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

From Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey (Dr Samtani); Beerse, Belgium (Dr Perez-Ruixo, Dr Cerneus); High Wycombe, UK (Ms Brown); and Spring House, Pennsylvania (Dr Molloy). Current affiliations: Amgen, Inc, Thousand Oaks, California (Dr Perez-Ruixo); AstraZeneca, Macclesfield, Cheshire, UK (Ms Brown); Astellas Pharma Europe R&D, Leiderdorp, Netherlands (Dr Cerneus); Rutgers, The State University of New Jersey, Piscataway (Dr Molloy).

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 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.

Key Words: PK/PD • target-mediated-disposition • life span model • platelets • PEG-TPOm

Address for reprints: Mahesh N. Samtani, PhD, Clinical Pharmacology, Advanced PK-PD Modeling and Simulation, Johnson & Johnson Pharmaceutical R&D, 920 Route 202, PRD 2723, Raritan, NJ 08869; e-mail: MSamtani{at}its.jnj.com.

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