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An Extended Terminal Half-Life for Darbepoetin Alfa

Results from a Single-Dose Pharmacokinetic Study in Patients with Chronic Kidney Disease not Receiving Dialysis

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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 µg/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 µg/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 µg/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.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

This study was funded by Amgen Inc. All authors are employees of Amgen Inc., Thousand Oaks, CA, USA.

The authors wish to acknowledge Thomas C. Marbury, MD, Orlando Clinical Research Center, Orlando, FL, USA, and William B. Smith, MD, New Orleans Center for Clinical Research, New Orleans, LA, USA, for their assistance in conducting this study. The authors would also like to thank Donna Harrell of Amgen Inc., Thousand Oaks, CA, USA, and Gardiner-Caldwell London (Maidenhead, UK) for writing and editorial assistance.

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Authors and Affiliations

  1. Amgen Inc., One Amgen Center Drive, Mail Stop 38-3-A, Thousand Oaks, California, 91320, USA

    Desmond Padhi, Liyun Ni, Blaire Cooke, Rafael Marino & Graham Jang

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  1. Desmond Padhi
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  2. Liyun Ni
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  3. Blaire Cooke
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  4. Rafael Marino
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  5. Graham Jang
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Correspondence to Desmond Padhi.

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Padhi, D., Ni, L., Cooke, B. et al. An Extended Terminal Half-Life for Darbepoetin Alfa. Clin Pharmacokinet 45, 503–510 (2006). https://doi.org/10.2165/00003088-200645050-00005

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