Semi-Mechanistic Modelling and Simulation of Inhibition of Platelet Aggregation by Antiplatelet Agents

Title
Semi-Mechanistic Modelling and Simulation of Inhibition of Platelet Aggregation by Antiplatelet Agents
Author(s)
윤휘열[윤휘열]강원구이병요[이병요]박선경윤영란[윤영란]권광일[권광일]Jin Yeul Ma[Jin Yeul Ma]
Keywords
MASS-SPECTROMETRY; HEALTHY-SUBJECTS; RAT PLASMA; PHARMACOKINETICS; CLOPIDOGREL; CILOSTAZOL; TRIFLUSAL; PHARMACODYNAMICS; ASPIRIN; HUMANS
Issue Date
201410
Publisher
WILEY-BLACKWELL
Citation
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, v.115, no.4, pp.352 - 359
Abstract
Antiplatelet agents are a class of pharmaceuticals that decrease platelet aggregation and thus inhibit thrombus formation. We examined the relationships between plasma concentrations of antiplatelet agents (triflusal, clopidogrel and cilostazol) and the platelet aggregation inhibitory effect after dosing. We used triflusal, cilostazol and clopidogrel for the development of a semi-mechanistic PK/PD model. The drugs chosen are used widely and reflect various mechanisms of antiplatelet agents. Time courses of plasma concentrations of the antiplatelet agents and their platelet aggregation effects were analysed using ADPAT V. Pharmacokinetic profiles were fitted to an extended parent-metabolite pharmacokinetic model, based on a two-compartment model, and the pharmacodynamic effects of the agents were fitted to a platelet aggregation effect model that consisted of the following parameters: K-s, the active-form platelet synthesis rate constant; K, the apparent reaction rate constant of the agent and active-form platelets; Kel-PRP, the apparent rate constant of platelets; and epsilon, an intrinsic activity parameter. This semi-mechanistic PK/PD model described well the relationship between plasma concentrations of antiplatelet agents and platelet aggregation effects. In addition, the estimated parameters were suitable for the explanation of the agents and also have a good correlation with platelet characteristics, such as platelet half-life and platelet aggregation baseline effects. Specifically, we discovered the strong correlations between estimated K parameter and in vitro drug activity. We conclude that this semi-mechanistic PK/PD model explained drug PK/PD characteristics well and will be useful for accurate predictions of antiplatelet effect in the clinical situations.
URI
http://hdl.handle.net/YU.REPOSITORY/30689http://dx.doi.org/10.1111/bcpt.12222
ISSN
1742-7835
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약학대학 > 약학부 > Articles
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