An extended terminal half-life for darbepoetin alfa: results from a single-dose pharmacokinetic study in patients with chronic kidney disease not receiving dialysis

Abstract

Background and objective: Anaemia is a major and persistent manifestation of chronic kidney disease (CKD) caused by the deficient production of erythropoietin in the kidneys, the prevalence of which is proportional to the deterioration in kidney function. Darbepoetin alfa, an erythropoiesis-stimulating protein, exhibits a lower clearance and longer terminal half-life in serum than recombinant human erythropoietin, thereby allowing for a reduced dosing frequency. A recent study in patients with CKD, using a 4-week sampling period, suggested that the terminal half-life of darbepoetin alfa in serum is longer than that reported in previous studies, which were based on a 1-week sampling period. This study was conducted to characterise the pharmacokinetic profile of a single subcutaneous dose of darbepoetin alfa 1 microg/kg in patients with CKD, using a sampling duration of 4 weeks, which was hypothesised to allow better characterisation of the terminal half-life in serum.

Methods: Twenty patients with CKD not on dialysis, with a calculated glomerular filtration rate of 20-60 mL/min and who had not been treated with erythropoietic agents in the previous 12 weeks, were enrolled into this single-dose, open-label study. Patients received a single subcutaneous dose of darbepoetin alfa (Aranesp) 1 microg/kg on day 1, and blood samples were collected for pharmacokinetic analyses predose, 6 and 12 hours postdose and up to 28 days postdose. Seroreactivity sampling and further safety laboratory tests (clinical chemistry and urinalysis) were also performed. Patients were assessed for adverse events at each study visit. The primary endpoint was characterisation of the terminal half-life following a single subcutaneous dose of darbepoetin alfa 1 microg/kg.

Results: The mean terminal half-life in serum of darbepoetin alfa was determined to be 69.6 hours. Peak serum concentrations were reached in a median time of 36 hours postdose, and a mean apparent clearance of 3.51 mL/h/kg was comparable to that observed previously in this patient population.

Conclusion: Based on an extended sampling schedule of 4 weeks, the terminal half-life of darbepoetin alfa was approximately 70 hours. This is longer than the 48.8 hours reported previously in patients with CKD on dialysis. These data suggest that the pharmacokinetic properties of darbepoetin alfa make this erythropoietic agent well suited to an extended dosing regimen.