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Pharmacokinetic and pharmacodynamic modeling of erythropoietin administration

a technology of erythropoietin and erythropoietin, which is applied in the field of pharmacokinetic and pharmacodynamic modeling of erythropoietin administration, can solve the problems of large loss of blood, inconclusive data, and reduced oxygen availability in the tissues, and achieve the effect of facilitating the maturation of young red cells

Inactive Publication Date: 2006-05-11
CHEUNG WING +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025] Another preferred embodiment of the present invention comprises a variety of methods including a business method of providing to a consumer an EPO dosing regimen that comprises a first dose of EPO followed by a second dose of EPO to a patient. The second dose of EPO is preferably administered to the patient at a time point after the first dose that coincides with the PD profile resulting from the first dose of EPO. The PD profile may include, number of progenitor cells produced in respect to time, reticulocyte concentration in respect to time, RBC number produced in respect to time, and hemoglobin concentration in respect to time. Most preferably, the PD profile will be the reticulocyte profile for this regimen. The second dose of EPO is preferably administered to coincide with the reticulocyte profile, i.e., when reticulocyte production peaks. The second dose of EPO facilitates the maturation of young red cells in the circulation into mature RBCs.

Problems solved by technology

The primary site for EPO synthesis in adult organisms is the kidney; although the liver and bone marrow have also been implicated, the data remains inconclusive.
The primary stimulus for increased EPO synthesis is tissue hypoxia, which results from decreased oxygen availability in the tissues.
Hypoxia can result from the loss of large amounts of blood, destruction of red blood cells by radiation, or exposure to high altitudes.
In addition, various forms of anemia cause hypoxia since red blood cells are responsible for oxygen transport in the body.
Until recently, the availability of EPO has been very limited.
Although the protein is present in human urine, excreted levels are too low to make this a practical source of EPO for therapeutic uses.
Presently, there are a number of disadvantages associated as the standard EPO dosage regimen administered to patients.
Moreover, the standard dosing regimens may not maximize the patient's physiological response; and standard dosing regimens may not be the most cost efficient.
Furthermore, there are a number of disadvantages associated with the route of EPO administration: regular intravenous administration is inconvenient for the patient; intravenous administration is impractical for individuals afflicted with certain conditions such as continuous ambulatory peritoneal dialysis and non-dialysis patients with restricted vascular access; the rapid dose delivery of rHuEPO via intravenous administration results in a lower bioavailability of rHuEPO for longer time periods and may not be as effective for stimulating production of RBC as desired.

Method used

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  • Pharmacokinetic and pharmacodynamic modeling of erythropoietin administration
  • Pharmacokinetic and pharmacodynamic modeling of erythropoietin administration
  • Pharmacokinetic and pharmacodynamic modeling of erythropoietin administration

Examples

Experimental program
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Effect test

example 1

Human Pharmacokinetics and Bioavailability for EPO

[0244] The following example of the present invention provides a summary of the PK / PD data that support a 40,000-IU q.w. dosing regimen. The data are derived from both the literature and four clinical studies conducted by RWJPRI, Raritan, N.J. Three studies were conducted under Investigational New Drug BB-IND-2318, and one study was conducted in the UK. A brief overview of the studies is given in FIG. 17.

[0245] The clinical pharmacokinetic studies included in this technical summary are described FIG. 18A-18D, and the pharmacokinetic data from these studies are summarized in FIG. 19. The analytical methods used for the determination of EPO concentration in serum are summarized, infra, and FIG. 20.

[0246] Clinical Study EPO-PHI-373 (FIG. 17) provides the data to support the 40,000 IU once weekly dosing regimen. Clinical Study EPO-PHI-370 (FIG. 17), which has a similar design as Clinical Study EPO-PHI-373.

[0247] In Clinical Study EPO...

example 2

Evaluation of EPO PK / PD Profile after Administration of 150 IU / kg t.i.w. and 40,000 IU q.w.

[0318] In specific indications, such as cancer, subjects are treated with 150 IU / kg epoetin alfa t.i.w. Thus, it remains an important goal to change the currently approved dosing schedule to a more convenient (i.e., once per week or once every two weeks) dosing schedule and regimen. A less frequent administration will improve user acceptance and convenience.

[0319] The pharmacokinetic and pharmacodynamic properties of the multiple dosing regimen of epoetin alfa have been defined in the previous example (EPO-PHI-358 and EPO-PHI-359). The data suggest that 150 IU / kg t.i.w. and 600 IU / kg / week dosing regimens have similar pharmacodynamic responses (e.g., a rise in hemoglobin). Therefore, epoetin alfa can potentially be administered as a weekly per kilogram dose. Since 600 IU / kg is equivalent to 42,000 IU for a 70-kg person, the present study was conducted to demonstrate that a fixed dosing regime...

example 3

Comparison of PK / PD Parameters After Administration of EPREX® and PROLEASE®

[0412]FIG. 62 is a schematic representation of the model for erythropoiesis stimulating effects of rHuEpo. This model was used to estimate the kinetic and dynamic parameters for rHuEpo responses after administration of 8 single doses of EPREX®as well as the kinetic parameters after single dose PROLEASE® administration.

Pharmacokinetics

[0413] The pharmacokinetics of 600 IU / kg / wk EPREX® administered for 4 weeks was simulated using parameters obtained from the simultaneous fitting of the eight single doses. Only the Tau and Fr values were estimated. For the INT-57 cancer regimen of 150 IU / kg / t.i.w, the F, Tau, and Vd values were fixed as indicated in FIG. 63 based on previous estimations from the earlier study (EPO 358 / 359). The pharmacokinetics for single dose PROLEASE® (2400 IU / kg) were estimated and these parameters were used to simulate the multiple dose regimen of 1800 IU / kg / month. The same sets of kineti...

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Abstract

The present invention relates to systems and methods for obtaining optimized EPO dosage regimens for a desired pharmacodynamic / pharmacokinetic response. The system includes choosing one or more EPO dosage regimens, then using a PK / PD model to determine the pharmacodynamic / pharmacokinetic profile of one or more EPO dosage regimens, and finally selecting one of the EPO dosage regimens for administration to achieve the desired pharmacodynamic / pharmacodynamic response based on the EPO profile.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to provisional application Ser. No. 60 / 133,418, filed May 11, 1999, the contents of which are incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention relates to systems and methods for obtaining optimized EPO dosage regimens for a desired pharmacodynamic / pharmacokinetic response. BACKGROUND OF THE INVENTION [0003] Erythropoietin (EPO) is the principal factor responsible for the regulation of red blood cell production during steady-state conditions and for accelerating recovery of red blood cell mass following hemorrhage. EPO is a glycoprotein hormone with a molecular mass of 30 KDa and is heavily glycosylated, which serves to protect the EPO molecule from rapid degradation in vivo. Serum EPO concentrations in humans normally range from 6 to 32 U / l (1), and the half-life (t1 / 2) of EPO is reported to range from 2 to 13 hours with a volume of distribution close to plasma volume....

Claims

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Application Information

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IPC IPC(8): A61K38/18G06F19/00A61K38/00A61K31/282A61K31/7072A61K33/243A61K38/12A61K38/22A61M37/00A61P7/00A61P7/06A61P7/08A61P13/12A61P19/02A61P29/00A61P31/18A61P35/00A61P43/00G06Q10/00
CPCA61K38/1816A61K38/14A61K33/24A61K31/70A61K31/505A61K31/475A61K31/28A61K2300/00A61K38/00G16H50/50G16C20/30A61P13/12A61P19/02A61P29/00A61P31/18A61P35/00A61P43/00A61P7/00A61P7/06A61P7/08A61K33/243A61K38/22
Inventor CHEUNG, WINGGIBSON, DAVIDCOTE, CHRISTINEVERCAMMEN, ELS
Owner CHEUNG WING
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