An Assessment of Pharmacokinetic Interaction Between Lobeglitazone and Sitagliptin After Multiple Oral Administrations in Healthy Men

Patients with type 2 diabetes mellitus require strict blood glucose control, and combination therapy with a thiazolidinedione and dipeptidyl peptidase-4 inhibitors, such as lobeglitazone and sitagliptin, is one of the recommended treatments. The objective of this study was to investigate a possible pharmacokinetic interaction between lobeglitazone and sitagliptin after multiple oral administrations in healthy Korean men. Two randomized, open-label, multiple-dose, 2-way crossover studies were conducted simultaneously in healthy men. In study 1, men were randomly assigned to 1 of 2 sequences, and 1 of the following treatments was administered in each period: 1 tablet of lobeglitazone sulfate (0.5 mg) once daily for 5 days and or 1 tablet each of lobeglitazone sulfate (0.5 mg) and sitagliptin (100 mg) once daily for 5 days. In study 2, men were also randomly assigned to 1 of 2 sequences and the treatments were as follows: 1 tablet of sitagliptin (100 mg) once daily for 5 days or 1 tablet each of sitagliptin (100 mg) and lobeglitazone sulfate (0.5 mg) once daily for 5 days. Serial blood samples were collected up to 48 h after dosing on the fifth day. Plasma drug concentrations were measured by LC-MS/MS. Pharmacokinetic parameters, including Cmax,ss and AUC0–τ , were determined by noncompartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% CIs of log-transformed Cmax,ss and AUC0–τ for separate or coadministration were calculated to evaluate pharmacokinetic interactions. Nineteen men from study 1 and 17 from study 2 completed the pharmacokinetic sampling and were included in the analyses. The GLSM ratios of Cmax,ss and AUC0–τ were 0.9494 (95% CI, 0.8798–1.0243) and 1.0106 (95% CI, 0.9119–1.1198) for lobeglitazone (from study 1) and 1.1694 (95% CI, 1.0740–1.2732) and 1.0037 (95% CI, 0.9715–1.0369) for sitagliptin (from study 2), respectively. Except for the slight 17% increase in the sitagliptin Cmax,ss value, the pharmacokinetic parameters of lobeglitazone and sitagliptin met the pharmacokinetic equivalent criteria when administered separately or in combination. The increase in Cmax of sitagliptin when coadministered with lobeglitazone would not be clinically significant in practice. ClinicalTrials.gov Identifier: NCT02824874 and NCT02827890. •Sitagliptin Cmax,ss increased after multiple administrations with lobeglitazone.•Not a clinically significant increase in sitagliptin Cmax,ss.•Lobeglitazone and sitagliptin may be used in co