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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.

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 Imax 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.

SUBMITTER: Noh YH

PROVIDER: S-EPMC6989252 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Prediction of the human <i>in vivo</i> antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on <i>in vitro</i> platelet aggregation test.

Noh Yook-Hwan YH Han Sungpil S Choe Sangmin S Jung Jin-Ah JA Jung Jin-Ah JA Hwang Ae-Kyung AK Lim Hyeong-Seok HS

Translational and clinical pharmacology 20181219 4

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 ...[more]

PMID: 32055570

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Project description:BackgroundDual antiplatelet therapy (DAPT) is recommended in patients undergoing off-pump coronary artery bypass graft surgery (OPCAB). Clopidogrel is less effective among patients with loss-of-function (LoF) of CYP2C19 alleles, while ticagrelor has direct effects on P2Y12 receptor. Whether a CYP2C19 genotype plus platelet aggregation test (PAgT)-guided DAPT after CABG could improve clinical outcomes remain uncertain.Materials and methodsFrom August 2019 to December 2020, 1,134 consecutive patients who underwent OPCAB received DAPT for 1 year after surgery in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. According to the actual treatment they received in real-world, 382 (33.7%) of them received a traditional DAPT: aspirin 100 mg qd + clopidogrel 75 mg qd, no matter the CYP2C19 genotype and response in platelet aggregation test (PAgT). The other 752 (66.3%) patients received an individual DAPT based on CYP2C19 genotype and PAgT: aspirin 100 mg qd + clopidogrel 75 mg qd if CYP2C19 was extensive metabolizer, or moderate metabolizer but normal response in PAgT; aspirin 100 mg qd + ticagrelor 90 mg bid if CYP2C19 was poor metabolizer, or moderate metabolizer but no or low response in PAgT. One-year follow-up was achieved for all patients. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. The safety outcome was thrombolysis in myocardial infarction (TIMI) criteria major bleeding.ResultsCompared with the traditional DAPT group, the risk of MACE in the individual DAPT group was significantly lower (5.5 vs. 9.2%, HR 0.583; 95% CI, 0.371-0.915; P = 0.019), mainly due to the decreased risk of MI (1.7 vs. 4.2%, HR 0.407; 95% CI, 0.196-0.846; P = 0.016). The risk of TIMI major bleeding events was similar between the two groups (5.3 vs. 6.0%, RR 0.883; 95% CI, 0.537-1.453; P = 0.626).ConclusionFor patients who underwent OPCAB, individual DAPT (CYP2C19 genotype plus PAgT-guided strategy) was associated with a lower risk of MACE and a similar risk of major bleeding.

Dataset Information

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.

Publications

Prediction of the human <i>in vivo</i> antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on <i>in vitro</i> platelet aggregation test.

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