Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 44, Issue 9, Pages 991-1002Publisher
WILEY
DOI: 10.1177/0091270004268411
Keywords
recombinant human erythropoietin; erythropoietin; pharmacokinetics; pharmacodynamics; dosing
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Funding
- NIGMS NIH HHS [GM 57980] Funding Source: Medline
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This study describes a pharmocokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were obtained from 4 clinical studies carried out in healthy volunteers. Epoetin alfa (rHuEpo) was administered as 5 single IV doses ranging from 10 to 500 IU/kg, as 8 single SC doses ranging from 300 to 2400 IU/kg and as 2 multiple SC dosage regimens (150 IU/kg/3 times a week [tiw] and 600 IU/kg/wk). A dual-absorption rate model (fast zero-order and slow first-order inputs) with nonlinear disposition characterized the PK of SC rHuEpo. A high K-m value was obtained indicating that clearance was mildly nonlinear Absorption was slow (t(max) similar to24 hours), and the bioavailability of SC rHuEpo increased with dose (ranging from 46%-100%). A catenary cell production and loss model with a feedback down regulation component was used to fit the reticulocyte data yielding estimates of the stimulatory capacity (S-max), sensitivity (SC50), and life span parameters. These parameters were used for simulations of RBC and Hb profiles. A 17 SC50 of 27 to 61 IU/L was estimated indicating that low physiological plasma rHuEpo concentrations were sufficient to produce pharmacological effects. No marked sex-dependent differences in clinical responses to rHuEpo therapy were found despite baseline differences. Realistic pharmocokinetic and physiological models accounted for clinical responses from a wide array of dosing conditions with rHuEpo. The rationale for greater efficacy of SC administration of rHuEpo compared to IV was ascertained.
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