Pharmacokinetics of serelaxin in patients with hepatic impairment: a single‐dose, open‐label, parallel group study

Kobalava, Zh. D.; Villevalde, S.; Kotovskaya, Y.; Hinrichsen, Holger; Petersen-Sylla, Marc; Zaehringer, Andreas; Pang, Yinuo; Rajman, Iris; Canadi, Jasna; Dahlke, Marion; Lloyd, Peter; Halabi, Atef

doi:10.1111/bcp.12572

Cited by 27 publications

(25 citation statements)

References 15 publications

(13 reference statements)

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“…In addition, a bolus injection would be advantageous in an emergency setting, such as hypoperfusion, where a fast restoration of blood flow in the brain would be intended. The animals were administered the equivalent of a daily dose (9), which ensures almost immediately a peak serum level of about 100 ng/ml, which is almost 10-fold higher than the levels observed during 24-h infusions in humans (27). With respect to the solvent of Serelaxin (20 mM sodium acetate, pH 5.2, in the stock solution) an effect can be excluded, as this translates into an increase of less than 0.1 percent of the physiological blood concentration in sheep, a ruminant animal in which acetate net fluxes from blood are high (35).…”

Section: Discussionmentioning

confidence: 99%

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Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model

Bischoff

Schmidt

Irintchev

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Serelaxin, recombinant human relaxin-2, modulates endothelial vasodilatory functionality and is under evaluation for treatment of acute heart failure. Little is known about acute effects on cerebral perfusion. We tested the hypothesis that Serelaxin might also have effects on the cerebral microcirculation in a sheep model, which resembles human brain structure quite well. We used laser Doppler flowmetry and sidestream dark-field (SDF) imaging techniques, which are reliable tools to continuously assess dynamic changes in cerebral perfusion. Laser Doppler flowmetry shows that bolus injection of 30 g Serelaxin/kg body wt induces an increase (P ϭ 0.006) to roughly 150% of cortical cerebral blood flow (CBF), whereas subcortical CBF remains unchanged (P ϭ 0.688). The effects on area-dependent CBF were significantly different after the bolus injection (P ϭ 0.042). Effects on cortical CBF were further confirmed by SDF imaging. The bolus injection of Serelaxin increased total vessel density to 127% (P ϭ 0.00046), perfused vessel density to 145% (P ϭ 0.024), and perfused capillary density to 153% (P ϭ 0.024). Western blotting confirmed the expression of relaxin receptors RXFP1 and truncated RXFP2-variants in the respective brain regions, suggesting a possible contribution of RXFP1 on the effects of Serelaxin. In conclusion, the injection of a high dose of Serelaxin exerts quick effects on the cerebral microcirculation. Therefore, Serelaxin might be suitable to improve cortical microcirculation and exert neuroprotective effects in clinically relevant scenarios that involve cortical hypoperfusion. These findings need to be confirmed in relevant experimental settings involving cerebral cortical hypoperfusion and can possibly be translated into clinical practice. RELAXIN-2 IS A HUMAN HORMONE that mediates cardiovascular adaptations during pregnancy and particularly systemic and renal vasodilatation (7). Moreover, these effects are observed in nonpregnant animals and in ex vivo studies following the artificial administration of the substance as well (33). An intravenous bolus injection of a recombinant form of human relaxin-2, Serelaxin (Novartis Pharma, Basel, Switzerland), modulates a sustained endothelial vasodilatory function. Serelaxin mediates systemic hemodynamic changes and increases renal blood flow through a fall in systemic intravascular resistance with a concomitant increase in arterial compliance (15,22,31,38,39). In the RELAX-AHF study, cardiovascular and all-cause mortality was reduced 37% in patients treated with Serelaxin (42). Furthermore, initial positive studies on the cerebral effects of this peptide hormone in a stroke model (47) and in a high blood pressure situation (6) have already been published. Serelaxin induces a nitric oxide-mediated vasodilatation (40) and can particularly reduce the infarction size of the cerebral cortex, suggesting a neuroprotective effect (47).Nonetheless, studies on the influence of Serelaxin on the cerebral blood flow (CBF) have not been performed to this day. Moreover, desp...

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Section: Discussionmentioning

confidence: 99%

“…For measurement of Serelaxin in serum samples, a human relaxin-2 immunoassay (Quantikine ELISA, DRL200, R&D Systems, Minneapolis, MN) was used (27).…”

Section: Methodsmentioning

confidence: 99%

Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model

Bischoff

Schmidt

Irintchev

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Antiserelaxin antibodies were evaluated in serum in a 4‐tiered approach with validated assays. The details of these assays have been described previously . Samples were initially screened for potential immunogenicity in a screening assay.…”

Section: Methodsmentioning

confidence: 99%

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

Dahlke

Halabi

Canadi

et al. 2015

The Journal of Clinical Pharma

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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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“…Analysis of liver and serum indicated that RLN stimulation of RXFP1 was associated with the augmentation of intrahepatic NO signaling and a reduction in contractile filament expression in myofibroblasts/activated HSC, but circulating serum levels of NO were unaffected [19] . Recombinant human RLN-2 (serelaxin) is in the process of clinical development for the treatment of acute heart failure and has already been shown to have a favourable pharmacokinetic and safety profile in patients with hepatic impairment (Child-Pugh class A, B, and C) [20] . We are undertaking studies of portal pressure and hepatic and renal blood flow in models of human cirrhosis to further examine the therapeutic effects of RLN (ClinicalTrials.gov identifier: NCT01640964).…”

Section: Rln and Myofibroblast Contraction -Identifying A Dynamic Phymentioning

confidence: 99%

Liver Fibrosis: Understanding the Dynamics of Bidirectional Wound Repair to Inform the Design of Markers and Therapies

Iredale

Pellicoro²,

Fallowfield³

2017

Dig Dis

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Background: Liver fibrosis is the final common pathway of iterative or chronic liver damage. When it reaches an advanced stage, cirrhosis develops and this indicates a loss of normal liver architecture, disruption of normal blood flow, the development of nodules of proliferative hepatocytes and consequent functional failure. Cirrhosis is also associated with life-threatening complications. Importantly, this dysregulation of blood flow involves changes resulting from both architectural disruption and a dynamic rise in portal pressure mediated in part by the contraction of myofibroblasts - the major cell mediator of the fibrogenic process - which are derived from hepatic stellate cells (HSC) and termed activated HSC (myofibroblast/activated HSC). Key Messages: There is now compelling data from both rodent and human models that liver fibrosis is bidirectional. By studying models of progressive and regressing liver fibrosis it has been possible to identify mediators that may be therapeutic targets. Arguably, by identifying the mediators of spontaneous resolution that result in a return of normal architecture, the attributes of a highly effective antifibrotic or pro resolution therapy can be defined. Among these key attributes, understanding the balance of matrix-degrading enzymes and their inhibitors (the metalloproteinases and Tissue inhibitors of metalloproteinases (TIMPs), respectively) led to the identification of both therapeutic targets and the value of TIMP-1 as a serum marker of fibrosis. Furthermore, the action of a potential therapeutic agent, relaxin (RLN) acting through its cognate G-protein coupled receptor (RXFP1) on the surface of activated HSC shows promise. Activation of the RLN-RXFP1-mediated pathway can be detected in vivo by measuring the dynamic contractility of activated HSC and the consequent changes in portal pressure and blood flow as a responsive physical biomarker. Conclusion: By understanding progressive and resolving liver fibrosis, a series of therapeutic targets have been identified. At the same time, key mediators of fibrosis may have an integral role to play as soluble or physical biomarkers.

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Pharmacokinetics of serelaxin in patients with hepatic impairment: a single‐dose, open‐label, parallel group study

Cited by 27 publications

References 15 publications

Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model

Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model

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

Liver Fibrosis: Understanding the Dynamics of Bidirectional Wound Repair to Inform the Design of Markers and Therapies

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