Prediction of the human in vivo antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on in vitro platelet aggregation test
10.12793/tcp.2018.26.4.160
- Author:
Yook Hwan NOH
1
;
Sungpil HAN
;
Sangmin CHOE
;
Jin Ah JUNG
;
Jin Ah JUNG
;
Ae Kyung HWANG
;
Hyeong Seok LIM
Author Information
1. Department of Clinical Pharmacology and Therapeutics, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea. mdhslim@gmail.com
- Publication Type:Original Article
- Keywords:
Dosage scheme;
Indobufen;
In vitro;
NONMEM;
Platelet aggregation;
Population pharmacodynamics
- MeSH:
Blood Platelets;
Colon, Sigmoid;
Healthy Volunteers;
Humans;
In Vitro Techniques;
Plasma;
Platelet Aggregation;
Platelet-Rich Plasma;
Treatment Outcome
- From:Translational and Clinical Pharmacology
2018;26(4):160-165
- CountryRepublic of Korea
- Language:English
-
Abstract:
Indobufen (Ibustrin®), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using NONMEM® and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0–128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid I(max) model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.
