A pharmacodynamic model of erythropoietin therapy for uremic anemia

Abstract

Fifty-seven patients receiving chronic high-flux hemodialysis began receiving recombinant alpha-human erythropoietin (rHuEPO). The mean initial rHuEPO dose used in 54 evaluable patients was 9963 +/- 4364 U/week; the final dose was 8972 +/- 4058 U/week. Treatment over a mean period of 154 +/- 40 days (84 to 224 days) resulted in an average increase in hematocrit from 24.7% +/- 3.7% to 32.5% +/- 4.4%. We present a model for these data that describes changes in hematocrit during rHuEPO therapy and that allows simultaneous estimation of red blood cell lifespan and rHuEPO-induced increases in red blood cell production rate. Analysis of the hematocrit values of the patients with the model, by use of NONMEM, a computer program for analysis of population data, reveals a nonlinear dose-response relationship with large interindividual variability (coefficient of variation) of about 50%. The estimated mean red blood cell lifespan is 64 days, with interindividual variability of about 30% (coefficient of variation). The intraindividual random variability in hematocrit about its prediction is +/- 5% of the prediction. For clinical dose adjustment, we present a method that uses only simple calculations.

Difference in Hemoglobin Concentration by Timing of Blood Sampling in Hemodialysis Patients

“…Red blood cell survival is generally believed to be short in renal failure, averaging about 60 to 80 days. 11 Dosing changes should not be driven by 2 or 3 point changes during any 1 or 2 week interval. The trend over 4 to 6 weeks should be analyzed.…”

A ‘bottom‐up’ approach for endo‐PK/PD analysis

“…The background response is: (5) Steady-state condition is assumed to exist before the start of the phlebotomy. The progenitor activation rate, f ac (t), at steady-state is: (6) The background response can then be written as:…”

“…Several PK/PD models for assessing EPO stimulation of erythropoiesis have been developed [4][5][6][7]. However, these studies utilized exogenous r-HuEPO and did not investigate the physiology of endogenous EPO produced in response to anemia.…”

Unit dosing of darbepoetin alfa for thetreatment of anemia in patients with end-stage renal disease being switched from recombinant human erythropoietin: Results of a phase IIIb, 27-week, multicenter, open-label study in Greek patients

“…The Q2W dose of darbepoetin alfa was calculated by adding 2 total weekly doses of rHuEPO and then converting to the corresponding darbe- poetin alfa dose. The calculated darbepoetin alfa dose was then rounded to the nearest of the available unit doses (10,15,20,30,40, 50, 60, 80, 100, 130, and 150 pg). Darbepoetin alfa was the only investigational agent in this study, and it was provided free of charge to the study patients.…”

“…Due to the tl/2 of circulating RBCs (-60 days in patients with chronic renal disease), it was anticipated that the Hb concentration would reach equilibrium 20 to 24 weeks after switching from rHuEPO to darbepoetin alfa. 15 The starting dose of darbepoetin alfa was determined by the patient's accumulated weekly dose of rHuEPO at the time of assignment of his or her study subject number. Maintenance weekly dosing is initially half of the adjusted dose (3 x 20 pg/kg IV body weight, which is later modified accordingly per patient for epoetin beta 16 and 75-300 pg/kg IV with adjusted doses 50 pg/kg x 3 IV for epoetinum alfa17).…”