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Books: 0	Journals: 1	Articles: 4

Original Research

Modeling of the LDL cholesterol-lowering effect of atorvastatin in Korean dyslipidemic patients and non-patient volunteers

Eun Sil Oh, Sang-Hak Lee, Min Soo Park, Kyungsoo Park and Jae-Yong Chung

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Volume 50 p. 647 - 656

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 9/2012 (647-656)

Modeling of the LDL cholesterol-lowering effect of atorvastatin in Korean dyslipidemic patients and non-patient volunteers

Eun Sil Oh¹, Sang-Hak Lee², Min Soo Park¹,³, Kyungsoo Park¹,⁴ and Jae-Yong Chung¹,⁴

¹Department of Clinical Pharmacology, Yonsei University Severance Hospital, ²Cardiology Division, Department of Internal Medicine, ³Department of Pediatrics, and ⁴Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
Objective: The aim of this study was to develop a longitudinal pharmacodynamic model describing the time-courses of low-density lipoprotein cholesterol (LDL) profiles during and after atorvastatin treatment in Korean dyslipidemic patients and non-patient volunteers. Methods: 15 dyslipidemic patients and 11 non-patient volunteers with no prior therapy participated in a parallel, 2-step dose escalation study. Subjects received atorvastatin doses ranging from 10 to 80 mg for 42 days (dyslipidemic patients) or 10 mg for 21 days (non-patient volunteers). Plasma samples were collected before and during the treatment period and up to 2 weeks after the last administration. A population pharmacodynamic model was built using the NONMEM software package. An indirect response model consisting of production in hepatocyte and elimination from plasma stimulated by atorvastatin described the LDL time-course. Results: The typical population value of the estimated dose producing 50% of maximal stimulation on LDL elimination (SD50) for dyslipidemic patients was 11.9 mg, which was about 6 times higher than that of non-patient volunteers (2.0 mg). Conclusion: A longitudinal population pharmacodynamic model for the LDL-lowering effect of atorvastatin in both dyslipidemic patients and non-patient volunteers was developed. This could help guide optimal therapies according to the target population.Correspondence to:
Dr. Jae-Yong Chung, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Seoul National University College of Medicine and Bundang Hospital
300 Gumi-dong, Bundanggu,
Seongnam, Kyounggi 463-707, Korea
Email: [email protected]

Original

The MATE1 rs2289669 polymorphism affects the renal clearance of metformin following ranitidine treatment

Sung Kweon Cho and Jae-Yong Chung

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Volume 54 p. 253 - 262

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 4/2016 (253-262)

The MATE1 rs2289669 polymorphism affects the renal clearance of metformin following ranitidine treatment

Sung Kweon Cho¹ and Jae-Yong Chung²

¹Department of Pharmacology, Yonsei University College of Medicine, Seoul, and ²Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea
Purpose: Human multidrug and toxin extrusion member 1 (MATE1, SLC47A1) and Organic Cation Transporter 2 (OCT2, SLC22A2) play important roles in the renal elimination of various pharmacologic agents, including the anti-diabetic drug metformin. The goal of this study was to determine the association between metformin’s pharmacokinetics and pharmacodynamics and the genetic variants of MATE1 (rs2289669) and OCT2 (rs316019) before and after treatment with the potential MATE inhibitor, ranitidine. Methods: We recruited 26 healthy Koreans balanced across the OCT2 and MATE1 genetic variants, and conducted a prospective clinical trial to investigate their effects on metformin’s pharmacokinetics and pharmacodynamics before and after ranitidine treatment. Results: Neither MATE1 rs2289669 nor OCT2 rs316019 affected metformin’s pharmacokinetics and pharmacodynamics before ranitidine treatment. However, the renal clearance of metformin was significantly higher (15.2%) after ranitidine treatment in the MATE1 GG group compared with the MATE1 GA + AA group. Only the effect of MATE1 on the renal clearance of metformin after ranitidine treatment was significant (b = –0.465, p ≤ 0.05) after including demographic data and the OCT2 genotype in the model. Conclusion: Our study suggests that MATE1 rs2289669 may be a significant determinant in the renal clearance of metformin in the case of transporter-mediated drug interactions.Correspondence to:
Dr. Jae-Yong Chung,MD, PhD
Seoul National University Bundang Hospital
173-82 Gumi-ro, Bundang-gu, Seongnam,
Kyounggi 463-707, Korea
Email: [email protected]

Bioavailability Section

Pharmacokinetic comparison of gemigliptin 50 mg and metformin 500 mg as a fixed-dose combination and loose combination 

Sang Won Lee, Sang-In Park, SeungHwan Lee, Jae-Yong Chung, and Kyung-Sang Yu

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Volume 57 (2019) p. 117 - 124

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 57 – No. 2/2019 (117-124)

Pharmacokinetic comparison of gemigliptin 50 mg and metformin 500 mg as a fixed-dose combination and loose combination 

Sang Won Lee¹, Sang-In Park¹, SeungHwan Lee¹, Jae-Yong Chung², and Kyung-Sang Yu¹

¹Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, ²Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea
Background: Metformin and dipeptidyl peptidase-4 (DPP-IV) inhibitors are commonly combined to treat patients with diabetes mellitus (DM). A new fixed-dose combination (FDC) drug containing gemigliptin, a DPP-IV inhibitor, and sustained-release metformin has been developed. This study aimed to compare the PKs and tolerability of FDC versus loose combination of gemigliptin 50 mg and metformin 500 mg. Materials and methods: A randomized, open-label, two-treatment, two-period, two-sequence, crossover study was conducted in 28 healthy subjects, who received a single oral dose of an FDC tablet of gemigliptin (50 mg) and sustained-release metformin (500 mg) or were coadministered gemigliptin (50 mg) and extended-release metformin (500 mg) with a 1-week washout. Serial blood samples were collected up to 48 hours after study drug administration, and the plasma concentrations of gemigliptin, LC15-0636 (active metabolite of gemigliptin), and metformin were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were derived using a noncompartmental method. Safety and tolerability were evaluated based on vital signs, adverse events, clinical laboratory tests, and electrocardiography. Results: The concentration-time profiles of gemigliptin and metformin were similar when they were administered as FDC or were coadministered. The geometric mean ratio (GMR) and its 90% CIs of Cmax for gemigliptin, LC15-0636, and metformin were 0.93 (0.85 – 1.02), 1.00 (0.94 – 1.06), and 1.03 (0.98 – 1.09), respectively. The corresponding values of AUClast were 0.97 (0.93 – 1.01), 1.00 (0.97 – 1.04), and 1.00 (0.95 – 1.05), respectively. There were no clinically meaningful differences in safety and tolerability. Conclusion: When comparing the AUClast and Cmax of gemigliptin, LC15-0636, and metformin, the 90% CIs were all within the range of 0.8 – 1.25, which is the commonly accepted range for evaluating bioequivalence.Correspondence to:
Kyung-Sang Yu, MD, PhD 
Department of Clinical Pharmacology and Therapeutics
Seoul National University College of Medicine and Hospital
101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea 
Email: [email protected]

Original Research

Multiple-dose pharmacokinetics and safety of amoxicillin/clavulanate in healthy elderly subjects 

Sang Won Lee, Yewon Choi, Kyungho Jang, Seo Hyun Yoon, and Jae-Yong Chung

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Volume 58 (2020) p. 634 - 641

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 58 – No. 11/2020 (634-641)

Multiple-dose pharmacokinetics and safety of amoxicillin/clavulanate in healthy elderly subjects 

Sang Won Lee¹, Yewon Choi², Kyungho Jang³, Seo Hyun Yoon¹, and Jae-Yong Chung⁴

¹Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, ²Genosco Inc., Cambridge, MA, USA, ³Center for Clinical Pharmacology, Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Jeonbuk, and ⁴Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea
Background: Amoxicillin/clavulanate is a widely used oral formulation of penicillin combined with a β-lactamase inhibitor. When using amoxicillin/clavulanate in the elderly, the risk of adverse drug reaction may be greater. This study aimed to evaluate the pharmacokinetics (PKs) and safety of multiple-dose amoxicillin/clavulanate administration in healthy elderly subjects and to compare the observed PK profiles with those in healthy younger adults. An open-label, one-sequence, multiple administration study was conducted in 16 healthy elderly subjects.
Materials and methods: Subjects orally received amoxicillin and clavulanate 750/187.5 twice daily for 9 days. For PK analysis, serial blood samples were collected up to 12 hours after the last administration of amoxicillin/clavulanate. The demographic and PK data of this study were compared to those of healthy young adults from a separate study with a similar design. Safety assessments including clinical laboratory tests, physical examination, vital signs, and adverse event (AE) monitoring were performed throughout the study.
Results: All AEs were mild, and no serious AEs were reported in this study. The systemic exposure of amoxicillin and clavulanate was ~ 90% and 60% higher, respectively, in the elderly subjects than in the younger subjects. However, the time required to reach maximum concentration at steady state and the elimination half-life were similar in the two age groups.
Conclusion: Although multiple administration of amoxicillin/clavulanate 750/187.5 mg was safe and well-tolerated, the systemic exposure of amoxicillin and clavulanate was higher in elderly subjects than in younger subjects.Correspondence to:
Jae-Yong Chung, MD, PhD 
Department of Clinical Pharmacology and Therapeutics
Seoul National University College of Medicine  and Bundang Hospital
Seongnam, Republic  of Korea
Email: [email protected]

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