Biology Reference
In-Depth Information
endogenous component [1, 2]. This method of correction assumes that the
endogenous EPO concentration remains constant over the course of the study.
This assumption ignores the natural diurnal fluctuation of endogenous EPO,
which has been shown to be lowest at 8:00 AM and increase by an average of
60% at its peak at 8:00 PM [3]. This method also ignores the potential impact
of exogenous administration on endogenous EPO through feedback mecha-
nisms. Two assay systems are generally used - radioimmunoassay (RIA) [1,
4-11] and enzyme immunoassay (EIA) [12, 13]. The limit of detection is gen-
erally in the range 2-15 mU/mL, which covers the endogenous range.
It should be noted that cross-study comparisons of the pharmacokinetics of
any drug have the inherent issues of differences in study design, including
duration and frequency of sample collection, and differences in bioanalysis,
including methodology, accuracy, and specificity.
Pharmacokinetics in healthy volunteers
Pharmacokinetic studies conducted in healthy volunteers tend to use treat-
ment-naive subjects for the sole purpose of determining single-dose parame-
ters, either over a dose range or for different routes of administration. In the
studies reviewed, the sampling duration after intravenous dosing was general-
ly sufficient (48 hours) with 10 or 11 samples (up to 16 or 18) collected over
that time. The sampling duration after subcutaneous dosing should be longer
for full characterization of the terminal phase; it varied greatly from 48 hours
to 672 hours [4] with generally nine to 13 samples, and as many as 23 or 26,
collected during that time. In general,the higher the dose investigated,the
longer the test article is quantifiable in the serum, resulting in a more accurate
determination of the full pharmacokinetic profile. A sampling duration of at
least 72 hours would allow reasonable determination of the parameters of a
subcutaneously administered dose.
Intravenous dosing
General
Generally, one [9, 14-17] or two [18] phases were evident in the serum con-
centration-time profiles. In cases where only one phase was observed, it is
likely that the early rapid phase was not captured (due to sampling schedule
and/or inter-individual variation) and that the slower, later phase dominated.
The volume of distribution was generally similar to plasma volume
(40-60 mL/kg), indicating limited extravascular distribution [14, 15].
Single dose, dose range
Key pharmacokinetic parameters determined after single-dose, intravenous
administration to healthy volunteers are presented in Table 1. In healthy vol-
