Pharmacokinetics and Pharmacodynamics of epoetin delta in two studies in healthy volunteers and two studies in patients with chronic kidney disease

Background: Epoetin delta, unlike recombinant erythropoietins, is produced in a human cell line and therefore has a human-type glycosylation profile.Objectives: The pharmacokinetics of epoetin delta were examined in 2 studies in healthy volunteers and 2 studies in patients with chronic kidney disease.Methods: In study 1, 21 healthy men were randomized to receive epoetin delta 15, 40, or 100 IU/kg IV tiw or placebo for 4 weeks. In study 2, an open-label, cross-over study, 32 healthy volunteers were randomized to receive single doses of epoetin delta 75 IU/kg IV or SC. In study 3, 40 patients receiving hemodialysis were withdrawn from epoetin alfa and randomized to receive epoetin delta or epoetin alfa 50 or 100 IU/kg tiw for 4 weeks. Study 4 was a single-dose study comparing epoetin delta 150 and 300 IU/kg IV or SC in 28 hemodialysis patients.Results: In study 1, after repeated dosing (day 24) in healthy men, mean Cmax values ranged from 219.9 to 1793.0 enzyme-linked immunosorbent assay units (EU)/L; AUC from 827 to 9318 h · EU/L; C1 from 0.014 to 0.024 L/h per kg; Vd from 0.067 to 0.076 L/kg; and tl/2 from 2.23 to 3.35 hours. There was evidence of a dose-dependent effect of epoetin delta on hemoglobin levels and hematocrit, with doses of 40 and 100 IU/kg associated with significant increases compared with 15 IU/kg (P < 0.001 for dose trend). The only adverse event occurring in ≽10% of healthy individuals in study 1 was headache (1 [20.0%] in the epoetin delta 15 IU-kg group, 3 [60.0%] in the epoetin delta 100-IU/kg group, 2 [33.3%] in the placebo group). In study 2 in healthy volunteers, mean values for epoetin delta 75 IU/kg IV were 1771 EU/L for Cmax, 10,632 h · EU/L for AUC, 0.010 L/h per kg for Cl, 0.074 L/kg for Vd, and 5.12 hours for tl/2; the corresponding values for epoetin delta 75 IU/kg SC were 113 EU/L, 3231 h · EU/L, 0.035 L/h per kg, 0.760 L/kg, and 14.90 hours. The serum epoetin delta concentration peaked after 10.9 hours with subcutaneous administration. The most common adverse event in study 2 was back pain (10 [31.3%] individuals). In study 3 in patients receiving hemodialysis, mean values for Cmax and AUC with a single dose of epoetin delta 50 IU/kg were 1103 EU/L and 10,896 h · EU/L, respectively, and with the corresponding dose of epoetin alfa were 1354 EU/L and 9957 h · EU/L. Values for the 100-IU/kg doses were approximately double those for the 50-IU/kg doses. Values for Cl, Vd, and t1/2 were numerically similar for epoetin delta and epoietin alfa across doses. Epoetin delta 100 IU/kg was associated with a numerically greater rate of increase in hemoglobin compared with the 50-IU/kg dose (mean, 0.025 vs -0.004, respectively); the results were similar for epoetin alfa (0.029 vs -0.001). The difference between epoetin alfa and epoetin delta was not statistically significant. The most common adverse events were related to edema (peripheral edema: 60%/50% for epoetin delta 50/100 IU/kg and 60%/60% for epoetin alfa 50/100 IU/kg; facial edema: 30%/30% and 50%/70%, respectively; generalized edema: 50%/30% and 40%/40%). In study 4 in patients receiving hemodialysis, mean Cmax values with epoetin delta 150 and 300 IU/kg IV were 3257 and 4770 EU/L, respectively; the corresponding mean values were 36,208 and 77,736 h · EU/L for AUC, 0.007 and 0.005 L/h per kg for Cl; 0.097 L/kg for Vd in both groups; and 9.9 and 13.2 hours for t1/2. With epoetin delta 150 and 300 IU/kg SC, the respective values were 162.2 and 467.7 EU/L, 9547 and 27,888 h · EU/L, 0.026 and 0.020 L/h per kg, 1.28 and 0.78 L/kg, and 33.1 and 27.8 hours. The only adverse event occurring in ≥10% of subjects was headache (2 [40.0%] in the epoetin delta 150-IU/kg IV group, 3 [50.0%] in the epoetin delta 300-IU/kg SC group). No neutralizing antierythropoietin antibodies were detected in any individual. The bioavailability of subcutaneous epoetin delta is ≈30%, and concentrations peak later and decline more slowly than with intravenous injection. Pharmacokinetic parameters in hemodialysis patients were similar to those in healthy individuals, although AUC and tl/2 were numerically higher (by 49% and 34%, respectively).Conclusions: These studies in healthy volunteers and patients with chronic kidney disease indicate that the pharmacokinetics of epoetin delta are dose dependent but nonlinear, leading to dose-dependent increases in hemoglobin levels. The pharmacodynamic response to epoetin delta appeared to be as expected for an epoetin.