口服西他沙星在中国健康受试者中的药动学及药动学/药效学研究

Pharmacokinetic and pharmacokinetic/pharmacodynamic study on oral administration of sitafloxacin in healthy Chinese subjects

目的研究中国健康受试者单剂或多剂口服西他沙星(DU-6859a)片剂后的药动学(PK)及PK/药效学(PD)。方法单剂给药组:单中心、开放、3个剂量组平行研究设计。每个剂量组入选12名受试者,分别单剂空腹口服西他沙星片50mg、100mg和200mg;多剂给药组:单中心、开放、单个剂量组研究设计。共入组12名受试者,口服西他沙星片100mg,1次/12h,连续给药10d,其中第1天和第10天仅早晨给药1次。收集受试者给药后的血样和尿样,采用经过方法学验证的超高效液相色谱-串联质谱方法(UPLC-MS/MS)测定血清及尿液样本中西他沙星浓度,并结合西他沙星对社区获得性肺炎(CAP)和尿路感染(UTI)常见病原菌的体外PD结果(MIC)进行PK/PD分析。结果受试者单剂口服西他沙星片50mg、100mg和200mg后,分别于0.92h、1.42h和1.21h达到高峰血清浓度(C_(max)),C_(max)分别为(0.72±0.19)mg/L、(1.39±0.36)mg/L和(2.32±0.78)mg/L,平均药时曲线下面积(AUC_(0-∞))分别为(3.67±0.67)mg·h/L、(8.19±1.15)mg·h/L和(14.20±3.21)mg·h/L,消除半衰期(T_(1/2))分别为(6.55±0.97)h、(6.84±1.17)h和(7.81±0.89)h。给药后48h内平均累积尿排出率在61.4%~70.0%。多剂给药后第1天和第10天血C_(max)分别为(1.01±0.19)mg/L和(1.26±0.20)mg/L,第10天达到稳态后,AUC_(0-12h(ss))为(6.88±0.81)mg·h/L,稳态时总清除率(CL_(ss)/F)、总清除率(CL_r/F)分别为(14.72±1.79)L/h和(10.58±1.40)L/h,达峰时间(T_(max))和表观分布容积V_(dz)/F分别为(2.08±0.76)h和(128.95±24.86)L。蓄积因子(R_(AUC))为1.35。第1天和第10天48h的药物平均累积尿排出率分别为67.64%和99.11%。体外PD结果提示西他沙星抗菌活性可覆盖CAP和UTI的主要病原菌,西他沙星对CAP患者中肺炎链球菌PK/PD参数可达到其靶值,给药后尿药浓度高,即使8~12h尿药浓度仍可维持在大肠埃希菌MIC_(90)至少5倍以上。结论健康受试者单剂和多剂口服西他沙星片后吸收迅速,在50~200mg剂量范围内呈线性PK特征,受试者耐受性良好。西他沙星片100mg2次/d的给药方案对CAP和UTI常见病原菌所致感染预期可达到良好的临床疗效和微生物学疗效。

Objective To evaluate the pharmacokinetics(PK)and PK/pharmacodynamics(PD)profiles of sitafloxacin(DU-6859a)after single dose and multiple dose administration of sitafloxacin tablets in healthy Chinese subjects.Methods The single dose study was designed as a single site,open-labeled,parallel group trial including 3 doses(50,100,and 200 mg),12 subjects in each dose group.Multiple dose study was designed as single site,open-labeled,one fixed dose group,including 12 subjects receiving sitafloxacin 100 mg,q12h for 10 consecutive days,but single dose in the morning on day 1 and day 10.Plasma and urine samples were collected.Sitafloxacin concentration was determined using a validated ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method.PK/PD parameters were analyzed using the PK data and in vitro PD data of sitafloxacin against the bacterial isolates in clinical trials of community-acquired pneumonia(CAP)and urinary tract infections(UTI).Results The mean value of peak concentration(Cmax)was(0.72±0.19),(1.39±0.36),and(2.32±0.78)mg/L following single oral dose of 50,100,and 200 mg sitafloxacin,respectively.The corresponding mean AUC0-∞was(3.67±0.67),(8.19±1.15),and(14.20±3.21)mg·h/L,and the mean value of T1/2 was(6.55±0.97),(6.84±1.17),and(7.81±0.89)h.The accumulative urinary excretion rate of sitafloxacin ranged from 61.4%to 70.0%within 48 h after single dose administration.After administration of multiple doses,the mean Cmax of sitafloxacin was(1.01±0.19)mg/L(Day1)and(1.26±0.20)mg/L(Day10).The corresponding AUC0-12h(ss)was(6.88±0.81)mg·h/L,CLss/F was(14.72±1.79)L/h,and CLr/F was(10.58±1.40)L/h,Tmax was(2.08±0.76)h,Vd2/F was(128.95±24.86)L.The accumulative factor(RAUC)was 1.35.The accumulative urinary excretion rate of sitafloxacin was 67.64%(Day1)and 99.11%(Day 10)within 48 h after multiple dose administration.In vitro pharmacodynamic study showed that sitafloxacin was active against common pathogens of CAP and UTI.PK/PD parameters achieved the target values in CAP patients.Sitaflocaxin showed high concentration in urine,at least 5 times higher than the MIC90 against Escherichia coli 8-12 h after dosing.Conclusions Sitafloxacin is absorbed quickly after oral dosing.It has shown a linear PK profile within 50-200 mg dose range.Sitafloxacin is well-tolerated in healthy Chinese subjects after single-dose and multiple-dose oral administration.Sitafloxacin 100 mg,q12h dosing regimen can achieve the desirable clinical and microbiological officacy targeting common pathogens of CAP and UTI.