Population pharmacokinetics of serelaxin in patients with acute or chronic heart failure, hepatic or renal impairment, or portal hypertension and in healthy subjects.
Br J Clin Pharmacol. 2018 Jul 16;:
Authors: Soubret A, Pang Y, Yu J, Dahlke M
AIMS: Serelaxin is a recombinant human relaxin-2 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients.
METHODS: Serum concentration-time data of 613 subjects from 9 Phase I and II studies were analyzed using non-linear mixed effects model to estimate population pharmacokinetics (PPK) and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from phase III study.
RESULTS: A three-compartment disposition model was established to describe serelaxin pharmacokinetics. Three out of 23 covariates, including baseline BMI and eGFR and study A1201, were identified as significant covariates for clearance but with moderate impact on steady-state concentration, reducing the inter-subject variability from 44% in base model to 41% in final model with covariates. Steady-state volume of distribution (Vss) was higher in patients with AHF (544 mL/kg) or chronic HF (434 mL/kg), compared with typical non-HF subject (347 mL/kg). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased serelaxin clearance by 9.2% or 5.2%, respectively.
CONCLUSIONS: Patients with HF showed higher Vss but similar clearance (and therefore steady-state exposure) versus non-HF subjects. BMI and eGFR were identified as the main covariates explaining inter-subject variability on clearance; however the impact of these covariates on steady-state concentration was moderate and therefore unlikely to be clinically relevant.
PMID: 30014598 [PubMed – as supplied by publisher]