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

PurposePatients 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.MethodsTwo 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 C_max,ss and AUC_0–τ , were determined by noncompartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% CIs of log-transformed C_max,ss and AUC_0–τ for separate or coadministration were calculated to evaluate pharmacokinetic interactions.FindingsNineteen men from study 1 and 17 from study 2 completed the pharmacokinetic sampling and were included in the analyses. The GLSM ratios of C_max,ss and AUC_0–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.ImplicationsExcept for the slight 17% increase in the sitagliptin C_max,ss value, the pharmacokinetic parameters of lobeglitazone and sitagliptin met the pharmacokinetic equivalent criteria when administered separately or in combination. The increase in C_max of sitagliptin when coadministered with lobeglitazone would not be clinically significant in practice. ClinicalTrials.gov Identifier: NCT02824874 and NCT02827890.     

Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes

ABSTRACT

Objective: As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions.

Methods: This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50?mg b.i.d.) with metformin (1000?mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50?mg sitagliptin twice daily and placebo to metformin twice daily; 1000?mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50?mg of sitagliptin twice daily and 1000?mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasma concentrations–time curve over the dosing interval (AUC_{0–12 h}), maximum observed plasma concentrations (C_max), and time of occurrence of maximum observed plasma concentrations (T_max). Renal clearance was also determined for sitagliptin.

Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC_{0–12 h} geometric mean ratio (GMR; [metformin + sitagliptin]/metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC_{0–12 h} GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics.

Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.     

Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes

ABSTRACT

Objective: The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A_1c ≥?8.0% and ≤?11.0%) type 2 diabetes mellitus (T2DM).

Research design and methods: This was a multi­national, randomized, placebo-controlled, parallel-group, double-blind study conducted in 190 patients with T2DM. After ≥?6?weeks of stable metformin monotherapy (≥?1500?mg/day), patients were randomized to either the addition of sitagliptin 100?mg once daily or placebo to ongoing metformin for 30?weeks.

Main outcome measures: The primary efficacy endpoint was reduction in hemoglobin A_1c (HbA_1c) measured after 18?weeks of sitagliptin treatment. Key secondary end­points included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA_1c at 30 weeks. The proportion of patients meeting the goal of HbA_1c <?7.0% was also analyzed.

Results: Sitagliptin significantly reduced HbA_1c, FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA_1c was –1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA_1c <?7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not signif­icantly increase the risk of hypoglycemia or gastro­intestinal adverse events.

Conclusions: Addition of sitagliptin 100?mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks.

Trial registration: ClinicalTrials.gov identifier: NCT00337610.     

Sitagliptin attenuates metformin-mediated AMPK phosphorylation through inhibition of organic cation transporters

1. To assess potential interactions between sitagliptin and metformin, we sought to characterize the in vitro inhibitory potency of sitagliptin on the uptake of MPP⁺ and metformin, representative substrates for OCTs, and to evaluate the pharmacological pathways that may be affected by the combination of metformin and sitagliptin.

2. Among the OATs and OCTs screened, OAT3-mediated salicylate uptake and OCT1- and OCT2-mediated MPP⁺ uptake were inhibited by sitagliptin. The K_i values of sitagliptin for OCT1- and OCT2-mediated metformin uptake were 34.9 and 40.8?μM, respectively.

3. As OCT1 is the gate protein for metformin action in the liver, we investigated whether sitagliptin-mediated OCT1 inhibition affected metformin-induced activation of AMPK signalling. Treatment with sitagliptin in MDCK-OCT1 and HepG2 cells resulted in a reduced level of phosphorylated AMPK, with K_i values of 38.8 and 43.3?μM, respectively.

4. These results suggest that the inhibitory potential of sitagliptin on OCT1 may attenuate the first step of metformin action, that is, the phosphorylation of AMPK. Nevertheless, the likelihood of a drug–drug interaction between sitagliptin and metformin is believed to be remote in usual clinical setting.

     

The hepatoprotective effect of sitagliptin against hepatic ischemia reperfusion-induced injury in rats involves Nrf-2/HO-1 pathway

BackgroundOxidative stress and inflammation play a key role in the development of hepatic ischemia reperfusion (HIR)-induced injury. Nuclear factor-erythroid 2-related factor-2 (Nrf-2) is a main regulator of numerous genes, encoding cytoprotective molecules including heme oxygenase-1 (HO-1). Sitagliptin (Sit) is an incretin enhancer acting via inhibition of dipeptidyl peptidase-4 (DPP-4) enzyme. This study was undertaken to investigate the ability of Sit to prevent the hepatic pathological changes of HIR induced injury and to modify Nrf-2 and its target HO-1.MethodsPringle's maneuver was used to induce total HIR in adult male rats that were randomly assigned into 4 groups. Group1 (sham-operated control), Group 2 (sham-operated + Sit-control group), Group 3 (HIR non-treated), and Group 4 (HIR + Sit). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities together with hepatic contents of malondialdhyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) and superoxide dismutase (SOD) activity were evaluated. Hepatic tissue mRNA of Nrf-2 and protein content of HO-1 along with histopathological examination and scoring of hepatic injury were performed.ResultsSit caused a significant reduction in ALT and AST activities together with attenuation of HIR-induced histopathological liver injury. Effect of Sit was associated with decreased hepatic level of MDA and NO with increased GSH level and SOD activity. Non-treated rats with HIR showed an increase in Nrf-2 mRNA expression and HO-1 content in hepatic tissue which was further increased by Sit treatment.ConclusionsThese results indicate that hepatoprotective activity of Sit against HIR is attributed at least in part to modulation of Nrf-2/ HO-1 signaling pathway.     

通过渗透微泵稳定抑制小鼠血浆CD26/DPPIV分子酶活性的研究

目的 研究采用皮下植入渗透微泵给予西他列汀对小鼠体内CD26/DDPIV蛋白酶活性的作用效果与持续时间。方法 将灌注西他列汀药物的渗透泵经手术植入BL6/C57小鼠皮下，通过高效液相色谱-质谱监测小鼠体内血液药物浓度，酶标法检测小鼠血浆DPPIV蛋白酶活性，流式细胞术观察小鼠脾T细胞CD26分子的表达，利用Transwell小室检测小鼠T细胞迁移能力。取渗透泵周围皮肤，病理切片检查小鼠皮下病理损害或炎性反应。结果 B6/C57小鼠在植入渗透泵后，体内药物浓度比采用直接皮下注射法稳定，持续时间久，血浆DPPIV蛋白酶活性抑制程度与血药浓度明显相关。给药24 h后，小鼠脾T细胞CD26分子表达无明显变化，渗透泵组迁移能力较对照组明显降低。皮下植入渗透泵小鼠组饮食活动度无明显改变，皮肤病理检查未见炎性反应与病理损害。结论 通过渗透泵给予小鼠药物能够保持西他列汀血药浓度稳定，持续抑制体内DPPIV活性，降低T细胞迁移能力，为CD26/DPPIV分子功能与免疫体内研究提供更方便有效的途径。     

DPP-4抑制剂治疗小鼠溃疡性结肠炎的疗效

目的 探讨DPP-4抑制剂单独及联合SASP治疗溃疡性结肠炎(UC)小鼠的疗效。方法 30只雄性BALB/c小鼠随机平均分为5组：空白对照组、模型对照组、DPP-4抑制剂治疗组、SASP治疗组、DPP-4抑制剂和SASP联合治疗组(联合治疗组)。除空白对照组外,其他各组均用5%葡聚糖硫酸钠(DSS)诱导小鼠UC模型,空白对照组和模型对照组给予0.5%羧甲基纤维素(CMC)灌胃,DPP-4抑制剂治疗组、SASP治疗组和联合治疗组分别给予西格列汀、SASP、西格列汀和SASP两者联合灌胃治疗,1次/d,连续6d。每天观察小鼠的临床症状,称量小鼠体质量,观察大便形状,检测大便隐血,计算疾病活动指数(DAI)。6d后处死小鼠,分离结肠组织,测量结肠长度,进行病理组织学观察,采用ELISA法检测小鼠血清胰高血糖素样肽-2(GLP-2)水平。结果 与模型对照组相比,DPP-4抑制剂治疗组、SASP治疗组和联合治疗组均明显改善UC小鼠临床症状, DAI评分显著降低(P<0.05),结肠长度明显增加(P<0.05),结肠病理损伤明显缓解;DPP-4抑制剂治疗组和联合治疗组血清GLP-2水平显著升高(P<0.01)。与DPP-4抑制剂治疗组比较,联合治疗组小鼠DAI评分显著降低(P<0.05),结肠长度明显增加(P<0.05)。结论 DPP-4抑制剂对UC小鼠有显著的治疗作用,与SASP联合用药可达到协同的效果。     

2型糖尿病患者应用西格列汀的短期疗效及影响因素

目的 分析2型糖尿病患者应用西格列汀的短期疗效及其影响因素,为临床患者的选择及提高疗效提供依据。 方法 收集2012年9月至2014年6月住院并应用西格列汀的2型糖尿病患者86例病例资料。根据患者空腹C肽水平四分位数分为C肽水平最高组和C肽水平最低组,每组12例。采用多元线性逐步回归分析患者临床资料中影响血糖下降水平的因素。 结果 使用西格列汀后,C肽水平最高组与C肽水平最低组空腹血糖(FBG)下降值、餐后2 h血糖(2h-PBG)下降值及百分数差异无统计学意义(P>0.05)。糖化血红蛋白(HbA1c)是影响FBG下降值及下降百分数的独立因素;用药前2h-PBG水平是影响2h-PBG下降值及其下降百分数的独立因素。患者使用西格列汀后,最大日内血糖波动值较使用前减小且低血糖发生显著减少(P<0.05)。 结论 西格列汀可同时降低患者FBG和2h-PBG,且疗效相当;其对FBG和2h-PBG的疗效不完全依赖于C肽水平;可显著减少血糖波动和低血糖事件的发生。