Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Dose Administration in Cynomolgus Monkeys

Abstract

The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c. administrations. The kinetic model suggests rapid zero-order absorption of part of the s.c. dose (35%) followed by a slow first-order entry through the lymphatics. The s.c. treatments caused a delayed dose-dependent rise in reticulocyte numbers peaking between 100 and 200 h and returning to baseline by 300 to 400 h. This was followed by steady rises in red blood cell (RBC) and hemoglobin counts. A physiological catenary model based on a life span concept with rHuEpo stimulating the production of two cell populations (progenitor cells and erythroblasts) was applied. The model could adequately describe the reticulocyte responses upon the various s.c. treatments, giving estimates of maturation times for cells in the various stages of differentiation including the early progenitor cells (70.4 h), erythroblasts (15.0 h), and reticulocytes (141.6 h) that are close to the literature reported values. An S max of 3.13 was estimated indicating a moderate maximum stimulation of erythropoiesis, whereas the SC 50 was 842 IU/l. The model was used to effectively predict the increases in RBC and hemoglobin counts as well. In conclusion, the physiological PK/PD model developed could adequately describe the time course of rHuEpo effects, yielding realistic estimates of cell life span parameters.Erythropoiesis involves a sequence of cellular differentiations that are controlled by specific hematopoietic growth factors. Erythropoietin (Epo) is a key lineage-specific humoral regulator of mammalian erythropoiesis. The recombinant form of human erythropoietin (rHuEpo) is structurally very similar to endogenous Epo (Egrie, 1990). It exerts its biological effects by binding to specific receptors in the bone marrow cells, which causes them to undergo a 5-to 9-day process of cellular proliferation, differentiation, and maturation leading to an increase in reticulocyte counts followed by rises in hematocrit and hemoglobin levels in the blood (Flaharty, 1990).rHuEpo has been shown to be an effective alternative to blood transfusion, ameliorating anemia associated with a variety of indications and producing consequent improvements in quality of life in many renal (Lundin et al., 1990) and nonrenal applications (Markham and Bryson, 1995) in humans. Several investigators have reported pharmacokinetic and dynamic studies of rHuEpo in humans and many animal species, including mouse, rat, dog, rabbit, sheep, and horse (Fu et al., 1988;Jaussaud et al., 1994;Bleuel et al., 1996;Souillard et al., 1996;Widness et al., 1996;Yoon et al., 1997;Cheung et al., 1998;Chapel et al., 2000;Kato et al., 2001). A clear mathematical quantification of the kinetics and dynamics of rHuEpo effects would greatly facilitate rational design of optimal dosage regimens and aid therapy. The Epo...

Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

“…In contrast to the previous analysis [23], this analysis also includes hemoglobin data in the estimation procedure. The determined 'a SS ' value (0.797 days or 19.1 h) is approximately the same as a similar physiological parameter determined in cynomolgus monkeys of 14.95 h and in humans of 10.76 h [19,20].…”

“…(21) generalizes to: (28) Differentiation of Eq. (19) and substitution of Eqs. (27) and (28), followed by subsequent substitution of the resulting equation along with Eq.…”

“…Analogous terminology used by other authors includes "lifespan" and "maturation time" [16][17][18][19][20][21][22][23]. Previous Epo-reticulocyte pharmacokinetic/pharmacodynamic (PK/PD) models have commonly assumed that all cells have a time invariant and common lifespan or maturation time (i.e., "point distribution") [16][17][18][19][20][21]. Recently, Epo-reticulocyte PK/ PD models have been presented that allow for a fixed (time invariant) distribution of cell lifespans [22].…”

Interspecies Comparisons of Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoietin

“…The PK and PD parameters of rHuEPO were obtained from rats (Woo et al, 2006), monkeys (Ramakrishnan et al, 2003), and humans (Ramakrishnan et al, 2004). Each study reported the parameter estimates by computational fittings using the PK and PD data from i.v.…”

“…The PK data following i.v. administration of rHuEPO-␣ (hereafter rHuEPO) were obtained from the literature for various species, including rats (Kato et al, 2001;Woo et al, 2006), rabbits (Yoon et al, 1997), monkeys (Ramakrishnan et al, 2003), dogs (Fu et al, 1988), sheep (Widness et al, 1996;McLennan et al, 2005), and humans (Ramakrishnan et al, 2004). The values of CL and steady-state volume of distribution (V ss ) were calculated based on a noncompartmental approach (Gibaldi and Perrier, 1982).…”