Herman Gary A, Bergman Arthur, Yi Bingming, Kipnes Mark
Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
Curr Med Res Opin. 2006 Oct;22(10):1939-47. doi: 10.1185/030079906X132587.
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.
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(0-12h)), maximum observed plasma concentrations (C(max)), and time of occurrence of maximum observed plasma concentrations (T(max)). Renal clearance was also determined for sitagliptin.
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(0-12h) 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.
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.
作为二肽基肽酶-4抑制剂西他列汀用于治疗2型糖尿病临床开发的一部分，正在仔细评估其与用于治疗2型糖尿病患者的其他降糖药物发生药代动力学相互作用的可能性。本研究的目的是评估在稳态条件下，联合使用西他列汀和二甲双胍的耐受性，以及西他列汀对二甲双胍药代动力学的影响和二甲双胍对西他列汀药代动力学的影响。
这项针对2型糖尿病患者的安慰剂对照、多剂量、交叉研究评估了联合使用西他列汀（50mg，每日两次）和二甲双胍（1000mg，每日两次）的耐受性。患者以随机交叉方式接受三种治疗（每种治疗持续7天）：每日两次服用50mg西他列汀和每日两次服用二甲双胍安慰剂；每日两次服用1000mg二甲双胍和每日两次服用西他列汀安慰剂；每日两次联合服用50mg西他列汀和1000mg二甲双胍。在每个治疗期的第7天给药后，测定血浆中西他列汀和二甲双胍的这些药代动力学参数：给药间隔内血浆浓度-时间曲线下面积（AUC(0-12h)）、观察到的最大血浆浓度（C(max)）以及观察到最大血浆浓度出现的时间（T(max)）。还测定了西他列汀的肾清除率。
在本研究中，13名患者中有11名未报告不良事件。两名患者出现不良事件，但经研究者判定与研究药物无关。无论是否联合使用西他列汀，二甲双胍的平均血浆浓度-时间曲线几乎相同[二甲双胍AUC(0-12h)几何平均比值（GMR；[二甲双胍+西他列汀]/二甲双胍）为1.02（90%CI 0.95，1.09）]。同样，服用二甲双胍也未改变血浆中西他列汀的药代动力学[西他列汀AUC(0-12 h) GMR（[西他列汀+二甲双胍]/西他列汀）为1.02（90%CI 0.97，1.08）]或西他列汀的肾清除率。在本研究期间未进行疗效测量（糖化血红蛋白或空腹血糖）。由于西他列汀对血浆二甲双胍药代动力学无影响，因此未测定二甲双胍的尿药代动力学。
在本研究中，2型糖尿病患者联合使用西他列汀和二甲双胍通常耐受性良好，且未显著改变任何一种药物的稳态药代动力学。
