群体药代动力学指导中间型或重型血友病A患者个体化预防治疗疗效及安全性的真实世界研究

Real-world study on efficacy and safety of population pharmacokinetics to guide individualized prophylaxis in patients with intermediate or severe hemophilia A

目的探讨采用群体药代动力学(PK)指导中间型或重型血友病A(HA)患者个体化预防治疗的疗效及安全性。方法选择2021年1月至2023年10月于成都市第三人民医院血友病门诊采取重组人凝血因子Ⅷ(rhFⅧ)固定给药剂量和频次的常规预防模式治疗方案(以下简称为B模式)治疗1年后,继续进行群体PK指导下个体化预防模式治疗方案(以下简称为A模式)治疗1年的24例中间型或重型HA患者为研究对象。这24例患者均为男性,中位年龄为16.5岁(13.3,24.3岁),中间型、重型HA患者分别为4和20例。采用血友病WAPPS软件计算24例HA患者rhFⅧPK参数半衰期和谷浓度,并根据其PK参数制定A模式方案。采用回顾性研究方法,收集患者A、B模式下rhFⅧ静脉注射剂量和频次、年总出血次数(ABR)、年关节出血次数(AJBR)、关节超声评分、血友病关节健康评分(HJHS),以及FⅧ抑制物产生情况等临床资料。对这24例患者采取A、B模式治疗期间临床病例资料采用Wilcoxon符号秩和检验进行比较。本研究遵循的程序符合成都市第三人民医院药物临床试验伦理委员会制定的标准,并且经过该伦理委员会批准(批准文号:2023-S-236)。结果①本组24例HA患者的中位rhFⅧ半衰期为11.9 h(9.6,13.4 h)。其中,<16岁(n=11)与≥16岁患者(n=13)的中位rhFⅧ半衰期比较,差异无统计学意义[11.5 h(9.8,12.3 h)比12.0 h(9.1,14.1 h),Z=-0.80,P=0.424]。②采取A模式治疗时,本组患者中位单次和周rhFⅧ静脉注射剂量分别为27.3 IU/kg(22.6,29.3 IU/kg)和81.8 IU/kg(66.4,89.6 IU/kg),较采取B模式治疗时的26.6 IU/kg(21.6,28.7 IU/kg)和58.4 IU/kg(51.1,76.9 IU/kg)均增加,并且差异均有统计学意义(Z=-2.20,P=0.028;Z=-3.41,P=0.001)。③采取A模式治疗时,本组患者中位ABR、AJBR及年膝关节出血次数分别为2.0次(0,7.3次),2.0次(0,5.5次),0次(0,1.8次),较采取B模式治疗时的4.0次(0.5,10.0次),4.5次(0.5,6.0次)和2.0次(0,5.0次)均下降,并且差异均有统计学意义(Z=-2.90,P=0.004;Z=-2.78,P=0.005;Z=-2.70,P=0.007)。④采取A模式治疗时,本组患者中位膝关节超声评分为7.0分(2.0,18.0分),高于采用B模式治疗时的7.0分(1.3,15.8分),并且差异有统计学意义(Z=-2.50,P=0.012)。⑤采取A模式治疗时,本组患者中位HJHS、关节健康总评分、肘关节HJHS、膝关节HJHS、踝关节HJHS,均低于采取B模式治疗时,并且差异均有统计学意义(Z=-3.82,P<0.001;Z=-3.73,P<0.001;Z=-3.42,P<0.001;Z=-3.49,P<0.001;Z=-2.74,P=0.006)。⑥本组患者纳入研究期间,FⅧ抑制物均呈阴性。结论采取A模式治疗,对HA患者疗效可靠,相对于B模式治疗,可以进一步减少患者关节出血,延缓关节损害的进展,改善关节功能。

Objective To investigate the efficacy and safety of population pharmacokinetics(PK)to guide individualized prophylaxis in patients with intermediate or severe hemophilia A(HA).Methods From January 2021 to October 2023,a total of 24 patients with intermediate or severe HA who received routine prophylaxis with recombinant human coagulation factorⅧ(rhFⅧ)(hereinafter referred to as model B)for 1 year and continued with individualized rhFⅧprophylaxis guided by population PK(hereinafter referred to as model A)for 1 year at Chengdu Third People′s Hospital,were selected as study subjects.Among them,all 24 patients were male with median age of 16.5 years(13.3,24.3 years).There were 4 intermediate and 20 severe HA patients.The WAPPS-Hemo software was used to calculate the PK parameters of these patients,including half-life and minimum concentration of rhFⅧ.Model A were formulated based on these PK parameters.A retrospective study was conducted to collect clinical data,including intravenous injection dose and frequency of rhFⅧ,annual bleeding rate(ABR),annual joint bleeding rate(AJBR),joint ultrasound score,hemophilic joint health score(HJHS),and incidence of FⅧinhibitors.Clinical data were compared between patients during receiving model A and B treatment periods using the Wilcoxon signed rank sum test.The procedures followed in this study were in line with the standards set by the Ethics Committee for Drug Clinical Trials of Third People′s Hospital of Chengdu,and were approved by this Ethics Committee(Approval No.2023-S-236).Results①The median rhFⅧhalf-life of 24 patients with HA in this study was 11.9 h(9.6,13.4 h).There was no statistical difference in median rhFⅧhalf-life between patients<16 years old(n=11)and those≥16 years old(n=13)[11.5 h(9.8,12.3 h)vs 12.0 h(9.1,14.1 h),Z=-0.80,P=0.424].②During model B treatment period,the median single and weekly rhFⅧintravenous injection doses were 27.3 IU/kg(22.6,29.3 IU/kg)and 81.8 IU/kg(66.4,89.6 IU/kg),respectively,which were higher than those of 26.6 IU/kg(21.6,28.7 IU/kg)and 58.4 IU/kg(51.1,76.9 IU/kg)during model A period,and the differences were statistically significant(Z=-2.20,P=0.028;Z=-3.41,P=0.001).③During model B treatment period,the median ABR,AJBR,and annual knee joint bleeding rate were 2.0 times(0,7.3 times),2.0 times(0,5.5 times),and 0(0,1.8 times),respectively,which were lower than those of 4.0 times(0.5,10.0 times),4.5 times(0.5,6.0 times),and 2.0 times(0,5.0 times)during model A treatment period,and all differences were statistically significant(Z=-2.90,P=0.004;Z=-2.78,P=0.005;Z=-2.70,P=0.007).④During model B treatment period,the median knee joint ultrasound score was 7.0 scores(2.0,18.0 scores),which was higher than that of 7.0 scores(1.3,15.8 scores)during model A treatment period,and the difference was statistically significant(Z=-2.50,P=0.012).⑤During model B treatment period,the median HJHS,overall joint health score,elbow joint HJHS,knee joint HJHS,and ankle joint HJHS were lower than those during model A treatment period(Z=-3.82,P<0.001;Z=-3.73,P<0.001;Z=-3.42,P<0.001;Z=-3.49,P<0.001;Z=-2.74,P=0.006).⑥During the study period,all patients′FⅧinhibitors were negative.Conclusions The efficacy of model A in treating patients with HA is reliable.Compare to model B treatment,model A could further reduce joint bleeding,slow the progression of joint damage,and improve joint function in patients.