Pharmacodynamic Modelling of Recombinant Human Erythropoietin Effect on Reticulocyte Production Rate and Age Distribution in Healthy Subjects
Wojciech Krzyzanski (1) and Juan Jose Perez Ruixo (2)
(1) Department of Pharmaceutical Sciences, University at Buffalo, 547 Cooke Hall, Buffalo, NY 14260. (2) Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica, Turnhoutseweg 30, B-2340, Belgium.
Objectives: To evaluate the effect of rHu-EPO on reticulocyte production rate and age distribution in healthy subjects.
Methods: Four pharmacokinetic (PK) and pharmacodynamic (PD) non-linear mixed effect models were used to describe the time course of natural cells, and their age distribution, as a function of the hematopoietic growth factor concentrations. The models account for a) stimulation of production of progenitor cells in bone marrow (Model A); b) shortening of differentiation and maturation times of early progenitors in bone marrow (Model B); c) the combination of the two previous mechanism of action (Model C), and d) the stimulation of production of progenitor cells in bone marrow and the increase of maturation times of the circulating reticulocytes (Model D). Published data collected from 87 subjects who received a single subcutaneous dose of rHu-EPO (dose range: 20 - 160 kIU) in 3 phase I studies were used to develop and validate the PKPD model [1,2]. Model evaluation was examined using goodness of fit plots, non-parametric bootstrap and posterior predictive check.
Results: The previously published PK model describing rHu-EPO serum concentrations in healthy subjects was adopted and the individual PK parameter estimates fixed and used in all PD models [3]. If the value of the objective function (OFV) was used as a criterion of goodness of fit, the models can be ordered A > B > C >> D with Model D corresponding to the lowest OFV different from Model C by 150. Although the numbers of estimated parameters (fixed effect + interindividual variability + residual variability) were ordered inversely 9 < 11 = 11 < 13, the notable change in the OFV (Akaike Information Criterion) indicated Model D as the best. Model validation evidenced accurate and precise prediction of model parameters and the time course of percentage of reticulocytes. Model D attributed the observed increase in reticulocyte counts to the stimulation of production of progenitor cells in bone marrow as well as transient increase in the mean maturation time of the circulating reticulocytes.
Conclusions: A semi-physiological model quantifying the hematopoietic growth factor effects on production rate of precursor cells and its age distribution were developed. The most successful model indicated an indirect and delayed effect of rHu-EPO on the age distribution of the circulating reticulocytes that augments its stimulatory effect on the bone marrow precursor cells.
References:
[1] Krzyzanski W, Perez-Ruixo JJ, An assessment of recombinant human erythropoietin effect on reticulocyte production rate and lifespan distribution in healthy subjects. Pharm. Res. (2007).
[2] Cheung WK, Goon BL, Guilfoyle MC, et al., Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects. Clin. Pharmacol. Ther. 64: 412-23 (1998).
[3] Olsson-Giskeskog P, Jacqmin P, Perez-Ruixo JJ, Population pharmacokinetics meta-analysis of recombinant human erythropoietin in healthy subjects. Clin. Pharmacokinet. 46: 159-173 (2007).
