健康志愿者单次皮下注射重组人胰高血糖素类多肽-1(7-36)[rhGLP-1(7-36)]耐受性研究

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。

Study on tolerance of subcutaneous injection in single dose of recombinated human glucagon-like peptide-1 in Chinese healthy volunteers

AIM:To estimate the safety and tolerance of recombinated human glucagon-like peptide-1(rhGLP-1) (7-36) after subcutaneous injection of single dose of the drug in Chinese healthy volunteers. METHODS: The protocol was designed according to GCP and approved by ethics committee. All volunteers signed the informed consent. The volunteers were 18-45 years old and divided into 7 dosage groups. The clinical and laboratory tests were observed in order to evaluate the safety and tolerance of rhGLP-1 (7-36). RESULTS: All laboratory and clinical indexes of the subjects were within the normal range and qualifications were equilibrate before administration of the drug, so they were comparable. After administration of rhGLP-1 (7-36), the incidence of adverse events (nausea, vomiting) exceeded 50% in 0.30 mg group, so only 24 cases in 4 groups (0.10-0.30 mg) joined the phasa I clinical trial. After administration of the drug, the significant changes in laboratory tests were not seen, but adverse reactions such as dizziness, nausea and emesia in 10 cases (15 times) were found which might be related to the drug. They could be tolerable, were temporary response, and disappeared one hour after the administration. The ADR occurred mainly in the 0.25 mg and 0.30 mg groups (7 of 12 subjects), while the ADR in the low-dose groups (0.10, 0.20 mg) were only found for 3 cases. There were 10 cases with dizziness and nausea and 5 emesia among 15 ADR. There were no serious adverse events during the clinical trial. CONCLUSION: rhGLP-1(7-36) is safe and tolerable in Chinese healthy volunteers when the single dose under 0.20 mg is subcutaneously injected, and the most tolerable dose is 0.20 mg. When the dose is up to 0.25 mg or 0.30 mg, the incidence of ADR is higher. The mechanisms for ADR of the nausea and vomiting will be studied in future.