创新药物阿托伐他汀钙/阿昔莫司缓释胶囊人体耐受性试验

Tolerance of Innovative Drug Atorvastatin Calcium/Acipimox Sustained-Release Capsule

目的：通过单次和多次口服1类创新药阿托伐他汀钙／阿昔莫司缓释胶囊，评价其在中国健康人体内的耐受程度和安全范围，为创新药物下一步临床试验提供安全的剂量范围和制定临床给药方案的依据。方法采用随机单中心临床研究，将38名健康受试者随机分为 A（10例）、B（10例）、C（10例）和 D（8例）4组，每组分别单次给予阿托伐他汀钙／阿昔莫司缓释胶囊1粒（260 mg，含阿托伐他汀钙10 mg＋阿昔莫司250 mg）、2粒、3粒和4粒；在完成单次给药安全性良好的基础上，将相对应剂量的4组再进行多次给药的耐受性试验。观察受试者用药前后生命体征、心电图及实验室检查的变化，并记录不良事件。结果单次和多次给药耐受性试验的受试者用药前后生命体征、心电图无改变，实验室检查表明无器质性损伤；单次给药有11例、多次给药有15例受试者在口服药物15 min 后出现不同程度的斑疹或红疹，未经处理自行消退，评价为阿昔莫司的扩张血管不良反应。结论中国健康人体对阿托伐他汀钙／阿昔莫司缓释胶囊在260～1040 mg 剂量范围内单、多次给药安全性和耐受性良好，最大耐受剂量为1040 mg，推荐多次给药剂量为520～780 mg（2～3粒）。

Objective To evaluate the tolerance and safety of single and multiple oral adminis-tration of atorvastatin calcium/acipimox sustained-release capsules in Chinese healthy volunteers, and to provide a safe dose range for clinical trials and a basis for development of clinical adminis-tration regimen.Methods A randomized single-center clinical trial was performed to study the tolerance of atorvastatin calcium/acipimox sustained-release capsules.Thirty-eight healthy volun-teers were randomly divided into four groups：group A （n=10）,group B （n=10）,group C （n=10）,and group D （n=8）.Each group was given single administration of 1,2,3 and 4 atorvastatin calcium/acipimox sustained-release capsules,respectively.Each capsule contained atorvastatin cal-cium 10 mg and acipimox 250 mg.On the premise of safe single administration,the tolerance of multiple administration of atorvastatin calcium/acipimox sustained-release capsules was analyzed. Vital signs,electrocardiogram and laboratory test findings were observed before and after admin-istration.In addition,adverse events were recorded.Results No changes in vital signs and elec-trocardiogram were found and no organic injuries were observed before and after single and multi-ple administration of atorvastatin calcium/acipimox sustained-release capsules.Different degrees of maculae or rash occurred 15 minutes after oral administration but spontaneously subsided with-out treatment in 11 volunteers who received single administration and 15 volunteers who received multiple administrations.The adverse side effect occurred from the blood vessel dilation caused by acipimox.Conclusion Single and multiple administration of atorvastatin calcium/acipimox sus-tained-release capsules in a range from 260 to 1 040 mg are safe and well tolerated in Chinese healthy volunteers （maximum tolerated dose 1 040 mg）.The recommended doses of multiple ad-ministration of atorvastatin calcium/acipimox sustained-release capsules range from 520 to 780 mg（2-3 capsules）.