Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects

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Abstract

A pharmacokinetic and pharmacodynamic (PK/PD) model for recombinant human erythropoietin (Epoetin alfa) in healthy subjects was developed to describe the time profiles of changes in serum Epoetin alfa and the pharmacological responses of percent reticulocytes, total red blood cell counts, and hemoglobin after single and multiple subcutaneous administration of Epoetin alfa. Data used in the development of the model were obtained from a clinical study carried out in healthy volunteers in which Epoetin alfa was administered either as 150 IU/kg three-times-a-week (t.i.w.) or fixed 40,000 IU weekly (q.w.) doses for 4 weeks. A dual-absorption rate model (fast zero-order and slow first-order inputs) with linear disposition kinetics was used to characterize the pharmacokinetics of erythropoietin after subcutaneous administration. A new catenary cell production and lifespan loss model was used to fit the pharmacodynamic data yielding estimates of SC50, Smax, and other pharmacodynamic parameters. Flip–flop kinetics was apparent in the pharmacokinetics as the absorption rate was slower (ka = 0.7 day−1) than the elimination rate (CL/Vd = 1.2–9.2 day−1). In the pharmacodynamics, an SC50 of 58 mIU/mL was estimated indicating that low serum erythropoietin concentrations were sufficient to produce pharmacological effects. The established PK/PD model predicts similar pharmacological responses of hemoglobin and total red blood cell counts for the 150 IU/kg t.i.w. and 40,000 IU q.w. regimens in healthy subjects.

Introduction

Erythropoietin (EPO), a natural glycoprotein hormone, is synthesized predominantly in the kidneys in response to tissue hypoxia. EPO stimulates production of erythrocytes by binding to its receptors expressed on erythroid progenitor cells in bone marrow. There are specific receptors for erythropoietin on the cell surface of erythroid cell membranes (Sawyer and Hankins, 1993, Youssoufian et al., 1993, Sawyer and Penta, 1996, D’Andrea et al., 1989, Sawada et al., 1987). The burst-forming unit erythroid (BFU-E), the earliest identifiable cell in the erythroid lineage, has fewer erythropoietin receptors than the colony-forming unit erythroid (CFU-E). The density of the erythropoietin receptors increases as BFU-E matures into CFU-E (Sawada et al., 1990). The highest number of erythropoietin receptors occurs at the stage of development between the CFU-E and proerythroblasts (Sawada et al., 1990, Sawyer and Koury, 1987). There are data which suggest that suppression of programmed cell death (apoptosis) is the primary mechanism by which erythropoietin maintains erythropoiesis (Koury and Bondurant, 1992). These erythroid progenitor cells will not survive in the absence of erythropoietin. In the presence of erythropoietin, these cells will survive and complete differentiation into reticulocytes. The reticulocytes are then released into the blood circulation where they eventually mature into red blood cells.

Epoetin alfa, a 165-amino acid glycoprotein manufactured by recombinant DNA technology, has the same biological effects as endogenous erythropoietin (Egrie et al., 1986). Further, endogenous EPO and Epoetin alfa are considered to be the same entities. Epoetin alfa has been approved in the US for the treatment of anemia and the reduction of transfusions in patients with non-myeloid malignancies scheduled to receive concomitant chemotherapy for a minimum of 2 months. In addition, it is used worldwide for the treatment of anemia associated with renal failure, cancer, and HIV, as well as in surgical settings.

Endogenous circulating EPO concentrations in healthy humans range from 6 to 32 mIU/mL. Less than 10% of EPO is excreted in the urine (Lappin and Rich, 1996). Receptor-mediated endocytosis has been recently suggested as a major pathway for EPO clearance (Chapel et al., 2001). After intravenous (IV) administration, Epoetin alfa is distributed in a volume comparable to the plasma volume, and plasma concentrations decay with mean half-life values ranging from 4 to 11.2 h (Macdougall et al., 1991). There were dose-proportional increases in Cmax and AUC values between single intravenous doses of 50–1000 IU/kg in healthy subjects (Flaharty et al., 1990). Mean tmax values of Epoetin alfa ranged from 15.6 to 28.8 h with dose-proportional increases in Cmax after single subcutaneous (SC) administrations of 300 to 2400 IU/kg in volunteers (Cheung et al., 1998). Epoetin alfa plasma concentrations decay at a much slower rate after SC than IV administration. A mean half-life value of 18 h had been reported after SC dosing (Ashai et al., 1993). This longer half-life value is probably a reflection of the slow absorption from subcutaneous tissues and implies flip–flop kinetics.

The approved dosing regimen for Epoetin alfa in the treatment of chemotherapy-associated anemia is 150–300 IU/kg three-times-a-week (t.i.w.). The efficacy, quality-of-life benefits, and safety of a weekly (q.w.) regimen of Epoetin alfa were established in clinical trials of cancer patients with anemia (Gabrilove et al., 2001, Shasha et al., 2003). Overall, the efficacy and safety of the q.w. regimen were similar to those reported in trials of t.i.w. regimens (Gabrilove et al., 2001, Shasha et al., 2003, Glaspy et al., 1997, Demetri et al., 1998, Littlewood et al., 2001, Case et al., 1993, Ludwig et al., 1993, Abels, 1993). A single SC dose of Epoetin alfa with tmax between 15 and 39 h yields a peak reticulocyte count on day 10 (Cheung et al., 1998). The total increase in hematocrit depends on both the increases in RBC production rate and the RBC lifespan (Kato et al., 1997). A study of the duration of the RBC lifespan of 120 days would be necessary to establish a definitive relationship between circulating Epoetin alfa concentrations and RBC count. However, a PK/PD model, developed based on known pharmacokinetic (PK) and pharmacological properties of Epoetin alfa, can be used to predict pharmacological responses of percent reticulocytes, RBC, and hemoglobin after single and multiple SC doses.

Our objectives were: (i) to develop a PK/PD model for Epoetin alfa that can be capable of description of previously published data from studies in healthy subjects and (ii) to determine if there was a difference between hematological responses (percent reticulocyte, RBC counts, and hemoglobin levels) for two dosing regimens of 40,000 IU q.w. and 150 IU/kg t.i.w.

Section snippets

Subjects

Details of the experimental procedure of the study from which the present data were described previously (Cheung et al., 2001). Briefly, this was a single-center, open-label, parallel-design, randomized study conducted in 36 healthy adults. Subjects comprised two treatment groups and received Epoetin alfa SC as either a weekly fixed dose of 40,000 IU (days 0, 7, 14, and 21, Group A) or 150 IU/kg t.i.w. (days 0, 2, 4, 7, 9, 11, 14, 16, 18, 21, 23, and 25, Group B) for 4 weeks. All subjects were

Results

Our first objective was to develop a PK/PD model capable of describing the data for Groups A and B. We then simulated the PD responses to determine if they differed intrinsically between these groups.

Discussion

A one-compartment model with Michaelis–Menten disposition had been used to describe the disposition kinetics of EPO kinetics in rats (Kato et al., 1997). Other studies suggest that binding to receptors in bone marrow contributes to the saturable elimination of EPO (Chapel et al., 2001). However, recent data in patients with cancer suggested that the pharmacokinetics of Epoetin alfa is linear at IV doses between 500 and 1500 IU/kg (Xenocostas et al., 2002). Data listed in this report suggested

Nomenclature

    aC, bC

    variance parameters for C

    aY, bY

    variance parameters for RETI%, RBC, and Hb

    AEPO

    amount in blood

    ASC

    amount in the subcutaneous site

    BFU0

    baseline BFU-E cell number

    BFUE

    number of BFU-E cells in bone marrow

    C

    EPO serum concentration

    Cb

    endogenous EPO serum concentration

    CFU0

    baseline CFU-E cell number

    CFUE

    number of CFU-E cells in bone marrow

    CL

    clearance

    EPO

    erythropoietin

    F

    bioavailability

    Fr

    fraction of dose absorbed via the first-order process

    Hb

    hemoglobin concentration in blood

    H(C)

    Hill function

    k0

    zero-order

Acknowledgement

This work was supported in part by Grant GM57980 from the National Institute of General Medical Sciences, National Institutes of Health.

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