Abstract
Most pharmacodynamic (PD) models of cellular response assume a time-invariant (i.e., constant) cellular disposition despite known changes in the disposition with time, such as the reticulocyte residence time in the systemic circulation during stress erythropoiesis. To account for changes in cellular disposition, a comprehensive PD model that involves endogenous erythropoietin (Epo), reticulocytes, and hemoglobin responses was developed in phlebotomized sheep that considers a time-variant reticulocyte residence time and allows for the simultaneous determination of changes in the cellular disposition and cellular production. Five sheep were phlebotomized to hemoglobin concentrations of approximately 4 g/dl. Epo concentrations, reticulocytes, and hemoglobin concentrations were frequently sampled for 5–7 days prior to and 25–30 days following the phlebotomy. Initial steady-state conditions were assumed and the time-variant reticulocyte residence time in the systemic circulation was semiparametrically represented using a constrained spline function. Hemoglobin production was modeled using a Hill function via an effect site compartment. The initial steady state reticulocyte residence time in the systemic circulation was estimated as 0.477 (0.100) (mean (SD)) days, which maximally increased 2.01- to 2.64-fold higher than the initial steady-state residence time 5.95 (0.899) days post-phlebotomy (P < 0.01). On average, the residence time returned to steady-state values 15.4 (2.36) days post-phlebotomy, which was not significantly different from the initial steady-state value (P > 0.05). The baseline hemoglobin production rate was estimated at 0.0929 (0.0472) g/kg/day and the maximum production rate under stress phlebotomy was estimated at 0.504 (0.0422) g/kg/day. These data indicate that endogenously released Epo under acute anemic conditions can increase hemoglobin production approximately 5-fold. The determined increase in reticulocyte residence time produced under stress erythropoiesis is similar to the commonly reported 2- to 3-fold increase observed in human patients.
Similar content being viewed by others
References
Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (2005) Hematology: basic principles and applications, 4th edn. Elsevier Inc, USA
Brugnara C (1998) Use of reticulocyte cellular indices in the diagnosis and treatment of hematological disorders. Int J Clin Lab Res 28:1–11
Brugnara C (2000) Reticulocyte cellular indices: a new approach in the diagnosis of anemias and monitoring of erythropoietic function. Crit Rev Clin Lab Sci 37:93–130
Hillman RS, Ault KA, Rinder HM (2005) Hematology in clinical practice, 4th edn. McGraw-Hill Companies, Inc, USA
Riley RS, Ben-Ezra JM, Tidwell A, Romagnoli G (2002) Reticulocyte analysis by flow cytometry and other techniques. Hematol Oncol Clin North Am 16:373–420, vii
Hirose A, Yamane T, Shibata H, Kamitani T, Hino M (2005) Automated analyzer evaluation of reticulocytes in bone marrow and peripheral blood of hematologic disorders. Acta Haematol 114:141–145
Watanabe K, Kawai Y, Takeuchi K, Shimizu N, Iri H, Ikeda Y, Houwen B (1994) Reticulocyte maturity as an indicator for estimating qualitative abnormality of erythropoiesis. J Clin Pathol 47:736–739
Pradella M, Cavill I, d’Onofrio G (1996) Assessing erythropoiesis and the effect of erythropoietin therapy in renal disease by reticulocyte counting. Clin Lab Haematol 18:35–37
Aulesa C, Ortega JJ, Jou JM, Colomer E, Montero J, Olano E, Remacha AF, Martino R, Yoldi F, Escribano I (1994) Flow cytometric reticulocyte quantification in the evaluation of hematologic recovery—Spanish multicentric study-group for hematopoietic recovery. Euro J Haematol 53:293-297
Davis BH, Bigelow NC (1989) Flow cytometric reticulocyte quantification using thiazole orange provides clinically useful reticulocyte maturity index. Arch Pathol Lab Med 113:684–689
Batjer JD, Riddell K, Fritsma GA (1994) Predicting bone-marrow transplant engraftment by automated flow cytometric reticulocyte analysis. Lab Med 25:22–26
Dubner D, Perez MD, Barboza M, Sorrentino M, Robinson A, Gisone P (2002) Prognosis and bone marrow recovery indicators in bone marrow transplantation after total body irradiation. Med Buenos Aires 62:555–561
Noronha JFA, De Souza CA, Vigorito AC, Aranha FJP, Zulli R, Miranda ECM, Grotto HZW (2003) Immature reticulocytes as an early predictor of engraftment in autologous and allogeneic bone marrow transplantation. Clin Lab Haematol 25:47–54
Houwen B (1992) Reticulocyte maturation. Blood Cells 18:167–186
Jandl JH (1996) Blood: textbook of hematology, 2nd edn. Little, Brown and Company, USA
Veng-Pedersen P, Chapel, Schmidt RL, Al-Huniti NH, Cook RT, Widness JA (2002) An integrated pharmacodynamic analysis of erythropoietin, reticulocyte, and hemoglobin responses in acute anemia. Pharm Res 19:1630–1635
Chapel SH, Veng-Pedersen P, Schmidt RL, Widness JA (2000) A pharmacodynamic analysis of erythropoietin-stimulated reticulocyte response in phlebotomized sheep. J Pharmacol Exp Ther 295:346–351
Krzyzanski W, Jusko WJ, Wacholtz MC, Minton N, Cheung WK (2005) Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects. Eur J Pharm Sci 26:295-306
Ramakrishnan R, Cheung WK, Farrell F, Joffee L, Jusko WJ (2003) Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous dose administration in cynomolgus monkeys. J Pharmacol Exp Ther 306:324–331
Ramakrishnan R, Cheung WK, Wacholtz MC, Minton N, Jusko WJ (2004) Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers. J Clin Pharmacol 44:991–1002
Krzyzanski W, Ramakrishnan R, Jusko WJ (1999) Basic pharmacodynamic models for agents that alter production of natural cells. J Pharmacokinet Biopharm 27:467–489
Krzyzanski W, Woo S, Jusko WJ (2006) Pharmacodynamic models for agents that alter production of natural cells with various distributions of lifespans. J Pharmacokinet Pharmacodyn 33:125–166
Al-Huniti NH, Widness JA, Schmidt RL, Veng-Pedersen P (2005) Pharmacodynamic analysis of changes in reticulocyte subtype distribution in phlebotomy-induced stress erythropoiesis. J Pharmacokinet Pharmacodyn 32:359–376
Widness JA, Veng-Pedersen P, Modi NB, Schmidt RL, Chestnut DH (1992) Developmental differences in erythropoietin pharmacokinetics: Increased clearance and distribution in fetal and neonatal sheep. J Pharmacol Exp Therapeut 261:977–984
Peters C, Georgieff MK, Alarcon PAd, Cook RT, Burmeister LF, Lowe LS, Widness JA (1996) Effect of chronic erythropoietin administration on plasma iron in newborn lambs. Biol Neonate 70:218–228
Hutchinson MF, deHoog FR (1985) Smoothing noise data with spline functions. Numer Math 47:99–106
Mock DM, Lankford GL, Burmeister LF, Strauss RG (1997) Circulating red cell volume and red cell survival can be accurately determined in sheep using the [14C]cyanate label. Pediatr Res 41:916–921
Veng-Pedersen P (1977) Curve fitting and modelling in pharmacokinetics and some practical experiences with NONLIN and a new program FUNFIT. J Pharmacokinet Biopharm 5:513–531
Hairer E, Norsett SP, Wanner G (1993) Solving ordinary differential equations I: nonstiff problems, 2nd edn. Springer-Verlag, Berlin
Akaike H (1974) Automatic control: a new look at the statistical model identification. IEEE Trans 19:716–723
Hillman RS, Finch CA (1967) Erythropoiesis: normal and abnormal. Semin Hematol 4:327–336
Hillman RS (1969) Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia. J Clin Invest 48:443–453
Shimada A (1975) The maturation of reticulocytes. II. Life-span of red cells originating from stress reticulocytes. Acta Med Okayama 29:283–289
Stohlman F Jr (1961) Humoral regulation of erythropoiesis. VII. Shortened survival of erythrocytes produced by erythropoietine or severe anemia. Proc Soc Exp Biol Med 107:884–887
Krantz SG, Parks HR (2002) The implicit function theorem: history, theory, and applications. Birkhauser, Boston
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Freise, K.J., Widness, J.A., Schmidt, R.L. et al. Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep. J Pharmacokinet Pharmacodyn 34, 519–547 (2007). https://doi.org/10.1007/s10928-007-9056-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10928-007-9056-2