单剂量口服盐酸卡利哌嗪在健康成年人中的药代动力学研究

Pharmacokinetics of cariprazine hydrochloride after a single oral administration in healthy Chinese volunteers

目的评价在中国健康成年受试者中,单剂量口服盐酸卡利哌嗪1 mg的药代动力学特征和安全性。方法采用开放、单组试验设计,入选14例健康受试者,单次口服盐酸卡利哌嗪1 mg。用经验证的液相色谱串联质谱分析方法测定卡利哌嗪及其代谢物去甲基卡利哌嗪(DCAR)和去二甲基卡利哌嗪(DDCAR)的血药浓度,以非房室模型分析关键药代动力学参数;将所有报告的不良事件(AE)、严重不良事件(SAE)进行详细描述。结果卡利哌嗪、DCAR和DDCAR的血浆药代动力学参数:C_(max)分别为(1.01±0.40),(0.12±0.05),(0.08±0.03)g·mL^(-1),T_(max)分别为(2.57±0.65),(17.29±9.53),(348.00±191.71)h,AUC_(0-last)分别为(32.40±12.10),(10.78±9.53),(42.20±18.80)ng·h·mL^(-1)。卡利哌嗪和DCAR的半衰期(t_(1/2))分别为(133.90±72.90),(79.70±32.30)h。女性受试者中DCAR和DDCAR的全身暴露量均高于男性,体质量校正后的暴露量相当。研究未报告SAE,没有发生导致受试者退出研究的AE,所有AE均未经干预治疗,转归良好。结论中国健康受试者单次口服盐酸卡利哌嗪片剂1 mg的安全性良好。药代动力学分析表明,与DCAR和DDCAR相比,卡利哌嗪的C_(max)更高。女性受试者卡利哌嗪、DCAR和DDCAR的全身暴露量(C_(max)和AUC)比男性高,可归因于体质量差异。

Objective To evaluate the pharmacokinetic and safety of a 1 mg single dose of cariprazine hydrochloride that is administered orally in healthy Chinese adult volunteers.Methods An open label,single arm study,14 healthy subjects were administered cariprazine hydrochloride 1 mg orally.Plasma concentrations of unchanged cariprazine and its metabolites,esmethyl-cariprazine(DCAR)and didesmethyl-cariprazine(DDCAR)were determined by validated method of LC-MS/MS.Key pharmacokinetic parameters were analyzed by non-compartmental method.All reported adverse events(AE)and serious adverse events(SAE)were described in detail.Results Pharmacokinetic parameters of cariprazine,DCAR and DDCAR:C_(max) were(1.01±0.40),(0.12±0.05),(0.08±0.03)ng·mL^(-1),T_(max) were(2.57±0.65),(17.29±9.53),(348.00±191.71)h,AUC_(0-last) were(32.40±12.10),(10.78±9.53),(42.20±18.80)ng·h·mL^(-1),respectively.The half-lives of cariprazine and DCAR were(133.90±72.90)h and(79.70±32.30)h,respectively.Systemic exposure to DCAR and DDCAR was higher in female than in male,the weight-adjusted exposure were comparable.No SAE were reported in the study,no AE occurred that caused subjects to withdraw from the study,and all adverse events were untreated and were resolved.Conclusion The single oral administration of cariprazine tablet 1 mg is safe for healthy Chinese volunteers.Pharmacokinetic analysis showed that the C_(max) of the prototype Cariprazine was higher than that of DCAR and DDCAR.The systemic exposures(C_(max) and AUC)of cariprazine,DCAR and DDCAR in female were higher than in male,which could be attributed to weight differences.