Biology Reference
In-Depth Information
Other issues related to nephrology patients
Extent of renal function
Most pharmacokinetic studies in the nephrology population have been con-
ducted in patients with end-stage renal disease receiving dialysis. In a study
aimed at investigating the impact of varying degrees of renal function (as
determined by creatinine clearance, range: <3 to >80 mL/min per 1.73 m
2
) on
the pharmacokinetics of epoetin beta, Kindler et al. [24] investigated intra-
venously administered doses of 130 to 152 U/kg in rHuEPO-naive subjects
(n = 10). They determined that neither the terminal half-life nor total clearance
were related to renal function. Using a 48-hour urine collection, they also
determined (by RIA) that renal clearance contributed only 1.86% (n = 8) to
total clearance.
Mode of dialysis
A number of studies have demonstrated that loss of rHuEPO in the dialysate
is minimal. After intravenous dosing, Macdougall et al. [26] and Boelaert et al.
[10] reported that 2.3% (range: 1.7%-3.0%) (n = 8, 120 U/kg) and 2.63%
(n = 6, 300 U/kg) of the dose, respectively, was collected in the peritoneal dial-
ysis fluid over the first 24 hours. Petersen et al. [35] compared the loss of epo-
etin alfa in dialysate when administered intravenously at the end and the begin-
ning of the dialysis session. These authors concluded that the overall clearance
of rHuEPO is not affected by the presence of a dialysis system, with approxi-
mately 7% administered dose in the dialysis system at the end of the study (4
hours). Gladziwa et al. [6] determined, by comparison of rHuEPO concentra-
tions from the arterial and venous lines of the hemofilters and dialysers, that
rHuEPO was not eliminated by either of these means. Additionally, although
few direct comparisons are available, several authors have concluded that the
dialysis mode, i.e., hemodialysis
versus
peritoneal dialysis, has no impact on
the pharmacokinetics of intravenous or subcutaneous rHuEPO [10, 26, 33].
Stockenhuber et al. [33], in a direct comparison of epoetin beta by both intra-
venous and subcutaneous routes, found no statistically significant differences
in pharmacokinetic properties between patients on hemodialysis (n = 6)
versus
those on peritoneal dialysis (n = 6). Jensen et al. [16] found no difference
between hemodialysis (n = 7) and peritoneal dialysis (n = 5) for either intra-
venous or subcutaneous dosing after single or multiple dosing. In summary,
the mode of dialysis does not appear to impact the pharmacokinetic properties
of rHuEPO.
Intraperitoneal dosing for peritoneal dialysis patients
Given the use of peritoneal dialysis, intraperitoneal administration of rHuEPO
has been considered. Reported bioavailability estimates are generally very low
(3%, possibly an underestimate as the samples were only collected to 24
hours) [26] and 6.8% [2] with a large proportion of the dose (80%) being lost
in the effluent [10]. The feasibility of the intraperitoneal route increases if
