Biology Reference
In-Depth Information
Although the pharmacokinetic properties of rHuEPO are generally consid-
ered to be nonlinear with dose, there has been little attempt in the literature to
further characterize and describe this nonlinearity. In one study,Veng-
Pedersen et al. [19] simultaneously analyzed data from three dose levels of
intravenously administered epoetin alfa obtained in a three-way cross-over
study in ten subjects (10, 100, and 500 U/kg). These authors observed that
clearance decreased as dose increased,which they ascribed primarily to a sat-
urable nonlinear mechanism described by the Michaelis-Menten expression.
They determined V
max
(theoretical maximum rate of elimination associated
with the nonlinear pathway) to be 902 (175) mU/mL/hr and K
m
(plasma con-
centration at which half-maximal effect is observed) to be 4,814
(1,184) mU/mL.
Multiple dose
In healthy volunteers, limited information is available on the impact of multi-
ple dosing on the pharmacokinetic properties of rHuEPO. McMahon et al. [15]
examined the single-dose and multiple-dose pharmacokinetics of epoetin alfa
at intravenously administered doses of 150 and 300 U/kg in a parallel design
(n = 6/group). At both dose levels, the mean clearance increased by 25% after
five doses, resulting in a comparable reduction in terminal half-life. The
authors indicated that the biggest change in clearance occurred between the
first and second dose.
In summary, after intravenous dosing to healthy volunteers, the pharmaco-
kinetic properties of rHuEPO are non-linear with dose wherein clearance is
faster at lower doses. Additionally, clearance appears to increase over the ini-
tial period of multiple dosing.
Subcutaneous dosing
General
After subcutaneous dosing, the rate and extent of absorption are the determin-
ing characteristics of the serum concentration time profile for rHuEPO. The
rate of absorption, which is slower than the rate of elimination, becomes lim-
iting upon subcutaneous dosing, hence, it is represented by the terminal phase.
The extent of absorption, as represented by bioavailability, represents that per-
centage of the dose that is measured in the circulation after extravascular
administration.
Single dose; dose range
Key pharmacokinetic parameters determined after single-dose subcutaneous
administration in healthy volunteers are presented in Table 2. The most com-
prehensive dose-ranging study has been reported by Cheung et al. [4] who
studied single dose administration of epoetin alfa at eight dose levels ranging
from 300 to 2,400 U/kg over an extended sampling duration (672 hours post-
