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

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.

Altered Cerebral Blood Flow and Potential Neuroprotective Effect of Human Relaxin-2 (Serelaxin) During Hypoxia or Severe Hypovolemia in a Sheep Model

“…The increase in HR, however, can most likely be ascribed to the high dosage of serelaxin utilized in the experiments. In contrast to clinical application schemes for the treatment of heart failure [23], we utilized a bolus injection to facilitate the detection of weak responses on the CBF. In addition, a bolus injection would be preferable in an emergency setting, such as hypoperfusion, in which the objective would be quick restoration of the blood flow in the brain.…”

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

“…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).…”

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

“…Haemodialysis clearance (CLHD) was calculated using the following equation: CLHD = QBIN × R × f. In this equation, QBIN is the blood flow rate into the dialyser, R is the plasma‐to‐blood ratio [estimated using the blood‐to‐plasma AUC ratio (12·7) following single‐dose administration], and f is the fraction of ixazomib removed during haemodialysis, calculated as (AUC in  – AUC out )/AUC in , where AUC in and AUC out are the area under the concentration‐time curve during the haemodialysis interval using samples collected at the entry and exit of the dialyser, respectively (Chen et al , 2007; Khadzhynov et al , 2012; Dahlke et al , 2016). …”