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Prediction of the Pharmacokinetics and Pharmacodynamics of Gemigliptin after Multiple Oral Doses of Gemigliptin/Metformin Sustained Release Fixed-Dose Combination Tablet by Modeling and Simulation in Healthy Subjects : 건강 자원자에서 모델링 및 시뮬레이션을 통해 Gemigliptin/Metformin 서방정 복합제 다회 투여 후 Gemigliptin의 약동학 및 약력학적 특성을 예측하기 위한 연구

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의과대학 의과학과
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서울대학교 대학원
pharmacokineticspharmacodynamicsmodelingsimulationgemigliptinDPP-4 inhibitor
학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2017. 2. 유경상.
Introduction: A fixed-dose combination (FDC) of gemigliptin and metformin was developed to improve patient compliance compared with separate tablets taken together. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of gemigliptin after single oral administration of the FDC were evaluated using noncompartmental analysis (NCA). In this study, the PK/PD profiles of gemigliptin after multiple oral doses of gemigliptin/metformin sustained release FDC tablets (25/500 mg  2) were predicted by modeling and simulation. Furthermore, the PK/PD profiles estimated from the simulation were compared with those from the NCA method.

Methods: A PK/PD model was developed using the data derived from previous single (from 25 to 600 mg) and multiple (from 200 to 600 mg) dose escalation studies of gemigliptin. Changes in the percent inhibition of dipeptidyl peptidase-4 (DPP-4) activity were linked to the PK model consisting of a two-compartment model with first-order absorption. To explain the PK/PD relationship, a sigmoid maximum effect (Emax) model was selected. Based on the PK/PD parameter estimates, clinical studies with multiple doses of gemigliptin either as capsules or as FDC tablets were simulated using Trial Simulator software. For the simulation with gemigliptin given as two tablets of FDC, the effect of food on the absorption rate constant was considered. The predicted PK/PD results of gemigliptin in the FDC were compared with those of gemigliptin capsules (50 mg).

Results: PK profiles of gemigliptin estimated from the population compartmental analysis generally corresponded with those from the NCA, although the mean maximum plasma concentrations (Cmax) in the 25 and 50 mg dose groups were slightly overpredicted. However, these gaps between the predicted versus observed results were lessened in the prediction of DPP-4 inhibition. The EC50 was estimated to be 2.44 μg/L by the PK/PD model, indicating the high potency of gemigliptin. In the simulation, the Cmax of gemigliptin in FDC formulation under fed conditions decreased compared with that of gemigliptin capsule under fasted conditions, while the area under the plasma concentration-time curve (AUC) were not significantly different between the two treatments.

Conclusion: The simulation based on the PK/PD model from the single and multiple dosing studies with gemigliptin adequately described the percent inhibition of DPP-4 activity after FDC administration. Further investigation of several factors including formulation, food effect, and bioavailability could be helpful for improving the absorption profiles in the PK model.
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