Pharmacodynamics-Mediated Drug Disposition (PDMDD) and Precursor Pool Lifespan Model for Single Dose of Romiplostim in Healthy Subjects

• Published in: The AAPS journal 2010-12, Vol.12 (4), p.729-740
• Main Authors: Wang, Yow-Ming C., Krzyzanski, Wojciech, Doshi, Sameer, Xiao, Jim J., Pérez-Ruixo, Juan Jose, Chow, Andrew T.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Pharmacology/Toxicology; Pharmacy; Receptors, Fc; Receptors, Thrombopoietin - agonists; Recombinant Fusion Proteins - pharmacokinetics; Recombinant Fusion Proteins - pharmacology; Reference Values; Research Article; Thrombopoietin - pharmacokinetics; Thrombopoietin - pharmacology; Young Adult
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-010-9234-9

The objective of this study was to characterize the pharmacokinetics and pharmacodynamics (PK-PD) of romiplostim after single-dose administration in healthy subjects. The mean serum romiplostim concentrations (PK data) and mean platelet counts (PD data) collected from 32 subjects receiving a single intravenous (0.3, 1 and 10 μg/kg) or subcutaneous (0.1, 0.3, 1, and 2 μg/kg) dose were fitted simultaneously to a mechanistic PK-PD model based on pharmacodynamics - mediated drug disposition (PDMDD) and a precursor pool lifespan concept. The two-compartment PK model incorporated receptor-mediated endocytosis and linear mechanisms as parallel elimination pathways. The maximal concentration of receptors (assumed to be proportional to the platelet count), the equilibrium dissociation constant, and the first-order internalization rate constant for endocytosis of the drug-receptor complex were 0.022 fg/platelet, 0.131 ng/mL, and 0.173 h −1 , respectively. Romiplostim concentration stimulates the production of platelet precursors via the Hill function, where the SC 50 was 0.052 ng/mL and S max was 11.2. The estimated precursor cell and platelet lifespans were 5.9 and 10.5 days, respectively. Model-based simulations revealed that the romiplostim exposure and the platelet response are both dependent on the dose administered and the baseline platelet counts. Also, weekly dosing produced a sustained PD response while dosing intervals ≥2 weeks resulted in fluctuating platelet counts. Thus, the mechanistic PK-PD model was suitable for describing the romiplostim PK-PD interplay (PDMDD), the dose-dependent platelet stimulation, and the lifespans of thrombopoietic cell populations.