Original Research
Multiple-dose pharmacokinetics of fesoterodine sustained-release in healthy Korean volunteers
Dongseong Shin, Kwang-Hee Shin, SeungHwan Lee, Kyoung Soo Lim, Joo-Youn Cho, In-Jin Jang, Sang-Goo Shin and Kyung-Sang Yu
Price
42.00 $
Volume 50 p. 722 - 728
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 10/2012 (722-728)
Multiple-dose pharmacokinetics of fesoterodine sustained-release in healthy Korean volunteers
Dongseong Shin, Kwang-Hee Shin, SeungHwan Lee, Kyoung Soo Lim, Joo-Youn Cho, In-Jin Jang, Sang-Goo Shin and Kyung-Sang Yu
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
Objective: Fesoterodine is a pro-drug of the active metabolite 5-hydroxymethyl tolterodine (5-HMT), a muscarinic receptor antagonist. This study aimed to evaluate the safety profile and pharmacokinetic characteristics of multiple oral doses of sustained-release fesoterodine (fesoterodine SR) in healthy Korean males. Methods: A randomized, double-blind, placebo-controlled, multiple-dose study with two oral doses (4 mg and 8 mg) was conducted in healthy Korean male participants. The study drug was administered once daily for 5 days. The plasma concentration of 5-HMT was measured up to 72 hours after the last drug administration. The CYP2D6 genotype was analyzed using polymerase chain reaction (PCR) methods to assess the effect of genetic polymorphisms on the pharmacokinetic parameters. Results: 20 participants completed the study. The mean (SD) areas under the plasma concentration-time curves during the dosing interval (AUCτ) of the 4 mg and 8 mg dose groups were 26.1 (8.0) and 64.2 (30.5) μg∙h/ml and the mean peak concentrations (Cmax) were 2.6 (0.7) and 6.0 (2.0) μg/ml, respectively, at steady-state. The mean AUCτ and Cmax of 5-HMT increased in approximately the same proportion as the dose increased. Fesoterodine SR was well tolerated without any serious adverse events or abnormal clinical laboratory findings. Conclusion: Systemic 5-HMT exposure showed dose-proportional characteristics in the 4 mg to 8 mg dose range in healthy Korean males. Thus, 4 mg or 8 mg doses of fesoterodine SR taken once-daily were tolerable in healthy Korean males.Correspondence to:
Kyung-Sang Yu, MD, PhD
Department of Clinical Pharmacology and Therapeutics Seoul
National University College of Medicine and Hospital Seoul
101 Daehangno, Jongno-gu
Seoul 110-744, Korea
Email: [email protected]
Bioavailability Section
Comparative pharmacokinetic and bioequivalence evaluation of two formulations of morniflumate 350-mg tablets in healthy male subjects
Heechan Lee, Sung-Vin Yim, Bo-Hyung Kim, SeungHwan Lee
Price
42.00 $
Volume 55 (2017) p. 95 - 101
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (95-101)
Comparative pharmacokinetic and bioequivalence evaluation of two formulations of morniflumate 350-mg tablets in healthy male subjects
Heechan Lee1,2, Sung-Vin Yim3, Bo-Hyung Kim3,4, SeungHwan Lee2
1Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, College of Medicine and Hospital, 3Department of Clinical Pharmacology and Therapeutics, and 4East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Korea
Background: Morniflumate is a nonsteroid anti-inflammatory drug (NSAID) that inhibits cyclooxygenase-1, 2 (COX-1, 2). Objective: This study aimed to compare the pharmacokinetics (PKs) and assess the bioequivalence of two different formulations of morniflumate 350-mg tablets in healthy Korean male subjects. Methods: A randomized, single-dose, two-period, two-sequence crossover study was conducted with 38 subjects. Subjects received a single dose of two tablets of either a test or a reference formulation and the alternated formulation in the next period. Serial blood samples for the PK analysis were collected over 12 hours. PK parameters were determined by a noncompartment analysis. PK parameters, including the maximum concentration (Cmax) and the area under-the-concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) were compared in bioequivalence tests. Results: The Cmax of the test and reference formulations were 985.72 ± 6.80 mg/L and 947.09 ± 6.73 mg/L, respectively, while the AUClast values were 2675.92 ± 7.84 mg×h/L and 2653.06 ± 7.78 mg×h/L, respectively. The geometric mean ratios (90% confidence interval) of the test formulation to the reference formulation for Cmax and AUClast were 1.0715 (0.9469 – 1.2124) and 1.0592 (0.9592 – 1.1695), respectively. Conclusions: The new formulation of morniflumate 350-mg tablet showed a PK profile similar to that of the marketed formulation, and the results of this study fell within in the conventional criteria of bioequivalence.
Correspondence to:
SeungHwan Lee, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Seoul National University Hospital and College of Medicine
Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
Email: [email protected]
Bioavailability Section
Pharmacokinetic comparison of two formulations of talniflumate 370 mg tablets in healthy Korean volunteers
Yun Kim, Sung- Yim, Bo-Hyung Kim, SeungHwan Lee
Price
42.00 $
Volume 55 (2017) p. 102 - 108
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (102-108)
Pharmacokinetic comparison of two formulations of talniflumate 370 mg tablets in healthy Korean volunteers
Yun Kim1#2, Sung- Yim3, Bo-Hyung Kim3#4, SeungHwan Lee2
1Program in Biomedical Radiation Sciences, Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University, College of Medicine and Hospital, 3Department of Clinical Pharmacology and Therapeutics, and 4East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Korea
Background: Talniflumate, a prodrug of niflumic acid, is a potent analgesic and anti-inflammatory drug that has been widely used for the treatment of rheumatoid diseases. Objective: The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two formulations of talniflumate 370 mg tablets (test formulation: Flumagen® 370 mg tablet; reference formulation: Somalgen® 370 mg tablet). Methods: A randomized, open-label, single dose, two-sequence, two-period crossover clinical study was conducted. After oral administration of the study drug in each period, blood samples were collected up to 15 hours post-dose. The plasma concentration of niflumic acid, a metabolite of talniflumate, was determined using HPLC-MS/MS. The pharmacokinetic parameters were estimated by non-compartmental method. Results: The maximum plasma concentration (Cmax) and area under the concentration-time curve from zero to the time point with the last measurable concentration (AUClast) for the test formulation were 290.7 ± 199 µg/L and 1,154 ± 643 µg×h/L, respectively, and the corresponding values for the reference formulation were 286.8 ± 193 µg/L and 1,151 ± 577 µg×h/L, respectively. The geometric mean ratio and 90% confidence intervals (CI) of the test formulation to the reference formulation for the Cmax and AUClast were 0.983 (0.829 – 1.166) and 0.979 (0.856 – 1.121), respectively. Conclusions: The pharmacokinetic profiles of the test and reference formulations were found not to be significantly different, meeting the Korean regulatory criteria for bioequivalence.
Correspondence to:
SeungHwan Lee, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Seoul National University
College of Medicine and Hospital
Daehak-ro, Jongno-gu, Seoul, 03080, Korea
Email: [email protected]
Bioavailability Section
The pharmacokinetic comparison and bioequivalence evaluation of two 10-mg baclofen formulations in healthy male subjects
Sumin Yoon, SeungHwan Lee, Kyung-Sang Yu, Sung-Vin Yim, Bo-Hyung Kim
Price
42.00 $
Volume 55 (2017) p. 194 - 200
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (194-200)
The pharmacokinetic comparison and bioequivalence evaluation of two 10-mg baclofen formulations in healthy male subjects
Sumin Yoon1, SeungHwan Lee1, Kyung-Sang Yu1, Sung-Vin Yim2, Bo-Hyung Kim2#3
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Department of Clinical Pharmacology and Therapeutics, and 3East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Korea
Backgrounds: Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients. It depresses the transmission of monosynaptic and polysynaptic reflex by stimulating GABAβ (gamma-aminobutyric acid) receptors. Objectives: The aim of this study was to compare the pharmacokinetic characteristics of two 10-mg baclofen formulations and to assess bioequivalence. Methods: A randomized, single-dose, two-period, two-sequence crossover study was conducted in healthy male subjects. Each subject received the test or reference formulations. After washout period, all subjects received the alternative formulation. Blood samples were collected for up to 24 hours after the dose in each period. Pharmacokinetic (PK) parameters, including tmax, Cmax, and AUClast were calculated by noncompartmental methods. The geometric mean ratio (GMR) of the test to the reference formulation and its 90% confidence interval (CI) for Cmax and AUClast were calculated for assessment of bioequivalence. Results: A total of 22 subjects completed the study. The median tmax of the test and the reference formulation were 1.50 and 1.25 hours, respectively. The mean (± SD) Cmax of the test and the reference formulation were 141.401 ± 29.447 ng/mL and 138.837 ± 31.392 ng/mL, respectively. The mean (± SD) AUClast of the two formulations were 702.404 ± 82.149 ng×h/mL and 726.803 ± 90.638 ng×h/mL, respectively. The GMR (90% CI) of the test to the reference formulation for the Cmax and AUClast were 1.0306 (0.9564 – 1.1106) and 0.9674 (0.9437 – 0.9916), respectively. Conclusions: The two different baclofen 10-mg formulations had similar PK profiles and were bioequivalent based on Cmax and AUClast.
Correspondence to:
Bo-Hyung Kim, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Kyung Hee University College of Medicine and Hospital
23 Kyungheedae-ro, Dongdaemun-gu,
Seoul 02447, Korea
Email: [email protected]
Bioavailability Section
Bioequivalence of two formulations of pregabalin 150-mg capsules under fasting conditions in healthy male subjects
Hyun Lee, SeungHwan Lee, Sung-Vin Yim, Bo-Hyung Kim
Price
42.00 $
Volume 55 (2017) p. 171 - 176
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (171-176)
Bioequivalence of two formulations of pregabalin 150-mg capsules under fasting conditions in healthy male subjects
Hyun Lee1,2, SeungHwan Lee2, Sung-Vin Yim3, Bo-Hyung Kim3,4
1Program in Biomedical Radiation Sciences, Program in Biomedical Radiation Sciences, Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 3Department of Clinical Pharmacology and Therapeutics, and 4East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Korea
Background: Pregabalin binds to the α2δ auxiliary subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems and modulate calcium-dependent neurotransmitter release. Pregabalin is indicated for the treatment of peripheral and central neuropathic pain, partial seizures with or without secondary generalization, and treatment of generalized anxiety disorder (GAD). Objective: The purpose of this study was to assess the bioequivalence of two different formulations of pregabalin 150-mg capsules in healthy Korean male subjects under fasting conditions. Methods: This bioequivalence study was based on an open-label, single-dose, randomized, 2-period, 2-sequence crossover design with a washout period of 7 days. Blood samples for pharmacokinetic (PK) evaluation were collected up to 24 hours postdose. Plasma concentrations of pregabalin were determined using a validated LC-MS/MS method. PK parameters were determined using noncompartmental analysis. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of log-transformed Cmax and AUClast values met the bioequivalence criteria specified by Korean regulatory guidelines (90% CI 0.8 – 1.25). Results: The extent of exposure in terms of AUClast amounted to 26,018.3 – 3,580.8 µg×h/L for the test formulation and 25,680.2 ± 3,083.6 µg×h/L for the reference formulation. Cmax reached values of 4,782.7 ± 1,124.2 µg/L and 4,654.0 ± 911.4 µg/L for the test product and reference product, respectively. The geometric mean ratio and 90% CIs of the test product to the reference product were 1.0132 (0.9862 – 1.0351) for AUClast and 1.0153 (0.9351 – 1.1044) for Cmax, which were well within the range necessary to establish bioequivalence (90% CI 0.8 – 1.25). Conclusions: The bioequivalence between test and reference formulations under fasting conditions was confirmed both in terms of the rate and extent of absorption.
Correspondence to:
Bo-Hyung Kim, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Kyung Hee University College of Medicine and Hospital
23 Kyungheedae-ro, Dongdaemun-gu,
Seoul 130-872, Korea
Email:
[email protected]
Bioavailability Section
Pharmacokinetic comparison using two tablets of an evogliptin/metformin XR 2.5/500 mg fixed dose combination vs. 1 tablet each of evogliptin 5 mg and metformin XR 1,000 mg
Sumin Yoon, Su-jin Rhee, Sang-In Park, Seo Hyun Yoon, Joo-Youn Cho, In-Jin Jang, SeungHwan Lee, Kyung-Sang Yu
Price
42.00 $
Volume 55 (2017) p. 533 - 539
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 6/2017 (533-539)
Pharmacokinetic comparison using two tablets of an evogliptin/metformin XR 2.5/500 mg fixed dose combination vs. 1 tablet each of evogliptin 5 mg and metformin XR 1,000 mg
Sumin Yoon1, Su-jin Rhee1, Sang-In Park1, Seo Hyun Yoon1, Joo-Youn Cho1, In-Jin Jang1, SeungHwan Lee1,2, Kyung-Sang Yu1
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, and 2Clinical Trials Center, Seoul National University Biomedical Research Institute, Seoul, Republic of Korea
Objectives: The aim of this study was to compare the pharmacokinetic (PK) characteristics of evogliptin and metformin following the administration of 2 evogliptin/metformin extended-release (XR) 2.5/500 mg FDC tablets with the coadministration of separate evogliptin 5-mg and metformin XR 1,000-mg tablets (separate formulations). Methods: A randomized, two-period, two-sequence crossover study was conducted. Subjects were randomly assigned to receive 2 FDC tablets or the individual tablets, followed by a 14-day washout period and the administration of the alternate treatment. Blood samples were collected predose and up to 72 hours postdose for each period. PK parameters including Cmax and AUClast were calculated. The geometric mean ratios (GMRs) and the 90% confidence intervals (CIs) between FDC and the separate formulations were calculated for the Cmax and AUClast of evogliptin and metformin. Results: 33 subjects completed the study. The GMR (90% CI) values of Cmax and AUClast for evogliptin were 1.011 (0.959 – 1.066) and 1.010 (0.977 – 1.043), respectively. The GMR (90% CI) values of Cmax and AUClast for metformin were 0.892 (0.827 – 0.963) and 0.893 (0.841 – 0.947), respectively. There was no significant difference between the FDC and separate formulations regarding the occurrence of adverse events. All drug-related adverse events were considered to be mild and resolved without any treatment. Conclusions: Two FDC tablets of evogliptin/metformin XR 2.5/500 mg showed a similar PK profile to the separate formulations of evogliptin 5 mg and metformin XR 1,000 mg. All of the 90% CIs of GMR satisfied the regulatory bioequivalence criteria of 0.800 – 1.250.
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, Republic of 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
Price
42.00 $
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 C<sub>max</sub> 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 AUC<sub>last</sub> 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 AUC<sub>last</sub> and C<sub>max</sub> 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]
Bioavailability Section
Pharmacokinetic comparison between tablet of varenicline tartrate and orally disintegrating film of varenicline salicylate in healthy subjects
Eunwoo Kim, Jun Gi Hwang, Su Jun Park, Ji Young Han, Young-Sim Choi, Se-Rin Park, Kyung-Sang Yu, Min Kyu Park, and SeungHwan Lee
Price
42.00 $
Volume 59 (2021) p. 478 - 484
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 59 – No. 6/2021 (478-484)
Pharmacokinetic comparison between tablet of varenicline tartrate and orally disintegrating film of varenicline salicylate in healthy subjects
Eunwoo Kim1, Jun Gi Hwang1#2, Su Jun Park3, Ji Young Han3, Young-Sim Choi2, Se-Rin Park2, Kyung-Sang Yu1, Min Kyu Park2, and SeungHwan Lee1#4
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2Department of Clinical Pharmacology and Therapeutics, Chungbuk National University Hospital, Cheongju-si, Chungcheongbuk-do, 3CTCBIO Inc., Ansan-si, Gyeonggi-do, and 4Clinical Trials Center, Seoul National University Hospital, Seoul, Republic of Korea
Objective: Varenicline is an efficacious aid for smoking cessation. In this study, the pharmacokinetics and safety were compared between film-coated tablets of varenicline tartrate (reference drug) and the newly developed orally disintegrating films of varenicline salicylate (test drug), both of them contained 1 mg of varenicline.
Materials and methods: A randomized, open-label, single-dose, two-sequence, two-period crossover study was conducted in healthy male subjects. Serial blood samples were obtained for up to 72 hours in each period, with a washout period of 7 days or more. The pharmacokinetic parameters were calculated using the noncompartmental method. Safety profiles were assessed throughout the study.
Results: A total of 28 subjects completed the study. The plasma varenicline concentration-time profiles were similar for the two study drugs. The maximum plasma varenicline concentration (Cmax) was 5,768.95 ng/L (mean) and 5,780.55 ng/L for the test drug and reference drug, respectively. The areas under the concentration-time curve from time 0 to the last measurable time point (AUC0–t) were 94,086.30 h×ng/L and 89,958.55 h×ng/L for the test drug and reference drug, respectively. The geometric mean ratios (90% confidence intervals) of the test drug to the reference drug for Cmax and AUC0–t were 0.9955 (0.9488 – 1.0444) and 1.0449 (0.9848 – 1.1088), respectively, which fell within the bioequivalence range of 0.8 – 1.25. There was no difference in safety between the study drugs.
Conclusion: The pharmacokinetics and safety profiles were similar between the two study drugs. The orally disintegrating film of varenicline salicylate can be an alternative to varenicline tartrate tablets.Correspondence to:
SeungHwan Lee,
MD, PhD
Department of Clinical Pharmacology and Therapeutics
Seoul National University College of Medicine and Hospital
101 Daehak-ro, Jongno-gu,
Seoul 03080,
Republic of Korea
Email: [email protected]
