Elementary Pharmacokinetics and Pharmacodynamics

Maxwell, George M.

doi:10.1007/978-1-4684-7544-9_2

Cited by 1 publication

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“…A k in of 0.007 × 10 10 cells/L/h in males and 0.02 × 10 10 cells/L/h in females was obtained, which translates to 0.084 × 10 11 and 0.24 × 10 11 cells/day, assuming a blood volume of 5 L. It is not clear if these differences are meaningful. However, these values are consistent with findings that 1% of all RBC are destroyed daily and replaced by reticulocytes in healthy humans, yielding an erythrocyte production rate (k 0 ) of 2 × 10 11 cells/day 20 , 21 . The estimated S max was 4 to 8, which indicates that rHuEpo can produce a maximum 5‐ to 9‐fold increase in the zero‐order production rate of reticulocytes, a relatively modest degree of stimulation that accounts for the slow and limited rise in blood RBC.…”

Section: Discussionsupporting

confidence: 89%

Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin After Single and Multiple Doses in Healthy Volunteers

Ramakrishnan

Cheung

Wacholtz

et al. 2004

The Journal of Clinical Pharma

123

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This study describes a pharmacokinetic (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) approximately 24 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 (SC(50)), and life span parameters. These parameters were used for simulations of RBC and Hb profiles. An SC(50) 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 pharmacokinetic 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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Section: Discussionsupporting

confidence: 89%