Biology Reference
In-Depth Information
• Do the pharmacokinetic properties remain the same upon repeated admin-
istration over time, i.e., are they time linear?
•How do the pharmacokinetic parameters vary from one population to the
next?
In addition, the preclinical and clinical literature relating to clearance mech-
anisms is reviewed. Discussion of the relationship of rHuEPO serum concen-
trations to efficacy outcomes is beyond the scope of this review. For clarity
purposes it should be noted that rHuEPO is currently available as two mole-
cules - epoetin alfa and epoetin beta. Epoetin alfa is marketed as Epogen,
Procrit, Eprex, and Erypo (depending on region) in most of the developed
world, including the United States, Europe, Canada, Australia, and Asia.
Epoetin beta is marketed as NeoRecormon in Europe and Japan. Each of these
marketed products is available in a range of concentrations and, in some cases,
formulations. This review does not address concentration-specific or formula-
tion-specific effects. Although minor differences in both pharmacokinetic and
pharmacodynamic properties have been noted between the two molecular
forms (to be discussed), the molecules are generally used interchangeably. All
values in this review are given as mean (SD) unless explicitly noted otherwise.
Challenges in determining and comparing properties
The accurate determination of the pharmacokinetic properties (and associated
variability) of a drug in a given population has a number of prerequisites. The
most important of these are summarized. Blood samples should be collected
for a duration sufficient to fully characterize the serum-concentration time pro-
file. The exact dose, as well as the exact sampling times relative to dosing
times, should be recorded and used in the analysis. The assay should be vali-
dated with a sufficiently low quantification limit and limited cross-reactivity
with interfering substances. The pharmacokinetic analysis should take advan-
tage of all available information, and characterization of the terminal phase
should use relevant data points. The most suitable pharmacokinetic analysis
technique should be used. In addition, the use of treatment-naive subjects,
crossover studies, and larger numbers of subjects allows for a better estimate
of certain pharmacokinetic characteristics.
In the case of rHuEPO, the most blatant, unavoidable rule-breaker is the use
of assays that cross-react with endogenous erythropoietin (EPO). Due to the
structural similarity between endogenous EPO and rHuEPO, most (if not all)
of the commonly used assays measure both the endogenous and exogenous
hormone. The most common method of correcting for the inability to differ-
entiate between the two products is by baseline-correction and all the articles
cited in this review have used baseline-corrected values. At least one, and up
to three samples, are collected pre-dose and these are used as a baseline esti-
mate to correct (by direct subtraction) subsequent concentrations for the
