After intravenous administration, peak (15-min) plasma rHuEPO concentrations correlate linearly with dose; a dose of 50 U/kg produces peak concentrations of about 1000 mU/mL (44). In single-dose studies, clearance decreases nonlinearly with increasing dose, resulting in a longer half-life of rHuEPO as the dose administered is increased (65). In multiple-dose studies of intravenous rHuEPO in healthy subjects, however, clearance appears to increase over the initial period of multiple dosing (70).
Flaharty et al. (65) administered epoetin alfa in single iv doses of 10, 50,150, 500, and 1000 U/kg, and found a trend of decreasing clearance with increasing dose, with the most dramatic difference being between 10 and 50 U/kg (approx threefold decrease). The reduction in clearance resulted in longer half-lives as dose increased, i.e., from 4.4 h at 10 U/kg to 5.3 h at 50 U/kg and 8.5 h at 500 U/kg (range: 4.4-11.0 h). Over the dose range of 100-150 U/kg, clearance was approx 7 mL/h/kg, and terminal half-life was approx 5 h.
rHuEPO's dose-nonlinearity has not been well characterized. In one study, Veng-Pedersen et al. (70) administered single iv doses of epoetin alfa at three dose levels (10, 100, and 500 U/kg) in a three-way crossover study in 10 healthy volunteers. Again, clearance decreased as dose increased, which they ascribed primarily to a nonlinear, saturable mechanism obeying Michaelis-Menten kinetics.
Generally, one (71) or two (72) phases are evident in the serum concentration-time profiles. When only one phase was observed, it is likely that the early rapid phase was not captured (owing to sampling schedule and/or interindividual variation) and that the slower, later phase dominated. The volume of distribution was generally similar to that of plasma volume (40-60 mL/kg), indicating limited extravascular distribution (65,69).
McMahon et al. (69) compared the single-dose and multiple-dose pharmacokinetics of epoetin alfa (150 and 300 U/kg iv) in a parallel design. At both dose levels, the mean clearance increased by 25% after five doses, resulting in a comparable reduction in terminal half-life. The largest change in clearance occurred between the first and second doses.
Was this article helpful?
Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.