Tolerability and Pharmacokinetics of Lobeglitazone (CKD-501), a Peroxisome Proliferator-Activated Receptor-γ Agonist: A Single- and Multiple-Dose, Double-Blind, Randomized Control Study in Healthy Male Korean Subjects

Kim, Jung Won; Yi, So Jeong; Shin, Kye Chul; Shin, Hyun Suk; Yoon, Seo Hyun; Cho, Joo Youn; Kim, Dal Hyun; Shin, Sang Goo; Jang, In Jin; Yu, Kyung‐Sang

doi:10.1016/j.clinthera.2011.09.023

Cited by 38 publications

(48 citation statements)

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“…The exposure to lobeglitazone in this study is similar to that in a published study using the same dose 4. The observed PK profiles of R - and S -warfarin in the absence of lobeglitazone are also consistent with those reported in previous studies 20,21.…”

Section: Discussionsupporting

confidence: 90%

“…Lobeglitazone has been shown to have more potent activity than the prototypic TZDs (ie, pioglitazone and rosiglitazone) in both in vitro and in vivo studies 2,3. In healthy volunteers, lobeglitazone has a favorable tolerability profile and exhibits linear pharmacokinetics (PK) over the dose range of 0.5–4.0 mg once daily 4. Following oral administration, lobeglitazone is rapidly absorbed with a time to maximum plasma concentration ( T max ) of 1.0–3.0 hours and is eliminated with a mean elimination half-life ( t 1/2 ) of 7.8–9.8 hours 1.…”

Section: Introductionmentioning

confidence: 99%

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Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, on the pharmacokinetics and pharmacodynamics of warfarin

Jung

Lee

Kim

et al. 2015

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AimsLobeglitazone has been developed for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate potential drug–drug interactions between lobeglitazone and warfarin, an anticoagulant with a narrow therapeutic index.MethodsIn this open-label, three-treatment, crossover study, 24 healthy male subjects were administered lobeglitazone (0.5 mg) for 1–12 days with warfarin (25 mg) on day 5 in one period. After a washout interval, subjects were administered warfarin (25 mg) alone in the other period. Pharmacokinetics of R- and S-warfarin and lobeglitazone, as well as pharmacodynamics of warfarin, as measured by international normalized ratio (INR) and factor VII activity, were assessed.ResultsThe geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for area under the curve from time zero to the time of the last quantifiable concentration (AUClast) for warfarin + lobeglitazone: warfarin alone were 1.0076 (90% CI: 0.9771, 1.0391) for R-warfarin and 0.9880 (90% CI: 0.9537, 1.0235) for S-warfarin. The maximum observed plasma concentration (Cmax) values were 1.0167 (90% CI: 0.9507, 1.0872) for R-warfarin and 1.0028 (90% CI: 0.9518, 1.0992) for S-warfarin, both of which were contained in the interval 0.80–1.25. Lobeglitazone had no effect on the area under the effect–time curve from time 0 to 168 hours (AUEC) of INR and factor VII activity, as demonstrated by the GMRs of 1.0091 (90% CI: 0.9872, 1.0314) and 0.9355 (90% CI: 0.9028, 0.9695), respectively. In addition, the pharmacokinetics of lobeglitazone was also unaffected by warfarin.ConclusionConcomitant administration of lobeglitazone and warfarin was well tolerated. Lobeglitazone had no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin. These findings indicate that lobeglitazone and warfarin can be coadministered without dosage adjustments for either drug.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, on the pharmacokinetics and pharmacodynamics of warfarin

Jung

Lee

Kim

et al. 2015

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“…Lobeglitazone is a new PPARγ agonist with a TZD moiety and substituted pyrimidines, currently used to treat T2DM after completing clinical trials [15]. Phase III clinical trial data show that lobeglitazone treatment resulted in an approximately 0.6% to 0.74% decrease in glycated hemoglobin compared with that of the placebo [1617].…”

Section: Introductionmentioning

confidence: 99%

Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

et al. 2017

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BackgroundRenal tubulointerstitial fibrosis is a common feature of the final stage of nearly all cause types of chronic kidney disease. Although classic peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on diabetic nephropathy, much less is known about their direct effects in renal fibrosis. This study aimed to investigate possible beneficial effects of lobeglitazone, a novel PPARγ agonist, on renal fibrosis in mice.MethodsWe examined the effects of lobeglitazone on renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) induced renal fibrosis mice. We further defined the role of lobeglitazone on transforming growth factor (TGF)-signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study.ResultsThrough hematoxylin/eosin and sirius red staining, we observed that lobeglitazone effectively attenuates UUO-induced renal atrophy and fibrosis. Immunohistochemical analysis in conjunction with quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that lobeglitazone treatment inhibited UUO-induced upregulation of renal Smad-3 phosphorylation, α-smooth muscle actin, plasminogen activator inhibitor 1, and type 1 collagen. In vitro experiments with rat mesangial cells and NRK-49F renal fibroblast cells suggested that the effects of lobeglitazone on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway.ConclusionThe present study demonstrates that lobeglitazone has a protective effect on UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of non-diabetic origin renal disease.

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“…This simple and rapid LC-MS/MS method was successfully applied to the pharmacokinetic study of lobeglitazone after single-and multiple-dose administration of lobeglitazone in healthy male volunteers [8]. The pharmacokinetic parameters of lobeglitazone following singleand multiple-dose administration are summarized in Table 2.…”

Section: Application Of the Methods To Pharmacokinetic Study In Healthmentioning

confidence: 99%

“…Samples were centrifuged at 4°C and 10,000 rpm for 10 min and stored below -70°C until analysis. The PK parameters from single-and multiple-dose administration study were calculated by non-compartmental methods using Phoenix WinNolin (Version 6.0; Pharsight Corporation, Sunnyvale, CA, USA) [8].…”

Section: Application To Pharmacokinetic Studymentioning

confidence: 99%

Quantitative and Qualitative Analysis of CKD-501, Lobeglitazone, in Human Plasma and Urine Using LC–MS/MS and Its Application to a Pharmacokinetic Study

et al. 2012

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A simple, rapid and sensitive LC-MS/MS method in positive ion mode was developed and validated to determine CKD-501, lobeglitazone, in human plasma and urine using glipizide as an internal standard (IS). Lobeglitazone is a novel thiazolidinedione (TZDs)-based peroxisome proliferatoractivated receptor (PPAR) agonist, used for the management of type-2 diabetes. After mixing the IS, dissolved in acetonitrile, with a plasma or urine sample containing lobeglitazone, 10 lL of supernatant was injected into the LC-MS/MS system. Quantification was performed in the multiple reaction monitoring (MRM) mode using transition of 481.5 ? 152.2 (m/z) for lobeglitazone and 446.1 ? 321.2 (m/z) for the IS. The method showed good linearity over concentration ranges of 0.5-1,000 ng mL -1 for plasma and 0.2-250 ng mL -1 for urine (r 2 C 0.9996). The mean percent extraction recovery of lobeglitazone was 90.8 % for plasma and 87.3 % for urine, while the recoveries of the IS were greater than 86.4 % for both. The intra-day and inter-day precision of plasma ranged from 1.1 to 3.7 and 2.5 to 3.3 % (RSD), respectively, and the intra-and inter-day precision of urine ranged from 1.5 to 2.7 and 3.2 to 3.5 %, respectively. This method is simple, sensitive, and applicable for the pharmacokinetic study of lobeglitazone in human plasma. Most of the urine concentrations of lobeglitazone were below the LLOQ because the lobeglitazone is extensively metabolized.

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Tolerability and Pharmacokinetics of Lobeglitazone (CKD-501), a Peroxisome Proliferator-Activated Receptor-γ Agonist: A Single- and Multiple-Dose, Double-Blind, Randomized Control Study in Healthy Male Korean Subjects

Cited by 38 publications

References 28 publications

Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, on the pharmacokinetics and pharmacodynamics of warfarin

Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, on the pharmacokinetics and pharmacodynamics of warfarin

Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

Quantitative and Qualitative Analysis of CKD-501, Lobeglitazone, in Human Plasma and Urine Using LC–MS/MS and Its Application to a Pharmacokinetic Study

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Tolerability and Pharmacokinetics of Lobeglitazone (CKD-501), a Peroxisome Proliferator-Activated Receptor-γ Agonist: A Single- and Multiple-Dose, Double-Blind, Randomized Control Study in Healthy Male Korean Subjects

Cited by 38 publications

References 28 publications

Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-&gamma; agonist, on the pharmacokinetics and pharmacodynamics of warfarin

Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-&gamma; agonist, on the pharmacokinetics and pharmacodynamics of warfarin

Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

Quantitative and Qualitative Analysis of CKD-501, Lobeglitazone, in Human Plasma and Urine Using LC–MS/MS and Its Application to a Pharmacokinetic Study

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Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, on the pharmacokinetics and pharmacodynamics of warfarin

Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, on the pharmacokinetics and pharmacodynamics of warfarin