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Pharmacodynamic Analysis of Changes in Reticulocyte Subtype Distribution in Phlebotomy-Induced Stress Erythropoiesis

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Abstract

Changes in the reticulocyte subtype distribution (high, medium and low reticulocytes count (HR, MR, LR)) measured by flow cytometry following phlebotomy-induced stress erythropoiesis (abruptly dropping hemoglobin to 3–4 g/dl over 4–5 hr) and the pharmacodynamic (PD) relationship to the stimulated erythropoietin (EPO) was investigated in sheep. A PD model was developed that describes the relationship between EPO and the reticulocyte maturity distribution fractions (r=0.95±0.02, mean ± SD). The lag-time between EPO activation of erythroid progenitor cells and the subsequent increase in the least mature HR fraction in the peripheral circulation was 0.72 ± 0.08 days. The mean transition times (in days) for all three reticulocyte fractions changed at baseline from, T HR : 0.09 ± 0.06, T MR : 0.06 ± 0.04, and T LR : 0.46 ± 0.24 to T HR : 0.13 ± 0.08, T MR : 0.29 ±  0.15, and T LR : 2.3 ± 0.24 under stress erythropoiesis. The total mean residence time for a reticulocyte in the peripheral circulation, T total (T HR + T MR + T LR), increased from 0.60 ± 0.33 days under basal to 2.8 ± 0.09 days during stress erythropoiesis. The statistically significant increase observed for T LR and T total supports the hypothesis that stress erythropoiesis perturbs the mean reticulocyte transition times. A correlation analysis between various new, proposed metrics involving the HR, MR and LR fractions and the total reticulocyte count, with the latter indicative of stress erythropoiesis at higher total counts, revealed a highly significant correlation indicating these new metrics may be a valuable adjunct to the reticulocyte maturation index (RMI) and the immature reticulocyte fractions index (IRF) previously used in assessing erythropoietic activity in response to anemia

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Abbreviations

EPO:

erythropoietin

rHuEPO:

recombinant human erythropoietin

PK:

pharmacokinetics

PD:

pharmacodynamics

SD:

standard deviation

HR:

high reticulocyte

MR:

medium reticulocyte

LR:

low reticulocyte

RMI:

reticulocytes maturity index

IRF:

immature reticulocytes fraction

RIA:

radioimmunoassay

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Authors and Affiliations

  1. College of Pharmacy, The University of Iowa, Iowa City, IA, 52242, USA

    Nidal H. Al-Huniti & Peter Veng-Pedersen

  2. College of Medicine, Department of Pediatrics, The University of Iowa, Iowa City, IA, 52242, USA

    John A. Widness & Robert L. Schmidt

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  1. Nidal H. Al-Huniti
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  2. John A. Widness
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  3. Robert L. Schmidt
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  4. Peter Veng-Pedersen
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Correspondence to Peter Veng-Pedersen.

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Al-Huniti, N.H., Widness, J.A., Schmidt, R.L. et al. Pharmacodynamic Analysis of Changes in Reticulocyte Subtype Distribution in Phlebotomy-Induced Stress Erythropoiesis. J Pharmacokinet Pharmacodyn 32, 359–376 (2005). https://doi.org/10.1007/s10928-005-0009-3

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