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AAPS PharmSci. Mar 2004; 6(1): 86–93.
Published online Mar 9, 2004. doi:  10.1208/ps060109
PMCID: PMC2750944
Pharmacokinetic model of target-mediated disposition of thrombopoietin
Feng Jin and Wojciech Krzyzanskicorresponding author
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 565B Hochstetter Hall, 14260 Buffalo, NY
Wojciech Krzyzanski, Phone: (716)645-2942, Fax: (716)645-3693, wk/at/
corresponding authorCorresponding author.
Received August 21, 2003; Accepted February 1, 2004.
Thrombopoietin, TPO, a 353 amino acid cytokine, is a primary regulator of platelet production that was cloned recently. A target-mediated (platelet receptors) pharmacokinetic model was developed to characterize the disposition of TPO. Receptor-mediated endocytosis was assigned as the major elimination pathway in the model. A nonspecific binding compartment was also incorporated into the model. TPO concentration vs time profiles from a published phase 1 and 2 clinical trial were used to apply this model. Noncompartmental analysis demonstrated that TPO exhibits nonlinear kinetics. The proposed model captured the concentration-time profiles relatively well. The first-order internalization rate constant was estimated as 0.1 h−1. The endogenous binding capacity was estimated as 164.0 pM. The second-order binding association constant (kon) was 0.055 h−1·pM−1 and the first-order dissociation constant (koff) was estimated as 2.5 h−1, rendering the equilibrium dissociation constant Kd as 45.5 pM. This model may be relevant to other therapeutic agents with receptor-mediated endocytotic disposition.
Keywords: thrombopoietin, receptor-mediated drug disposition, pharmacodynamic model
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