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

ABSTRACT: Lobeglitazone 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.In 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.The 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 (C max) 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.Concomitant 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.

SUBMITTER: Jung JA

PROVIDER: S-EPMC4354432 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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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 Jin Ah JA Lee Soo-Yun SY Kim Tae-Eun TE Kim Jung-Ryul JR Kim Chin C Huh Wooseong W Ko Jae-Wook JW

Drug design, development and therapy 20150302

<h4>Aims</h4>Lobeglitazone 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.<h4>Methods</h4>In 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 war ...[more]

PMID: 25767371

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Project description:Rheumatoid arthritis (RA), a chronic inflammatory disease, is associated with insulin resistance. Experimental evidence indicates that the relationship between insulin resistance and inflammation is bidirectional: Inflammation promotes insulin resistance, and insulin resistance promotes inflammation. Therefore, we examined the hypothesis that pioglitazone, a thiazolidinedione peroxisome proliferator-activated receptor ? agonist, would decrease inflammation and disease activity and improve insulin resistance in patients with RA.In a single-center, randomized, double-blind, placebo-controlled crossover study patients with RA (N = 34) receiving stable therapy were randomized to also receive either pioglitazone 45 mg daily (n = 17) or matching placebo (n = 17) for eight weeks. This was followed by a four-week washout period and alternative treatment for eight weeks. Outcomes included change in Disease Activity Score in 28 joints (DAS28) score, individual components of the DAS28 score and homeostatic model assessment for insulin resistance (HOMA). Intention-to-treat analysis and linear mixed-effects models were used.Patients had a mean (± SD) age of 51 (± 14.2) years, 82.4% were female and baseline DAS28 high-sensitivity C-reactive protein (DAS28-CRP) was 4.58 (± 1.1) units. Addition of pioglitazone was associated with a 9.3% reduction (95% confidence interval (CI) = 0.17% to 17.6%) in DAS28-CRP (P = 0.046), but no significant change in DAS28 erythrocyte sedimentation rate (DAS28-ESR) (P = 0.92). There was a 10.7 mm (95% CI = 0.4 to 20.9 mm) improvement in patient-reported global health (P = 0.042), a 48.6% decrease (95% CI = 27.6% to 63.5%) in CRP (P < 0.001) and a 26.4% decrease (95% CI = 3.7% to 43.8%) in insulin resistance as measured by HOMA (P = 0.025), but no significant reduction in swollen or tender joint count or in ESR (all P > 0.05). Lower-extremity edema was more common during pioglitazone treatment (16%) than placebo (0%).Addition of pioglitazone to RA therapy improves insulin resistance and modestly reduces RA disease activity measured by DAS28-CRP and two of its components, including patient-reported global health and CRP, but not DAS28-ESR or ESR.NCT00763139.

Project description:PurposeCombination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects.Subjects and methodsA randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25.ResultsThe steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well.ConclusionThe lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment.Trial registration numberNCT02854748, Registered on August 7, 2016.

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Dataset Information

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

Publications

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

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