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AAPS PharmSci. 2004 March; 6(1): 86–93.
Published online 2015 July 10. doi:  10.1208/ps060109
PMCID: PMC2750944

Pharmacokinetic model of target-mediated disposition of thrombopoietin


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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