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- Title
Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals.
- Authors
Krzyzanski, Wojciech; Sutjandra, Liviawati; Perez-Ruixo, Juan; Sloey, Bethlyn; Chow, Andrew; Wang, Yow-Ming
- Abstract
Purpose: Romiplostim is a novel thrombopoiesis-stimulating peptibody that targets the thrombopoietin c-Mpl receptor, resulting in increased platelet production. The pharmacodynamic-mediated disposition (PDMDD) and its stimulatory effect on platelet production in Sprague-Dawley rats, rhesus monkeys, and cynomolgus monkeys following IV bolus and SC administration at various dose levels were determined. Methods: The pharmacokinetic (PK) profile was described by a PDMDD model that accounts for romiplostim binding to the c-Mpl receptor. The PD model contained a series of aging compartments for precursor cells in bone marrow and platelets. The stimulatory function was described by an on-and-off function operating on the fractional receptor occupancy (RO). The threshold effect, RO, and K parameters were determinants of drug potency, whereas S reflected drug efficacy. Results: The model implicated that receptor-mediated clearance was negligible. RO estimated occupancies were 0.288, 0.385, 0.771 for rats, rhesus, and cynomolgus monkeys, respectively. The analogous estimated values of K were 4.05, 2320, and 429 ng/mL, implying that romiplostim was much more potent in rats, which was confirmed by a dose-response (ratio of peak platelet count to baseline) relationship. Conclusions: The model adequately described romiplostim serum concentrations and platelet counts in rats, rhesus monkeys, and cynomolgus monkeys, and quantified linear clearance, PDMDD, and potency of romiplostim.
- Subjects
PHARMACOKINETICS; PHARMACODYNAMICS; BLOOD platelets; DRUG administration; THROMBOPOIETIN; ANIMAL models in research; DRUG efficacy; MATHEMATICAL models
- Publication
Pharmaceutical Research, 2013, Vol 30, Issue 3, p655
- ISSN
0724-8741
- Publication type
Article
- DOI
10.1007/s11095-012-0894-2