Sarashina Akiko, Friedrich Christian, Crowe Susanne, Patel Sanjay, Graefe-Mody Ulrike, Hayashi Naoyuki, Horie Yoshiharu
Clinical Pharmacokinetics/Pharmacodynamics Department, Nippon Boehringer Ingelheim Co., Ltd, Hyogo, Japan.
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
J Diabetes Investig. 2016 Sep;7(5):744-50. doi: 10.1111/jdi.12482. Epub 2016 Mar 2.
AIMS/INTRODUCTION: The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post-hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase-4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials.
Study 1 (with a 12-week placebo-controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24-week trial) enrolled Asian (non-Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90).
Linagliptin trough concentrations were equivalent across study and race groups, and were higher than half-maximal inhibitory concentration, resulting in dipeptidyl peptidase-4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase-4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non-Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group.
Trough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non-Japanese) and white patients, confirming that the recommended 5-mg once-daily dose of linagliptin is appropriate for use among different race groups.
目的/引言：由于剂量与暴露量关系、药效学反应或临床疗效及安全性存在差异，药物的疗效和安全性在不同种族或族裔人群中可能有所不同。在本次事后分析中，我们评估了种族对二肽基肽酶-4抑制剂利格列汀单药治疗2型糖尿病患者的药代动力学、药效学、疗效和安全性的影响，这些患者来自两项可比的、先前报道的随机III期试验。
研究1（有12周安慰剂对照期）仅招募日本患者（利格列汀组，n = 159；安慰剂组，n = 80）；研究2（24周试验）纳入亚洲（非日本）患者（利格列汀组，n = 156；安慰剂组，n = 76）和白人患者（利格列汀组，n = 180；安慰剂组，n = 90）。
利格列汀的谷浓度在各研究组和种族组中相当，且高于半数最大抑制浓度，导致谷值时二肽基肽酶-4抑制率>80%。在研究1和研究2中，利格列汀对血浆二肽基肽酶-4活性的抑制程度相似。利格列汀在各组中降低空腹血糖浓度的幅度相似，使所有组的糖化血红蛋白水平出现具有临床意义的降低。在研究1（日本患者）和研究2的亚洲（非日本）患者中，糖化血红蛋白水平下降幅度略大。利格列汀在每个种族组中都具有良好的安全性。
在日本、亚洲（非日本）和白人患者中，利格列汀单药治疗的谷暴露量、药效学反应以及疗效和安全性相当，证实利格列汀每日一次5毫克的推荐剂量适用于不同种族组。
