目的:在中国健康成年志愿者中评价单次皮下注射重组人胰高血糖素类多肽-1(7-36)[rhGLP-1(7-36)]的安全性、耐受性。方法:根据GCP设计试验方案,并获得伦理委员会批准。受试者须自愿签署知情同意书。选择42名18~50岁健康成人,将受试者随机分至0.10~0.45mg7个剂量组,每组6名,男女各半,分别接受单次皮下注射rhGLP-1(7-36),进行临床和实验室检查,考察药物耐受性。结果:单次皮下注射rhGLP-1(7-36)耐受性试验中,各组受试者各项指标测定值均在正常范围内,条件均衡,具较好可比性。因剂量至0.30mg时,不良事件(恶心、呕吐)在该组发生率超过50%,故于该剂量组试验完成后终止了下一剂量组试验,仅有4个剂量组共24名健康受试者完成了本试验。24例受试者完成的4个剂量组耐受性试验中,给药后实验室检查未见有临床意义的改变。试验中出现10例(共15例次)可能与药物有关的不良反应,如头晕、恶心、呕吐等,但均可耐受,且为一过性反应,于给药后1h内自行消失。其中,不良反应主要发生在0.25、0.30mg组(共7例12例次),而低剂量组(0.10、0.20mg)仅有3例发生轻度不良反应。15例次不良反应中,头晕、恶心有10例次,呕吐有5例次;整个试验过程未见严重不良事件。结论:24名中国健康成年受试者分别单次皮下注射rhGLP-1(7-36),最大剂量至0.20mg,比较安全、耐受性较好,为最大耐受剂量。而单次给药剂量至0.25mg或0.30mg则不良反应发生率较高,最大耐受剂量为0.20mg。建议单次用药剂量不宜超过0.20mg。在II期临床试验中需严密观察恶心、呕吐这些与药物可能有关的不良反应及其发生机制。 OBJECTIVE: To evaluate the safety and tolerability of a single subcutaneous injection of recombinant human glucagon-like peptide-1 (7-36) [rhGLP-1 (7-36)] in Chinese healthy adult volunteers. Methods: According to the GCP design test program, and approved by ethics committee. Subjects must voluntarily sign the informed consent form. Forty-two healthy adults aged 18-50 years were enrolled in this study. Subjects were randomized to 7 doses of 0.10-0.45 mg, 6 in each group, with half male and half female subjects receiving a single subcutaneous injection of rhGLP-1 (7-36) Clinical and laboratory tests to examine drug resistance. Results: In single subcutaneous injection of rhGLP-1 (7-36) tolerance test, the indicators of each group were measured in the normal range, the conditions are balanced, with better comparability. Adverse events (nausea and vomiting) occurred in more than 50% of the patients at doses up to 0.30 mg, so the next dose group was discontinued after the dose was completed and only 4 of the 4 dose groups were healthy The test completed the test. Of the four dose-group tolerability trials completed in 24 subjects, no clinically relevant changes were noted in laboratory tests after dosing. There were 10 cases (15 cases) of drug-related adverse reactions, such as dizziness, nausea and vomiting, but all of them were tolerable and transient reactions, and disappeared within 1 h after administration. Among them, adverse reactions mainly occurred in 0.25,0.30mg group (a total of 7 cases in 12 cases), while the low-dose group (0.10,0.20mg) only 3 cases mild adverse reactions. Among the 15 adverse reactions, 10 were dizziness and nausea and 5 were vomiting. No serious adverse events were observed during the whole experiment. CONCLUSIONS: Twenty-four healthy adult Chinese subjects received a single subcutaneous injection of rhGLP-1 (7-36), respectively, at a maximum dosage of 0.20 mg. This is safe and well-tolerated and is the maximum tolerated dose. The single dose of 0.25mg or 0.30mg, the incidence of adverse reactions is higher, the maximum tolerated dose of 0.20mg. Proposed single dose should not exceed 0.20mg. Nausea and vomiting may be closely observed in phase II clinical trials and may be related to the adverse drug reactions and its mechanism.