Original Research
Pharmacokinetics of a fixed-dose glimepiride/sustained-release metformin combination
Kyu-pyo Kim, Kyoung Soo Lim, Bo-Hyung Kim, Hyun-Suk Shin, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang and Kyung-Sang Yu
Price
42.00 $
Volume 50 p. 142 - 149
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (142-149)
Pharmacokinetics of a fixed-dose glimepiride/sustained-release metformin combination
Kyu-pyo Kim1*, Kyoung Soo Lim*, Bo-Hyung Kim, Hyun-Suk Shin, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang and Kyung-Sang Yu
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea
*Both authors contributed equally to this work.
1Current affiliation: Department of Internal Medicine, Ulsan University College of Medicine and Asan Medical Center, Seoul, Korea
Objective: Pharmacokinetic (PK) profiles of glimepiride and metformin have been established for the combination drug as well as each agent individually. However, the PK profiles of a combination drug containing glimepiride and sustainedrelease (SR) metformin have not been reported. To compare the pharmacokinetic profiles of glimepiride/SR metformin (2 mg/500 mg) with the PK of immediate-release (IR) formulations, an open-label, randomized, 3-period, 3-sequence, 3-treatment, crossover study was conducted in 12 healthy subjects. Methods: After a single administration of glimepiride/SR metformin 2 mg/500 mg (Treatment) or glimepiride/metformin IR 2 mg/500 mg (Reference 1), or administration of 2 doses of glimepiride/metformin IR 1 mg/250 mg 12 h apart (Reference 2), serial blood samples were collected and drug concentrations determined by liquid chromatography/ tandem mass spectrometry. PK parameters (Cmax and AUC24) for glimepiride and metformin were log-transformed and compared using a mixed-effects model analysis of variance (ANOVA). The mean differences and 95% confidence intervals (CIs) were back-transformed to obtain geometric mean ratios along with the CIs for the ratios. Results: Treatment demonstrated similar systemic exposures for glimepiride; the geometric mean ratio (95% CIs) for glimepiride AUC24 was 1.05 (0.97 – 1.13) for Treatment relative to Reference 1 and 1.08 (1.00 – 1.17) for Treatment relative to Reference 2. The SR formulation showed a delay in the time to reach maximum concentration for metformin from 1.0 – 4.0 h to 4.0 – 8.0 h and a decreased AUC24 value; the geometric mean ratio for metformin AUC24 was 0.87 (0.74 – 1.03) for Treatment relative to Reference 1 and 0.75 (0.63 – 0.88) for Treatment relative to Reference 2. Conclusions: This study demonstrates for the first time that fixed-dose glimepiride and SR metformin 2 mg/500 mg shows a PK profile similar to that of glimepiride, but with a delayed time to maximum concentration and slightly decreased bioavailability for metformin compared with the IR fixed-dose combination, in healthy volunteers. PK profiles from this exploratory study will be helpful in designing and conducting further studies in diabetic patients.Correspondence to:
Kyung-Sang Yu, MD, PhD
Department of Pharmacology and Clinical Pharmacology
National University College of Medicine and Hospital
101 Daehangno, Jongno-gu, Seoul 110-744, Korea
Email: [email protected]
Original Research
Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15-0444 and pioglitazone in healthy volunteers
Sung Eun Kim, SoJeong Yi, Kwang-Hee Shin, Tae-Eun Kim, Min-Jeong Kim, Youn Hoa Kim, Seo Hyun Yoon, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang and Kyung-Sang Yu
Price
42.00 $
Volume 50 p. 17 - 23
Abstract
Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15-0444 and pioglitazone in healthy volunteers
Sung Eun Kim1, SoJeong Yi1, Kwang-Hee Shin1, Tae-Eun Kim1, Min-Jeong Kim2, Youn Hoa Kim3, Seo Hyun Yoon1, Joo-Youn Cho1, Sang-Goo Shin1, In-Jin Jang1 and Kyung-Sang Yu1
1Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, 2Department of Clinical Development and 3Department of DMPK, LG Life Sciences, Ltd, Seoul, Republic of Korea
Objective: LC15-0444, a newly developed selective dipeptidyl peptidase IV inhibitor, has the potential to be administered with other antihyperglycemic agents. The aim of this study was to investigate the interaction between LC15-0444 and pioglitazone by comparing the pharmacokinetics of both compounds and their metabolites. Methods: A randomized, open-label, multiple dosing, three-sequence, three-period, three-treatment crossover study was performed in healthy volunteers. The three treatment groups were comprised of LC15-0444 200 mg, pioglitazone 30 mg, or coadministration of both drugs once daily for 12 days. Blood samples were collected up to 48 hours after the last dosing. Safety and tolerability were assessed throughout the study. Results: The geometric mean ratios (GMRs; (LC15-0444+Pioglitazone coadministered)/(LC15-0444 or Pioglitazone alone)) (90% confidence intervals (CIs)) for Cmax,ss and AUCt,ss of LC15-0444 were 1.06 (0.96 – 1.16) and 0.98 (0.93 – 1.03), respectively. In the case of pioglitazone, the GMRs (90% CIs) for Cmax,ss and AUCt,ss were 0.84 (0.73 – 0.96) and 0.85 (0.76 – 0.96), respectively. All reported adverse events were mild in intensity. Conclusions: The pharmacokinetics of LC15-0444 and its metabolites were not altered by pioglitazone. The systemic exposure of pioglitazone was decreased by 15% after coadministration of LC15-0444 with pioglitazone, but this was not judged to be clinically relevant, considering the total active moiety of pioglitazone.Correspondence to:
K.-S. Yu, MD, PhD
Department of Pharmacology and Clinical Pharmacology
Seoul National University
College of Medicine and Hospital
101 Daehak-ro, Jongno-gu,
Seoul 110-744, Korea
Email: [email protected]
Original Research
A positron emission tomography microdosing study with sertraline in healthy volunteers
Kwang-Hee Shin, Kyu-pyo Kim, Kyoung Soo Lim, Ji Who Kim, Yun-Sang Lee, Bo Yeun Yang, Jae Sung Lee, Jae-Min Jung, Seo-Hyun Yoon, In-Jin Jang and Kyung-Sang Yu
Price
42.00 $
Volume 50 p. 224 - 232
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2012 (224-232)
A positron emission tomography microdosing study with sertraline in healthy volunteers
Kwang-Hee Shin1, Kyu-pyo Kim1, Kyoung Soo Lim1, Ji Who Kim2, Yun-Sang Lee2, Bo Yeun Yang2, Jae Sung Lee2, Jae-Min Jung2, Seo-Hyun Yoon1, In-Jin Jang1 and Kyung-Sang Yu1
1Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, and 2Department of Nuclear Medicine, Seoul National University College of Medicine and Hospital, Seoul, Korea
Objective: This study explored microdosing methods for evaluating the distribution and pharmacokinetics (PK) of a central nervous system (CNS) drug candidate. Methods: We used sertraline as a model drug. In this open-label, one-arm, three-period, multiple-dosing study, 10 healthy male volunteers received 6-day administrations of sertraline at doses of 5, 25 or 50 mg/d in three different periods. Before the first dose of Period 1, and 24 h after the last dose of each period, an intravenous bolus of [11C]sertraline was injected for positron emission tomography (PET) scanning. After the sixth dose in each period, serial blood samples were collected at scheduled intervals over 48 h; then serum sertraline concentrations were determined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Sertraline was distributed in the brain within 20 min, and it was highly distributed in the putamen, cingulate, and thalamus. Linearity in steady-state Cmax and AUClast were observed in the 5 – 50 mg dose range. The results suggested that microdosing with PET was a useful method for exploring the bloodbrain- barrier penetration and distribution of a candidate CNS drug. Conclusions: This study described a microdosing method that combined PET with LC-MS/MS for determining the brain distribution and PK characteristics of a CNS drug candidate.Correspondence to:
Kyung-Sang Yu, MD, PhD
Assistant Professor of Clinical Pharmacology
College of Medicine
Seoul National University Clinical Trials
Center Seoul National University Hospital
101 Daehangno, Jongno-gu,
Seoul, 110-744 Korea
Email: [email protected]
Original Research
Evaluation of intravenous midazolam limited sampling models to determine area under the concentration time curve during cytochrome P450 3A baseline, inhibition and induction or activation
Anh N. Nguyen, Justin T. Hoffman, Shirley M. Tsunoda, In-Jin Jang and Joseph D. Ma
Price
42.00 $
Volume 50 p. 468 - 475
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 7/2012 (468-475)
Evaluation of intravenous midazolam limited sampling models to determine area under the concentration time curve during cytochrome P450 3A baseline, inhibition and induction or activation
Anh N. Nguyen1, Justin T. Hoffman1, Shirley M. Tsunoda1, In-Jin Jang2 and Joseph D. Ma1
1University of California, San Diego (UCSD), Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA, and 2Seoul National University College of Medicine, Seoul, South Korea
Objective: This study evaluated if previously published limited sampling models (LSMs) accurately predict midazolam area under the concentration time curve (AUC) during cytochrome P450 (CYP) 3A baseline, inhibition and induction/activation. Materials and methods: Plasma midazolam concentrations (n = 108) were obtained where intravenous midazolam was co-administered alone or concomitantly with ketoconazole, itraconazole, aprepitant, rifampin, or pleconaril. Observed AUC was calculated using noncompartmental analysis. Predicted AUC was calculated from the LSMs. Bias and precision were determined by percent mean prediction error (%MPE), percent mean absolute error (%MAE), and percent root mean squared error (%RMSE). Results: Contrasting results were observed for LSMs in predicting CYP3A baseline activity, with the majority of studies resulting in unacceptable bias and precision. During CYP3A inhibition, unacceptable bias and precision were observed from single- and 2-time point LSMs. %MAE and %RMSE values exceeded acceptable limits during CYP3A induction with rifampin. Contrasting results were observed with pleconaril. Conclusion: The contrasting results during CYP3A baseline and induction/activation, as well as the unacceptable bias and precision during CYP3A inhibition, limits the widespread use of the previously published LSMs.Correspondence to:
Joseph D. Ma, PharmD, UCSD
Skaggs School of Pharmacy and Pharmaceutical Sciences
9500 Gilman Drive, MC 0714
La Jolla, CA 92093, USA
Email: [email protected]
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]
Original
Usefulness of oral loading of oxcarbazepine suspension in selected patients with epilepsy
Dong Wook Kim, Namyi Gu, Howard Lee, In-Jin Jang, Kon Chu, Kyung-Sang Yu, Joo-Youn Cho, Seo Hyun Yoon, Hyun Jeong Na and Sang Kun Lee
Price
42.00 $
Volume 51 p. 780 - 786
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 10/2013 (780-786)
Usefulness of oral loading of oxcarbazepine suspension in selected patients with epilepsy
Dong Wook Kim1, Namyi Gu2, Howard Lee2, In-Jin Jang2, Kon Chu3, Kyung-Sang Yu2, Joo-Youn Cho2, Seo Hyun Yoon2, Hyun Jeong Na2 and Sang Kun Lee3
1Department of Neurology, Konkuk University School of Medicine, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, and 3Department of Neurology, College of Medicine, Seoul National University Hospital, Seoul, Korea
Objectives: Oral loading of oxcarbazepine tablet is effective and well tolerated to adequately achieve the therapeutic levels of its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD) in epilepsy patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of oral loading of oxcarbazepine suspension in epilepsy patients with a high risk of recurrent seizures. Methods: Oxcarbazepine suspension was administered orally at a single loading dose of 30 mg/kg to 38 adult patients with recurrent seizures, who required rapid seizure control or temporarily discontinued antiepileptic drugs for diagnostic or pre-surgical evaluation. Plasma concentrations of oxcarbazepine and MHD were determined, and adverse events were assessed at 2, 4, 6, 8, 10, 12, 14, 16, and 24 hours after oral loading of oxcarbazepine suspension. Results: 30 patients experienced ≥ 1 adverse event during the first 24 hours after oral loading of oxcarbazepine (e.g., dizziness, transient diplopia, nausea or vomiting), most of which occurred within 4 hours after loading, suggesting no temporal association with MHD plasma levels. 35 (92.1%) patients were still compliant with a maintenance dose of oxcarbazepine after discharge from hospital. 34 (89.4%) patients reached the lower therapeutic level of MHD (12 mg/l) at 4 hours after oral loading of oxcarbazepine suspension, which lasted up to 24 hours in most patients. No patient reached the supratherapeutic levels of MHD (> 35 mg/l) during the study. The mean plasma concentration-time curves and pharmacokinetic profiles of oral loading of oxcarbazepine suspension were similar to those of oral loading of oxcarbazepine tablet. Conclusions: Oral loading of oxcarbazepine suspension followed by maintenance dosing is well tolerated and effective in steadily achieving the therapeutic level of MHD in selected patients with epilepsy.Correspondence to:
Sang Kun Lee, MD, PhD, Department of Neurology, Seoul National University Hospital, 28, Yongkeun dong, Chongno Ku, Seoul, 110-744, 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]
