Biology Reference
In-Depth Information
dose). The mean terminal half-life varied up to three-fold,with up to 100%
interindividual variability, however, no consistent pattern with dose was seen,
which is not unexpected given the rate-limited absorption of rHuEPO. For
groups with lower variability (%CV < 50%), the mean half-life was between
24-36 hours. Mean peak concentration generally occurred between 16-29
hours post-dose and the authors established a linear relationship between C
max
(peak concentration) and dose. These findings combined indicate that the
absorption rate and extent of epoetin alfa are not dose dependent.
In another dose-ranging study, Sans et al. [22] determined the single-dose
pharmacokinetics of epoetin beta at 30, 60, and 100 U/kg (n = 3/group). They
noted a dose-proportional increase in area-under-the curve (AUC) as well as a
constant T
max
. They also noted no dose-dependency for terminal half-life nor
mean residence time. In a third study,Hayashi et al. [23] used population phar-
macokinetic analysis (non-linear mixed effects modelling) to describe the data
from a bioequivalence study with epoetin beta in healthy volunteers. Using a
one-compartment model with first-order absorption, the authors did not
observe a dose-dependency in the parameter estimates obtained from 48 sub-
jects (1,500 and 3,000 U). These three studies consistently demonstrate that
the rate and extent (proportion) of absorption of rHuEPO are not dose-depend-
ent, however, higher exposure is obtained with higher doses.
Bioavailability
Despite the apparent non-linearity in the pharmacokinetics of rHuEPO, no
attempt appears to have been made to consider this when determining the sub-
cutaneous bioavailability (F). To gain an accurate determination of F for a non-
linear drug, it is necessary to initially determine the underlying intravenous
kinetics then quantify the subcutaneous bioavailability by modeling. All esti-
mates in the literature have been obtained by administration of the same dose
intravenously and subcutaneously with comparison of AUC; this method
would tend to under-estimate F, especially at lower doses where the non-lin-
earity in clearance is most evident. Estimates of F for subcutaneously admin-
istered rHuEPO, as determined in the literature, tend to lie between 20% and
40%, when determined in a cross-over study [7, 16, 20].
Multiple dose
The findings regarding the impact of multiple subcutaneous dosing on the
pharmacokinetics of rHuEPO are disparate. McMahon et al. [15] reported that
C
max
after five doses of 150 U/kg epoetin alfa was much increased relative to
single dose; however, after five doses of 300 U/kg, C
max
was similar to its sin-
gle-dose value. In a more recent study, Sans et al. [22] found a significant
decrease in AUC (between 57% and 90% of single-dose values) and C
max
(between 47% and 76% of single-dose values) after three doses of epoetin beta
at 30, 60, or 100 U/kg (n=3/group). For each group, there was a concomitant
increase in t
1/2,z
(by one- to two-fold) and mean residence time (MRT) and a
5-9 hour prolongation in mean T
max
. After four weekly doses of 600 U/kg
