中国临床药学杂志

目的 探讨重症成人和儿童患者泊沙康唑的药动学/药效学(PK/PD)特征,并分析其临床应用效果。方法 收集2020年1月至2022年12月住院接受泊沙康唑治疗并进行泊沙康唑血药谷浓度测定的成人和儿童病例共298例,分为泊沙康唑肠溶片组210例和泊沙康唑混悬液组88例。采用贝叶斯反馈法估算PK参数[表观分布容积(Vd)、清除率(CL/F)等],绘制药-时曲线,计算药-时曲线下面积(AUC)。记录微生物培养和药敏结果,以及泊沙康唑对念珠菌、烟/土曲霉及其他曲霉的最低抑菌浓度(MIC),计算AUC/MIC。根据PK/PD结果,对泊沙康唑混悬液组初始谷浓度未达标成人病例的给药方案进行调整,计算调整后的谷浓度达标率。结果 泊沙康唑混悬液组成人病例的年龄、谷浓度、C_avg,ss、C_avg,ss达标率和AUC均低于泊沙康唑肠溶片组(P <0.01),CL/F高于泊沙康唑肠溶片组(P <0.01)。泊沙康唑肠溶片组成人病例念珠菌、烟/土曲霉和其他曲霉的AUC/MIC分别为653.43±228.54、156.82±54.85和78.41±27.43;混悬液组成人病例念珠菌、烟/土曲霉和其他曲霉的AUC/MIC分别为181.61±45.58、43.59±10.94和21.79±5.47,泊沙康唑肠溶片组成人病例各真菌的AUC/MIC均高于混悬液组(P<0.01)。泊沙康唑混悬液组儿童病例的年龄、谷浓度、Vd/F、C_avg,ss和AUC均低于泊沙康唑肠溶片组(P <0.01),CL/F高于泊沙康唑肠溶片组(P<0.01)。泊沙康唑肠溶片组儿童病例念珠菌、烟/土曲霉和其他曲霉的AUC/MIC分别为1 008.34±342.65、242.00±82.24和121.00±41.12;混悬液组儿童病例念珠菌、烟/土曲霉和其他曲霉的AUC/MIC分别为486.14±137.25、116.67±32.94和58.34±16.47,泊沙康唑肠溶片组儿童病例各真菌的AUC/MIC均高于混悬液组(P <0.01)。泊沙康唑肠溶片组成人病例的C_avg,ss达标率为99.25%,泊沙康唑混悬液组成人病例的C_avg,ss达标率为16.67%。对泊沙康唑混悬液组C_avg,ss未达标的成人病例进行给药方案调整后,C_avg,ss达标率由16.67%提升至66.67%。结论 基于成人和儿童患者的泊沙康唑肠溶片和混悬液的PK/PD研究结果,对使用泊沙康唑患者的给药方案进行个体化调整和优化,能够提高疗效,有助于指导临床合理用药。

AIM To investigate the pharmacokinetic(PK)/pharmacodynamic(PD) of posaconazole in critically ill adults and children,and to analyze its clinical application effect.METHODS A total of 298 hospitalized adult and pediatric patients receiving posaconazole treatment in the hospital were selected and assigned to enteric-coated tablet group with 210 patients and suspension group with 88 patients.The Bayesian approach was utilized to determine pharmacokinetic parameters,including the apparent volume of distribution(Vd) and the clearance rate(CL/F).Subsequently,the drug-time profile was constructed,and the area under the curve(AUC) was computed.Microbial culture and susceptibility results were collected,and the minimum inhibitory concentration(MIC) data for posaconazole against Candida,Aspergillus fumigatus and Aspergillus terreus,and other Aspergillus species were recorded,with the AUC/MIC ratio being calculated.Based on the PK/PD results,the regimen adjustments were made for adult patients in the posaconazole suspension group where the initial trough concentrations failed to meet the standard,and the compliance rate of target trough concentrations was calculated.RESULTS The average age,trough concentrations,C_avg,ss,C_avg,ss compliance rate and AUC in the posaconazole suspension group from adult patients were lower than those in the enteric-coated tablet group(P<0.01),and the CL/F was higher than that in the enteric-coated tablet group(P<0.01).The AUC/MIC values of posaconazole enteric-coated tablets against Candida,Aspergillus fumigatus and Aspergillus terreus,and other species in adult patients were 653.43±228.54,156.82±54.85,and 78.41±27.43 respectively.For the suspension of posaconazole in adult patients,the AUC/MIC values against Candida,Aspergillus fumigatus and Aspergillus ter reus,and other Aspergillus species were 181.61±45.58,43.59±10.94,and 21.79±5.47 respectively.The AUC/MIC values of posaconazole enteric-coated tablets against various fungi in adult patients were all higher than those of the suspension group(P <0.01).The average age,trough concentrations,C_avg,ss and AUC in the posaconazole suspension group from pediatric patients were lower than those in the enteric-coated tablet group(P<0.01).The CL/F of pediatric patients treated with posaconazole suspension was higher than that of enteric-coated tablets(P<0.01).The AUC/MIC values of posaconazole enteric-coated tablets against Candida,Aspergillus fumigatus and Aspergillus terreus,and other species in pediatric patients were 1 008.34±342.65,242.00±82.24 and 121.00±41.12respectively.For the suspension of posaconazole in pediatric patients,the AUC/MIC values against Candida,Aspergillus fumigatus and Aspergillus terreus,and other Aspergillus species were 486.14±137.25,116.67±32.94 and 58.34±16.47respectively.The compliance rates to achieve the target trough concentration of C_avg,ss were 99.25% for adult patients in enteric-coated tablet group and 16.67% for adult patients in the suspension group.After adjusting the dosing regimen for adult patients in the posaconazole suspension group who initially failed to meet the target trough concentration of C_avg,ss,the compliance rate of the target trough concentration of C_avg,ss significantly improved from 16.67% to 66.67%.CONCLUSION The PK/PD of posaconazole enteric-coated tablets and suspension in ill adults and children was studied based on the Bayesian feedback method.This method was applied to dose adjustment and optimization of individual patients,which could enhance the efficacy and contribute to guide the clinical rational medication.