Pharmacokinetic and Pharmacodynamic Profiles of Extended Dosing of Epoetin Alfa in Anemic Patients Who Have Chronic Kidney Disease and Are Not on Dialysis

Abstract

Background and objectives: Emerging evidence suggests that epoetin alfa can be administered at extended intervals of up to 4 wk. This open-label, randomized study was performed to characterize the pharmacokinetic and pharmacodynamic profiles of four dosing regimens of epoetin alfa administered subcutaneously in anemic patients who had chronic kidney disease and were not on dialysis.Design, setting, participants, & measurements: Thirty-eight patients, enrolled from nine centers in the United States, were >18 yr of age and had hemoglobin <11.0 g/dl and GFR 12 to 60 ml/min per 1.73 m 2 . Patients received one of four epoetin alfa dosing regimens: 50 IU/kg three times per week, 10,000 IU once weekly, or 20,000 IU every 2 wk for 36 d or 40,000 IU every 4 wk for 64 d. Each regimen provided a similar dosage of epoetin alfa over 4 wk. Dosage adjustments were not permitted.Results: Drug exposure to epoetin alfa over 4 wk, based on area under the curve, was somewhat higher with the extended interval regimens compared with the three-times-weekly regimen. Mean change in hemoglobin during the study period was similar for all regimens. No patients were transfused. Three patients experienced five serious adverse events, none of which was considered treatment related.Conclusions: Extended dosing interval regimens of epoetin alfa yielded modest pharmacokinetic differences but a similar pharmacodynamic response, suggesting that less frequent, higher dosages of epoetin alfa may be as effective as the current three-times-weekly regimen in anemic patients who have chronic kidney disease and are not on dialysis.

A Randomized Controlled Study Comparing Once-Weekly to Every-2-Week and Every-4-Week Dosing of Epoetin Alfa in CKD Patients with Anemia

“…Erythropoiesis-stimulating agents (ESAs) are considered the standard of care for the treatment of patients with anemia associated with CKD (11)(12)(13). Epoetin alfa (EPO) is an ESA with an amino acid sequence identical to endogenous human erythropoietin (14).…”

A Randomized Controlled Study of Weekly and Biweekly Dosing of Epoetin Alfa in CKD Patients With Anemia

“…Since their development, erythropoiesis-stimulating agents (ESAs) have become the standard of care for the treatment of patients with anemia associated with CKD (10,11). Epoetin alfa is an ESA with an amino acid sequence identical to endogenous human erythropoietin (12).…”

“…For maintenance of hemoglobin (Hb) levels, the dosage of epoetin alfa is individualized to maintain the Hb within the target range of 11 to 12 g/dl (13) or between 10 and 12 g/dl (14). When administered subcutaneously, the serum half-life of epoetin alfa ranges from 28 to 43 h (12). However, the pharmacodynamic effect, as measured by an increase in red blood cell count, is evident for weeks to months.…”

Erythropoietin Stimulating Agents and Epoetin Alfa Revisited

“…The response to erythropoietin is best measured by reticulocyte counts, increasing Hb or hematocrit levels, and the life span of erythrocytesevents that are occurring well after the immediate time relevance of the serum half-life of the drug. Thus, the accompanying article by McGowan et al (10) confirms some minor differences in pharmokinetics across intervals of epoetin alfa dosing between 1 and 4 wk compared with traditional three times per week but importantly a consistent pharmacodynamic response, which was similar over the complete range of dosing intervals.…”