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

Abstract

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.

Specific Inhibition of the Distribution of Lobeglitazone to the Liver by Atorvastatin in Rats: Evidence for a Rat Organic Anion Transporting Polypeptide 1B2–Mediated Interaction in Hepatic Transport

“…In addition, the reduction in K p,liver for LB (i.e., from 2.34 to 1.55) by ATV did not appear to be significant in the total V ss , considering the fact that the contribution of the reduced distribution of LB to the liver would be approximately 27 ml/kg, which is relatively small for the V ss of 271 ml/kg. In other clinical DDI studies involving LB with metformin (i.e., T2DM agent), LB with warfarin (i.e., an anticoagulant with a narrow therapeutic index), or LB with amlodipine (i.e., an antihypertensive agent) (Shin et al, 2012;Jung et al, 2015;Kim et al, 2015), no apparent changes in the systemic pharmacokinetics was found. In contrast, however, the liver concentration of LB was significantly decreased by the coadministration of ATV ( Fig.…”

“…This suggests that drug-drug interactions (DDIs) are possible for LB in drug metabolism as well as in its distribution to tissues. Clinical pharmacokinetics studies of LB with other prescription drugs such as warfarin or amlodipine were recently conducted in Korea, and no significant differences in the systemic pharmacokinetics of LB were reported after coadministration (Jung et al, 2015;Kim et al, 2015). These studies were designed to investigate potential changes in the systemic pharmacokinetics of LB when these drugs were coadministered, considering the fact that they are known to share some of the same metabolic pathways of LB (i.e., CYP1A2, CYP2C9, and CYP3A4 with warfarin; CYP3A4 with amlodipine) (Guengerich et al, 1991;Kaminsky and Zhang, 1997).…”

Lobeglitazone: A Novel Thiazolidinedione for the Management of Type 2 Diabetes Mellitus

“…Exceptions were a slightly increased steady-state Cmax for sitagliptin (ratio, 1.1694; 90% CI, 1.0740 to 1.27320) and a slightly decreased Cmax for glimepiride (ratio, 0.910547; 90% CI, 0.78246 to 1.05960), when each was coadministered with lobeglitazone; however, neither of these changes were considered to be clinically significant [11,37]. There were also no significant changes in the pharmacokinetics of either drug when lobeglitazone was coadministered with amlodipine or warfarin [38,39]. However, coadministration with ketoconazole, a strong CYP3A4 inhibitor, increased the level of exposure to lobeglitazone by about 33% (geometric mean ratio for AUCinf, 1.33; 90% CI, 1.23 to 1.44) [40].…”

“…There were also no significant changes in the pharmacokinetics of either drug when lobeglitazone was coadministered with amlodipine or warfarin [ 38 , 39 ]. However, coadministration with ketoconazole, a strong CYP3A4 inhibitor, increased the level of exposure to lobeglitazone by about 33% (geometric mean ratio for AUC inf , 1.33; 90% CI, 1.23 to 1.44) [ 40 ].…”

Pharmacokinetics of a Lobeglitazone/Metformin Fixed‐Dose Combination Tablet (CKD‐395 0.5/1000 mg) Versus Concomitant Administration of Single Agents and the Effect of Food on the Metabolism of CKD‐395 in Healthy Male Subjects

“…Lobeglitazone is rapidly absorbed after oral administration, with a time to C max (T max ) of 1.0 to 3.0 hours, and is eliminated with a mean plasma elimination half‐life (t 1/2 ) of 7.8 to 9.8 hours in healthy subjects . Lobeglitazone was approved for the treatment of diabetes in 2013 by the Ministry of Food and Drug Safety, Republic of Korea …”