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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

  • Noh, Yook-Hwan (Department of Clinical Pharmacology and Therapeutics, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Han, Sungpil (Department of Clinical Pharmacology and Therapeutics, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Choe, Sangmin (Department of Clinical Pharmacology and Therapeutics, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Jung, Jin-Ah (Department of Clinical Pharmacology and Therapeutics, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Jung, Jin-Ah (Department of Clinical Pharmacology and Therapeutics, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Hwang, Ae-Kyung (Pharmacokinetic and Pharmacogenetic Laboratory, Clinical Research Center, Asan Medical Center) ;
  • Lim, Hyeong-Seok (Department of Clinical Pharmacology and Therapeutics, University of Ulsan College of Medicine, Asan Medical Center)
  • 투고 : 2018.11.23
  • 심사 : 2018.12.12
  • 발행 : 2018.12.15

초록

Indobufen ($Ibustrin^{(R)}$), 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 $NONMEM^{(R)}$ 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.

키워드

과제정보

연구 과제번호 : Establishment of risk management platform with aim to reduce attrition of new drugs and its service

연구 과제 주관 기관 : Ministry of Trade, Industry & Energy (MI), Korea Health Industry Development Institute (KHIDI)

참고문헌

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피인용 문헌

  1. Copper-promoted direct amidation of isoindolinone scaffolds by sodium persulfate vol.19, pp.35, 2018, https://doi.org/10.1039/d1ob01054a