title: Pharmacokinetic and pharmacodynamic modeling of pegylated thrombopoietin mimetic peptide (PEG-TPOm) after single intravenous dose administration in healthy subjects.
abstract: Pegylated thrombopoietin mimetic peptide (PEG-TPOm) is a novel, potent thrombopoietin receptor agonist with low immunotoxicity potential that protects against chemotherapy-induced thrombocytopenia in preclinical animal models. The aim of this study was to develop a population pharmacokinetic and pharmacodynamic model of PEG-TPOm following single intravenous doses in healthy subjects. Data were obtained from a double-blind, randomized, placebo-controlled study. A model based on target-mediated drug disposition and precursor pool life spans was applied. Model evaluation was performed through predictive checks and bootstrap analysis. The half-life of PEG-TPOm ranged between 18 and 36 hours, and the estimated distributional volume was 5 L. The increase in platelet counts was observed after a 4-day delay, consistent with the megakaryocyte cell life span. The platelet life span was estimated to be 5 days. After maximum platelets counts were achieved on day 9, platelets returned back to baseline on day 29. Model-based simulations were undertaken to explore pharmacodynamic effects after multiple dosing. Weekly dosing produced a sustained pharmacodynamic response, whereas an interdosing interval >or=2 weeks resulted in fluctuating pharmacodynamic profiles. Thus, the mechanistic pharmacokinetic/pharmacodynamic model was suitable for describing the complex PEG-TPOm pharmacokinetics/pharmacodynamics, including target-mediated disposition, dose-dependent platelet stimulation, and mean life spans of thrombopoietic cell populations.
authors.affiliation: Clinical Pharmacology, Advanced PK-PD Modeling and Simulation, Johnson & Johnson Pharmaceutical R&D, 920 Route 202, PRD 2723, Raritan, NJ 08869, USA. MSamtani@its.jnj.com
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Samtani
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Perez-Ruixo
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Brown
authors.forename: Dirk
authors.initials: D
authors.lastname: Cerneus
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Molloy
mesh_terms: D000328:Adult; D003198:Computer Simulation; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D010976:Platelet Count; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D013926:Thrombopoietin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D053628:Receptors, Thrombopoietin; D011092:Polyethylene Glycols; D013926:Thrombopoietin