期刊
JOURNAL OF CLINICAL PHARMACOLOGY
卷 49, 期 3, 页码 336-350出版社
WILEY
DOI: 10.1177/0091270008329559
关键词
PK/PD; target-mediated-disposition; life span model; platelets; PEG-TPOm
资金
- Johnson & Johnson Pharmaceutical Research & Development, LLC
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据