Pharmacokinetic and Pharmacodynamic Modeling of Pegylated Thrombopoietin Mimetic Peptide (PEG‐TPOm) After Single Intravenous Dose Administration in Healthy Subjects

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. Modelbased simulations were undertaken to explore pharmacodynamic effects after multiple dosing. Weekly dosing produced a sustained pharmacodynamic response, whereas an interdosing interval ≥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.