 60 to 109 mmHg and pulse rate, 45 to 100 beats analysis] and were significantly less likely to experience min–1. Corresponding requirements for healthy controls in-hospital worsening of HF than those receiving conven- were 100 to <140 mmHg, 60 to <95 mmHg and 45 to 100 tional therapy alone. A 37% reduction (P = 0.02) in the 180 beats min–1, respectively. Exclusion criteria for all subjects day cardiovascular and all-cause mortality rates was also included hepatic impairment due to non-liver disease, observed with serelaxin treatment [9]. hypersensitivity to the study drug, significant electrocar- As part of the clinical development of serelaxin, studies diogram abnormalities and any surgical or medical condi- examining the pharmacokinetics (PK) of this agent in tion (other than hepatic impairment) that might have special populations were conducted to help inform clinical significantly altered the distribution or elimination of decision making in a range of patient populations, includ- drugs. ing those with hepatic impairment. Indeed, hepatic impairment is relatively common in patients with HF [10, Sample size calculations 11] and is associated with poor prognosis [11]. Therefore, Sample size calculations were based on the comparison of we report on the findings of a study designed to evaluate the PK profile (in terms of the parameters, AUC from zero the effect of varying degrees of hepatic impairment on the to last measurable concentration [AUC(0–tlast)] and AUC PK of serelaxin administered as a single intravenous (i.v.) from zero to infinity [AUC(0–∞)] within the hepatically continuous infusion. impaired groups vs. the profile of the control group. In previous studies in HF subjects, the coefficient of variation (CV) for AUC in the 30 μgkg−1 day−1 dose group was Methods 21% (unpublished data on file, Novartis; yinuo.pang@ novartis.com). Considering at least eight subjects per Study design and participants group with an observed ratio of 1.4 (equivalent to a 40% This was an open-label, parallel group study increase in drug exposure), the 90% confidence interval (ClinicalTrial.gov identifier, NCT01433458) conducted (CI) for the ratio of PK parameters when CV = 21% would be across two clinical research centres (Clinical Research 1.18 to 1.66. If the CV was increased to 30%, then the 90% Services, Kiel, Germany and ASCENT Clinical Research CI would be 1.10 to 1.78. This was considered as sufficient Solutions, Moscow, Russia) in patients with mild, moderate for the purpose of this study. Under the assumption of a and severe hepatic impairment (Child–Pugh class A, 5–6 10% type I error and a two-sided t-test for the difference of points, class B, 7–9 points and class C, 10–15 points, means on the log normal scale, when the CV = 21%, we respectively), and with demographically matched healthy have a power of 92% and when the CV = 30%, we have a control subjects with normal hepatic function. The criteria power of 70% to test the equality of means (ratio of 1) in for matching included race, age (± 5 years), gender and favour of an alternative of 1.4. weight (± 15%). None of the study participants suffered from HF. All subjects received a single 24 h i.v. infusion of Assessments and analyses – PK assessment serelaxin (30 μgkg−1 day−1). Each subject underwent a Serum samples for PK analysis were collected at baseline, screening visit between 21 and 2 days before dosing and during the 24 h infusion (time points: 15 min, 1, 3, 6, 12 and eligible subjects were admitted to the study site at base- 24 h), and up to 48 h after the end of infusion. The final line (on day –1). Further visits were scheduled on days 4 serum samples were collected on day 15, the last day of and 15 and the end of the study period. Between days 4 the study, to help interpret the immunogenicity assay and 15, subjects were released from the study site pro- results. Serum serelaxin concentrations were determined 938 / 79:6 / Br J Clin Pharmacol Serelaxin pharmacokinetics in patients with hepatic impairment using a commercially available, validated enzyme-linked anti-serelaxin IgG was used as positive controls and a neat immunosorbent assay (Quantikine ELISA kit DRL200, R&D pool of human sera as the negative control. Plates were Systems, Minneapolis, MN, USA), modified so that the cali- incubated for 1.5 h at ambient temperature, washed and bration standard curve and samples were prepared using the bound anti-serelaxin antibodies were detected by the pooled naive male and female human serum (i.e.

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