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 (k(on)) was 0.055 h(-1).pM(-1) and the first-order dissociation constant (k(off)) was estimated as 2.5 h(-1), rendering the equilibrium dissociation constant K(d) as 45.5 pM. This model may be relevant to other therapeutic agents with receptor-mediated endocytotic disposition.
Jin
Feng
F
Department of Pharmaceutical Sciences, 565B Hochstetter Hall, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260, USA.
Krzyzanski
Wojciech
W
D001682:Biological Availability; D004705:Endocytosis / Q000502:physiology*; D006207:Half-Life; D008956:Models, Chemical; D017711:Nonlinear Dynamics; D013926:Thrombopoietin / Q000493:pharmacokinetics*
D013926:Thrombopoietin