Pharmacokinetics and Pharmacodynamics of Rusfertide, a Hepcidin Mimetic, Following Subcutaneous Administration of a Lyophilized Powder Formulation in Healthy Volunteers
Year: 2024
Type: article
Study design: Clinical Trial
Abstract: Hepcidin, an endogenous peptide hormone, binds to ferroportin and is the master regulator of iron trafficking. Rusfertide, a synthetic peptide, is a potent hepcidin mimetic. Clinical studies suggest rusfertide may be effective in the treatment of polycythemia vera. This study investigated the dose-ranging pharmacokinetics, pharmacodynamics, and safety of a lyophilized formulation of rusfertide. A randomized open-label crossover study was conducted in two groups of healthy adult subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous rusfertide doses that ranged from 10 to 60 mg of a lyophilized formulation and 20 mg of an aqueous prefilled syringe formulation that were used in clinical trials. Rusfertide showed a rapid initial absorption. Median time to peak plasma concentrations for the lyophilized formulation was 24 h for doses of 10–30 mg and 2–4 h for doses of 45 and 60 mg. Mean terminal half-life ranged from 19.6 to 57.1 h. Rusfertide peak concentration and area under the concentration–time curve increased with an increasing dose, but in a less than dose-proportional manner. Metabolites M4 and M9 were identified as major metabolites. At the rusfertide 20-mg dose, the lyophilized formulation had an area under the concentration–time curve from time zero to infinity approximately 1.5-fold higher than the aqueous formulation. The elimination half-life was comparable for the two formulations. Dose-related decreases in serum iron and transferrin-iron saturation were seen following rusfertide treatment. The majority of treatment-emergent adverse events were mild; treatment-related treatment-emergent adverse events seen in ≥10% of subjects were injection-site erythema and injection-site pruritus. Rusfertide was well tolerated; the pharmacokinetic and pharmacodynamic results indicate that lyophilized rusfertide is suitable for once-weekly or twice-weekly administration. Hepcidin is a natural peptide hormone produced by the liver that is responsible for iron homeostasis. Rusfertide is a potent peptide mimetic of hepcidin that is being investigated for the treatment of polycythemia vera. This trial was conducted in two groups of healthy subjects to describe the pharmacokinetics and pharmacodynamics of subcutaneous rusfertide. Doses of 10–60 mg of a lyophilized powder formulation and 20 mg of an aqueous formulation were studied in a randomized manner. Following subcutaneous dosing, maximum plasma concentration and exposure measured by area under the concentration–time curve increased with dose but in a less than proportional manner. Rusfertide reduced serum iron and transferrin-iron saturation in a dose-related manner. Rusfertide was generally well tolerated. Side effects seen in more than 10% of subjects that were considered possibly related to treatment were injection-site redness and itching.
Source: Drugs in R&D
Institution: Protagonist Therapeutics (United States)
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,490
OpenAlex ID: W4404425340