阿兹夫定片在健康成年及老年受试者中单次和多次给药的药代动力学研究

Pharmacokinetics study of single and multiple doses of azvudine in healthy young and elderly subjects

目的评价单次口服和多次口服阿兹夫定片在中国健康成年及老年受试者中的药代动力学特征及安全性。方法本研究采取开放、平行方案设计。试验分为2个试验组:健康成年受试者组和健康老年受试者组,分别入组12例受试者。入组的受试者首先进行单次给药,空腹口服阿兹夫定片5 mg,经3 d清洗期后进入多次给药阶段,空腹口服阿兹夫定片5 mg·d^(-1),连续给药7 d。结果单次给予阿兹夫定片5 mg后,健康成年受试者C_(max),AUC_(0-∞)分别为(4.76±2.12)ng·mL^(-1),(6.53±2.20)ng·mL^(-1)·h,T_(max),t_(1/2)的中位数分别为0.75,1.87 h;健康老年受试者平均C_(max),AUC_(0-∞)分别为(6.40±3.25)ng·mL^(-1),(9.50±3.70)ng·mL^(-1)·h,T_(max),t_(1/2)的中位数分别为0.63,2.66 h。连续7 d给予阿兹夫定片5 mg后,健康成年受试者C_(max,ss),AUC_(0-∞,ss)分别为(3.26±1.61)ng·mL^(-1),(5.38±2.19)ng·mL^(-1)·h,T_(max,ss),t_(1/2,ss)的中位数分别为0.88,2.13 h;健康老年受试者平均C_(max,ss),AUC_(0-∞,ss)分别为(3.97±2.09)ng·mL^(-1),(6.71±3.26)ng·mL^(-1)·h,T_(max,ss),t_(1/2,ss)的中位数分别为0.75,2.56 h。单次给药后,健康老年人和健康成年人C_(max)、AUC_(0-t)和AUC_(0-∞)的几何均数比值及其90%置信区间分别为128.37%(88.23%~186.76%)、139.93%(105.42%~185.72%)、140.03%(106.33%~184.41%)。连续7 d给予阿兹夫定片5 mg,健康老年人和健康成年人C_(max,ss)、AUC_(0-t,ss)和AUC_(0-∞,ss)的几何均数比值及其90%置信区间分别为118.66%(80.83%~174.20%)、118.41%(83.60%~167.69%),118.95%(84.78%~166.89%)。结论单次及多次口服阿兹夫定片后,健康老年人与健康成年人相比,系统暴露均有所提高。健康老年人服用阿兹夫定片后,其不良事件和药物不良反应发生的种类、严重程度和发生率与健康成年人相比无明显差异,安全性耐受性良好。

Objective To evaluate the pharmacokinetic characteristics and safety of single and multiple oral azvudine tablets in healthy young and elderly Chinese subjects.Methods This was a open-label and parallel-group study.The trial consisted of two groups:healthy young subjects group and healthy elderly subjects group,with 12 subjects in each group.Enrolled subjects were first given a single dose,fasting oral azvudine tablet 5 mg,after a 3-day cleansing period entered the multiple dose phase,fasting oral azvudine tablet 5 mg·d^(-1)for 7 days.Results After a single dose of azvudine 5 mg,C_(max)and AUC_(0-∞)were(4.76±2.12)ng·mL^(-1),(6.53±2.20)ng·mL^(-1)·h,and T_(max),t_(1/2)were 0.75,1.87 h in young subjects;C_(max)and AUC_(0-∞)were(6.40±3.25)ng·mL^(-1),(9.50±3.70)ng·mL^(-1)·h,and T_(max),t_(1/2)were 0.63,2.66 h in elderly subjects.After a multiple dose of azvudine 5 mg·d^(-1)for 7 d,C_(max)and AUC_(0-∞)were(3.26±1.61)ng·mL^(-1),(5.38±2.19)ng·mL^(-1)·h,and T_(max,ss),t_(1/2,ss)were 0.88,2.13 h in young subjects;C_(max,ss)and AUC_(0-∞,ss)were(3.97±2.09)ng·mL^(-1),(6.71±3.26)ng·mL^(-1)·h,and T_(max,ss),t_(1/2,ss)were 0.75,2.56 h in elderly subjects.Elderly/young geometric mean ratios and 90%CIs were 128.37%(88.23%-186.76%),139.93%(105.42%-185.72%),140.03%(106.33%-184.41%)for azvudineC_(max),AUC_(0-t),AUC_(0-∞)after a single dose,and were118.66%(80.83%-174.20%),118.41%(83.60%-167.69%),118.95%(84.78%-166.89%)for azvudine C_(max),AUC_(0-t),AUC_(0-∞)after a multiple dose of azvudine 5 mg·d^(-1)for 7 d.Conclusion After single and multiple oral administration of azvudine tablets,systemic exposure to azvudine was higher in healthy elderly subjects compared with healthy young subjects.After taking azvudine tablets,the types,severity and incidence of adverse events and adverse drug reactions in healthy elderly people were not significantly different from those in healthy young subjects.Azvudine was found to be safe and well tolerated in healthy elderly subjects.