Biology Reference
In-Depth Information
to 30%) with an accompanying decline in terminal half-life (approximately
10% to 40%) within several weeks. Generally no further changes were seen
with more chronic dosing. For the populations for which data are available, no
significant interpopulation differences were noted in pharmacokinetic proper-
ties of rHuEPO.
Application of pharmacokinetic principles and understanding the pharma-
cokinetic-pharmacodynamic relationship can explain one apparently anom-
alous situation for rHuEPO. That is, the reduced dose requirement (approxi-
mately 30% lower) in patients with CRF when rHuEPO is administered sub-
cutaneously
versus
intravenously [62] despite the low subcutaneous bioavail-
ability. This finding can be explained by the slow absorption after subcuta-
neous administration from the injection site that acts to prolong the blood con-
centrations for a longer time. For erythropoetic agents, it appears that maximal
benefit is obtained by maintaining a therapeutic concentration of the drug for
most of the dosing interval. Molecules that have an extended residence time
(such as darbepoetin alfa) have the advantage of prolonged maintenance of
therapeutic concentrations at a reduced frequency.
Despite the extensive body of work available, there are two main areas,
namely absorption and clearance, where understanding the underlying mecha-
nisms would greatly enhance our ability to rationalize and interpret data. For
subcutaneous dosing of rHuEPO, new evidence from sheep models indicates
that lymphatic uptake is the dominant uptake route, as opposed to direct entry
into the vasculature, as a high proportion of the dose (>80%) is absorbed
through the peripheral lymphatics. Additionally, a high proportion of this
(75%) is recovered in the central lymph, indicating minimal lymphatic clear-
ance [63]. Clarifying and quantifying the roles and relative contribution of var-
ious clearance pathways to the overall clearance of rHuEPO is crucial for fur-
ther development. The implications that the target organ (i.e., EPOR-bearing
cells) are at least partially responsible may help explain the limited increase in
clearance upon multiple dose administration.
In addition to these basic unresolved mechanistic issues, other more applied
questions exist:
• Do the pharmacokinetics of rHuEPO vary with hemoglobin/hematocrit val-
ues?
• What is the true bioavailability of rHuEPO when administered subcuta-
neously?
• What is the impact of rHuEPO treatment on endogenous EPO?
•What are the pharmacokinetic properties of rHuEPO in patients with can-
cer, either with or without chemotherapy?
•Should we expect the pharmacokinetic properties of rHuEPO to vary in cur-
rently unstudied populations, and if so, can we explain these differences
mechanistically?
•
What are the differences in the critical pharmacokinetic characteristics
between rHuEPO and second-generation erythropoeitic agents, such as dar-
