Changes in Endogenous Erythropoietin and the Pharmacokinetics of Darbepoetin Alfa in Patients with Non-myeloid Malignancies Receiving or Not Receiving Chemotherapy

Reviewer: Mary Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 9 de diciembre del 2001

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Presenter: A.C. Heatherington
Presenter's Affiliation:
Type of Session: Poster

Background
Several studies have reported an increase in endogenous erythropoietin (EPO) after chemotherapy, however, there is no published data on the pharmacokinetic (PK) properties of recombinant human erythropoietin (rHuEPO) in chemotherapy patients. Darbepoetin alfa has been shown to increase hemoglobin concentrations in cancer patients, however the effects of chemotherapy on the pharmacokinetics of darbepoetin alfa are not known. The PK properties of darbepoetin alfa and its relationship with chemotherapy as well as the effects of chemotherapy on EPO are addressed in this report of 4 independent clinical studies.

Materials and Methods

  • 810 patients have been enrolled of 4 separate trials. Three of these trials investigated darbepoetin alfa in patients receiving chemotherapy (n=709). Darbepoetin was given on q week, q 2 week, or q 3 weeks schedules.
  • Serum levels of darbepoetin were measure at 24-48 hour intervals over the first week of the first cycle of chemotherapy after a subcutaneous (SC) injection of darbepoetin alfa (given on the same day as chemotherapy).
  • Serum levels of darbepoetin were again measured during the first week of the third cycle of chemotherapy, approximately 7-9 weeks after the first cycle, with darbepoetin injected SC the same day as chemotherapy. These results were compared the serum levels measured after the first dose.
  • Serum concentrations of darbepoetin were measured 48 hours after SC injection in both patients receiving chemotherapy and patients not receiving chemotherapy.
  • Endogenous EPO serum levels were measured at 24 hour intervals over the first week following chemotherapy and a weekly intervals.

    Results

  • Darbepoetin alfa is absorbed slowly after subcutaneous dosing, with peak concentrations occurring 70.8 ?123 hours after injection
  • Median peak serum concentration with first dose was 10.6 ng/ml and with subsequent dose 11.3 ng/ml.
  • Mean serum concentrations 48 hours post-dose showed no accumulation or drug with q 2 week or q 3 week dosing.
  • Darbepoetin alfa concentrations in patients receiving chemotherapy were 1.2-3.4-fold higher than in patients not receiving chemotherapy.
  • Peak and trough serum concentrations of darbepoetin alfa administered with chemotherapy were 3-fold higher in the first week after chemotherapy compared to the third week. This effect was comparable among chemotherapy cycles, indicating no clear long-term effect of chemotherapy.
  • In patients receiving chemotherapy but not receiving darbepoetin alfa, there was a 2.1 fold increase in endogenous EPO 48 hours after chemotherapy administration.
  • Endogenous EPO levels returned to baseline before subsequent chemotherapy doses and rose again 48 hours after subsequent doses.

    Author's Conclusions

  • Pharmacokinetic properties of darbepoetin alfa are consistent with dose-linear kinetics, and there was no unexpected accumulation of darbepoetin alfa with multiple dosing.
  • Chemotherapy causes an increase in post-chemotherapy concentrations of darbepoetin alfa. This effect appeared to decrease throughout a single cycle, and was repeated with subsequent cycles.
  • Chemotherapy also caused a transient increase in endogenous EPO levels that was repeated with further chemotherapy cycles

    Clinical/Scientific Implications
    The data from these 4 studies provides valuable information about the effects of chemotherapy on both darbepoetin alfa as well as endogenous EPO. Further understanding of these effects will contribute to the optimal management of anemia in patients receiving chemotherapy.

    Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Amgen.



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