用蒙特卡罗模型探索头孢他美钠的给药方案

Exploring the dosage regimens of sodium cefetamet with Monte-Carlo simulation

目的用蒙特卡罗模型,研究注射用头孢他美钠在犬体内的药效学与药动学的关系,探索合理的给药方案,为临床用药提供参考。方法 6只健康beagle犬(A、B组)交叉静脉注射190mg或264mg头孢他美钠,不同时间点取血,采用HPLC法测定血药浓度,用一室模型计算药动学参数,用蒙特卡罗模型预测头孢他美钠在四种不同给药方案下的治疗效果。结果 190mg组的犬主要药动学参数T1/2,CL,V为(1.21±0.24)h,(115.46±13.02)mL/h/kg,(202.50±50.91)mL/kg。264mg组的犬主要药动学参数T1/2,CL,V为(1.27±0.51)h,(105.75±11.22)mL/h/kg,(189.94±62.23)mL/kg,通过蒙特卡罗模拟,得到头孢他美钠在不同给药方案下的PK-PD曲线及敏感性折点。结论敏感菌感染并以%T>MIC90≥50%为治疗目标时建议选择333mg静脉注射,每8h给药一次(q8h,下同)或500mg,3h静脉滴注,q12h;以%T>MIC90≥65%为治疗目标时建议选择333mg,3h静脉滴注,q8h;耐药菌感染则需要加大剂量或重新选择新的给药方案。

Objective Using Monte-Carlo simulation to study the relationship between PK and PD with sodium cefetamet injection in beagles, and find the rational dosage regimen to provide the reference for clinical safety medication, Methods Six health beagles （randomly divided into A and B groups） crossed Intravenous 190mg sodium cefetamet or 250mg sodium cefetamet, and blood samples are obtained in different times. Plasma concentrations are measured by HPLC and PK parameters are calculated with one-compartment model. Monte-Carlo simulation is used to simulate four different dosage regimens to obtain the PK-PD curves and susceptible breakpoints. Results The PK parameters T1/2, CL and V for 190mg group are （1.21±0.24）h, （115.46±13.02）mL/h/kg and （202.5±50.91）mL/kg （average±Std）, respectively; which are （1.27±0.51）h, （105.75±11.22）mL/h/kg and （189.94±62.23）mL/kg in 250mg group. Different dose regimens PK-PD curves are simulated to get the different susceptible breakpoints by Monte- Carlo simulation. Conclusion 333mg of intravenous,q8h or 500mg, 3h-infusion, ql2h are preferred for target f%T〉MIC90≥50% and 333mg, 3h-infusion, q8h is for target f%Y〉 IC90≥65%, and new dosage regimens or more dosages should be selected when drug-resistant bacteria infections are encountered.