Abstract
The purpose of this study was to apply the target-mediated drug disposition (TMDD) pharmacokinetic (PK) model to describe binding, internalization, and turnover of erythropoietin receptor (EPOR). This model allows one to determine from free drug (C) PK data not only parameters describing linear disposition of EPO such as the elimination rate constant (k el) and volume of distribution (V c), but also the total receptor concentration (R tot0), drug–receptor complex (RC) internalization rate constant (k int), as well as synthesis and degradation rate constants (k syn and k deg) for the receptor turnover. The previously published data on PK of recombinant EPO (rHuEPO) in humans and the results of EPOR binding studies were used for analysis. The estimated PK parameters were used to simulate time courses of free and bound EPOR after IV administration of clinically relevant rHuEPO doses. The estimates of k el = 0.106 h−1 and V c = 0.032 l/kg are consistent with reported in the literature values of rHuEPO linear disposition parameters. The determined value of R tot0 was 66.35 pM and the half-life for EPOR degradation was 8.8 h. Computer simulations showed a very rapid binding phase in the EPOR time profile followed by a decline to a nadir, and a subsequent return to the baseline. The nadir values decreased with increasing doses and resulted in the maximum values of the bound fractions of the total EPOR in the ranges 33–99%. At the baseline conditions, only 3.1% of EPOR were occupied. The saturation of EPOR was correlated with the time C remained above the K D level. In conclusion, the time courses of serum rHuEPO concentrations contain information about internalization and turnover of EPOR. Kinetics of EPOR can be utilized to determine the relationship between the pharmacologic effect and exposure to rHuEPO.
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This work was supported by grant GM57980 from the National Institutes of Health and funds from the University at Buffalo and Pfizer Strategic Alliance.
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Krzyzanski, W., Wyska, E. Pharmacokinetics and pharmacodynamics of erythropoietin receptor in healthy volunteers. Naunyn-Schmied Arch Pharmacol 377, 637–645 (2008). https://doi.org/10.1007/s00210-007-0225-z
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DOI: https://doi.org/10.1007/s00210-007-0225-z