群体药动学原理建立卡马西平和丙戊酸的定时定量给药模型及临床应用

目的:建立国人卡马西平和丙戊酸的群体药动学模型,并将其应用于临床,建立定时定量给药的癫痫临床药学服务模式。方法:筛选国内多中心卡马西平(carbamazepine,CBZ)和丙戊酸(valproic acid,VPA)的稳态谷浓度数据,建立适合神经内科癫痫患者个体化给药的群体药动学(population pharmacokinetics,PPK)模型,利用建模中心外数据评价所建模型的预测能力。结果:建立了CBZ的PPK最终模型: K_a(h^-1)=1.2, CL(CL/F)(L·h^-1)=0.074×TAMT_CBZ^0.41×WT^0.267×1.42(若合用苯妥因钠,否则为1)×1.18(若合用苯巴比妥,否则为1)×0.84(若年龄>65岁,否则为1),V(V/F)(L)=1.21×WT; VPA的PPK最终模型:K_a(h^-1)=1.9,CL(CL/F)(L·h^-1)=0.102×(WT/60)^0.696×TAMT_VPA^0.197×1.36(若合用CBZ,否则为1)×1.25(若合用苯妥英钠,否则为1)×1.11(若合用苯巴比妥,否则为1),V(V/F)(L)=0.14×WT;其中,K_a为吸收速率常数,CL为表观清除率,V为表观分布容积,F为生物利用度,TAMT_CBZ、TAMT_VPA为CBZ、VPA的日剂量(mg·d^-1),WT为体质量(kg)。经建模中心外数据验证,所建模型预测能力较强。建立的定时定量药学服务应用于临床后,取得了较好的临床疗效(案例略)。结论:新临床药学服务有助于医疗团队提高抗癫痫治疗质量。

Timing and quantitative administration of carbamazepine and valproic acid based on population pharmacokinetics models and its clinical application

OBJECTIVE To establish clinical pharmacy services for epilepsy patients based on timing and quantitative administration of carbamazepine (CBZ) and valproic acid (VPA).METHODS Steady-state trough concentrations of CBZ and VPA, which had multiple center and large sample, were selected to develop population pharmacokinetics (PPK) models for epilepsy patients. Data outside the model were used to evaluate predictive ability of these models.RESULTS Final model of CBZ: K_a(h^-1)=1.2, CL(CL/F)(L·h^-1)=0.074×TAMT_CBZ^0.41×WT^0.267×1.42(if taking phenytoin)×1.18 (if taking phenobarbital)×0.84 (if age>65 years old), V (V/F)(L)=1.21×WT. Final model of VPA: K_a (h^-1)=1.9, CL(CL/F)(L·h^-1)=0.102×(WT/60)^0.696×TAMT_VPA^0.197×1.36 (if taking CBZ)×1.25 (if taking phenytoin)×1.11(if taking phenobarbital), V(V/F)(L)=0.14×WT. In the above equations, K_a was absorption rate constant, CL was apparent clearance, V was apparent volume, F was bioavailability, WT was weight, TAMT_CBZ and TAMT_VPA were daily doses of CBZ and VPA, respectively. Final model had positive prediction for samples outside the model. Good efficacy was achieved after clinical pharmacy services based on timing and quantitative administration.CONCLUSION New clinical pharmacy services can help medical staff to improve quality of treatment against epilepsy patients.