Transl Clin Pharmacol.  2018 Dec;26(4):160-165. 10.12793/tcp.2018.26.4.160.

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 YH
• Han S
• Choe S
• Jung JA
• Jung JA
• Hwang AK
• Lim HS

• KMID: 2429511
• DOI: http://doi.org/10.12793/tcp.2018.26.4.160

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.

Keyword

Dosage scheme; Indobufen; In vitro; NONMEM; Platelet aggregation; Population pharmacodynamics

MeSH Terms

Blood Platelets*
Colon, Sigmoid
Healthy Volunteers
Humans*
In Vitro Techniques*
Plasma
Platelet Aggregation*
Platelet-Rich Plasma
Treatment Outcome

Figure

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  Figure 1 Schematic flow of the study design. Css, steady state concentration of R- and S-indobufen.

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  Figure 2 Diagnostic plots of the final in vitro PD model. Left, observed vs. predicted (open circles: individual prediction, filled triangles: population prediction). Right, population predicted vs. conditional weighted residuals (CWRES).

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  Figure 3 Response surface plot for model predicted median versus observed (black circle) maximum platelet inhibition on various combination of R- and S-indobufen.

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  Figure 4 Simulated pharmacodynamic effect of R- and S-indobufen. The black horizontal dotted line indicates the median predicted maximal platelet aggregation (MPA) on multiple dosing of indobufen at 400 mg/day, which is 35.60 % and was obtained from Monte-Carlo simulation using the average steady state concentrations of S- and R-indobufen in a literature[5] and the PD model constructed in this study; The blue horizontal dotted line indicates the median MPA on multiple dosing of R-indobufen only at 200 mg/day, which is 11.90 % and was obtained from Monte-Carlo simulation using the clearance of R-indobufen in a literature[5] and the PD model; The gray horizontal dotted line indicates the median MPA on multiple dosing of S-indobufen only at 200 mg/day, which is 7.58 % and was obtained from Monte-Carlo simulation using the clearance of S-indobufen in a literature[5] and the PD model. *Platelet aggregation was determined using a Chrono-log Lumi-Aggregometer as the percent change from the baseline.

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