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: Mahesh N Samtani, Juan Jose Perez-Ruixo, Kathryn H Brown, Dirk Cerneus, Christopher J Molloy
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 49 Issue 3 Pg. 336-50 (Mar 2009) ISSN: 0091-2700 [Print] England
• PMID: 19246731 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Thrombopoietin
• Polyethylene Glycols
• Thrombopoietin

Topics

• Adult
• Computer Simulation
• Double-Blind Method
• Half-Life
• Humans
• Injections, Intravenous
• Male
• Models, Biological
• Platelet Count
• Polyethylene Glycols (adverse effects, pharmacokinetics, pharmacology)
• Receptors, Thrombopoietin (agonists)
• Thrombopoietin (adverse effects, pharmacokinetics, pharmacology)
• Time Factors