目的应用蒙特卡洛模拟评价奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌和大肠埃希菌感染的疗效。方法结合药动学参数和药效学参数,以AUC/MIC为PK/PD模型进行蒙特卡洛模拟,得到6种给药方案对上述3种病原菌的达标概率(PTA)及累积...目的应用蒙特卡洛模拟评价奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌和大肠埃希菌感染的疗效。方法结合药动学参数和药效学参数,以AUC/MIC为PK/PD模型进行蒙特卡洛模拟,得到6种给药方案对上述3种病原菌的达标概率(PTA)及累积反应分数(CFR)。结果奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌(抑菌靶值下模拟),都能达到CFR>90%;对于金黄色葡萄球菌(杀菌靶值下模拟),仅600 mg po q24h和多剂量C组(负荷剂量450 mg po q12h,维持剂量450 mg poq24h)达到CFR>90%;但对大肠埃希菌,所有给药方案的CFR均不达标。结论奥马环素的说明书推荐给药方案(负荷剂量200 mg iv,维持剂量300 mg po q24h)对肺炎链球菌、金黄色葡萄球菌有较好的治疗效果;但对大肠埃希菌,6种给药方案均达不到预期疗效。展开更多
目的基于药动/药效(pharmacokinetic/pharmacodynamic,PK/PD)理论,应用蒙特卡洛模拟(Monte Carlo simulation,MCS)评价及优化不同病原菌感染时帕珠沙星的给药方案。方法将12名健康志愿受试者分为3组,分别给予300、500和1000 mg3种不同...目的基于药动/药效(pharmacokinetic/pharmacodynamic,PK/PD)理论,应用蒙特卡洛模拟(Monte Carlo simulation,MCS)评价及优化不同病原菌感染时帕珠沙星的给药方案。方法将12名健康志愿受试者分为3组,分别给予300、500和1000 mg3种不同剂量的帕珠沙星,以高效液相色谱法测得血药浓度,进而求出PK参数。用琼脂二倍稀释法确定大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、金黄色葡萄球菌、表皮葡萄球菌和肺炎链球菌6种临床分离菌株物的最低抑菌浓度以进行PD研究。根据PK/PD研究结果,以AUC_(0-24)/MIC作为帕珠沙星的PK/PD指数(靶值为30、100和125),通过蒙特卡洛模拟得出不同给药方案的达标概率(probability of target attainment,PTA)和累积响应百分率(cumulative fraction of response,CFR),评价出最佳给药方案。结果以CFR>90%的给药方案作为临床最佳给药方案,蒙特卡洛模拟10000次的结果得出,帕珠沙星在1000 mg的给药剂量下对肺炎链球菌的CFR可达到92.33%,在500和1000 mg的给药剂量下对表皮葡萄球菌的CFR可达到90.11%和93.79%;对大肠埃希菌、肺炎克雷伯菌、金黄色葡萄球菌和铜绿假单胞菌的CFR均小于90%。结论在表皮葡萄球菌感染时推荐使用500 mg qd的帕珠沙星;在日剂量为1000 mg时帕珠沙星对肺炎链球菌的感染有很好的效果,对大肠埃希菌、肺炎克雷伯菌、金黄色葡萄球菌和铜绿假单胞菌的抑制效果不佳,可作为辅佐治疗药物。不同致病菌感染时所需要的给药剂量存在明显差异,根据PK/PD理论以及蒙特卡洛模拟可为帕珠沙星临床最佳给药方案的制定提供依据。展开更多
目的:基于药动学(pharmacokinetics,PK)/药效学(pharmacodynamics,PD)模型和蒙特卡洛模拟(Mote Carlo simulation,MCS),分析大肠埃希菌所致脓毒症休克患者抗感染治疗方案的优化过程,为临床感染患者构建合理有效的治疗方案提供参考。方法...目的:基于药动学(pharmacokinetics,PK)/药效学(pharmacodynamics,PD)模型和蒙特卡洛模拟(Mote Carlo simulation,MCS),分析大肠埃希菌所致脓毒症休克患者抗感染治疗方案的优化过程,为临床感染患者构建合理有效的治疗方案提供参考。方法:一患者因不明原因发热入院,初步诊断为尿路感染和脓毒症休克。入院后第一时间完善了相关实验室检查,随后采用PK/PD模型和MCS依据微生物培养结果及其药敏试验确定最优的抗感染治疗方案。结果:入院第3天,微生物培养检出大肠埃希菌,随后的药敏试验提示其对美罗培南、亚胺培南敏感,而对头孢哌酮-舒巴坦钠中介;采用PK/PD模型和MCS对拟定的几个抗感染治疗方案进行分析,结果发现美罗培南(1 g,q8h)和亚胺培南(0.5 g,q6h)的达标概率(probability of target attainment,PTA)均为100.00%,而头孢哌酮-舒巴坦钠(3 g,q12h)的PTA为1.14%,头孢哌酮-舒巴坦钠(3 g,q8h)的PTA为7.65%;最终,临床选择了美罗培南(1 g,q8h)治疗,1周后患者的感染指征基本消失。结论:PK/PD模型和MCS两个工具可以较好地帮助临床药师预测抗感染治疗方案的可能效果,从而更好地协助医生制定和优化治疗方案,进而最大程度保证患者的治疗效果。展开更多
In this study,we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic(WB-PBPK)/pharmacodynamic(PD)model for saxagliptin,simulate its pharmacokinetic and pharmacodynamic properties in health...In this study,we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic(WB-PBPK)/pharmacodynamic(PD)model for saxagliptin,simulate its pharmacokinetic and pharmacodynamic properties in healthy adults and patients with hepatic function impairment,and provide a new method for the research to the clinical pharmacy of special patients.Based on the drug-specific properties,such as log D,plasma protein binding collected by the published literature,the WB-PBPK model and the PD model were established.After comparing the simulated concentration-time profiles and the pharmacokinetic parameters with data in healthy adults from oral and intravenous clinical investigation,the WB-PBPK model could be optimized.After comparing the simulated DPP-4 inhibition profile with the observed pharmacodynamic in healthy subjects,the PD model could be optimized.The PK/PD model was utilized to predict the mean and variability of the pharmacokinetic and pharmacodynamic profiles in subjects with different hepatic impairment.All of the predicted pharmacokinetic curves were comparable to the observed curves both in healthy subjects and hepatic impairment subjects(Cmax and AUC were less than 1.3-fold).The predicted pharmacodynamic curves were comparable to the observed ones in different oral dosage after optimization,and pharmacodynamics of saxagliptin in hepatic impairment subjects were predicted successfully.The WB-PBPK/PD model can accurately simulate the pharmacokinetics and pharmacodynamics of saxagliptin in normal adults and different hepatic impaired patients.展开更多
Peptides play multiple functions in cellular processes and are considered an attractive paradigm for the development of novel drugs and therapeutic approaches. However, the complexity of their pharmacokinetics/pharmac...Peptides play multiple functions in cellular processes and are considered an attractive paradigm for the development of novel drugs and therapeutic approaches. However, the complexity of their pharmacokinetics/pharmacodynamics and physicochemical properties presents challenges in their development. Currently, there is no single analytical method that fully meets the requirements for studying peptide drug pharmacokinetics. Interdisciplinary teams and multiple technical platforms are required to address these challenges. This article explores the pharmacokinetics, bioanalytical methods, challenges, and strategies in the development of peptide drugs. As our understanding of peptide drug pharmacokinetics and bioanalytical characteristics deepens, it will facilitate their development and provide scientific evidence for rational clinical use.展开更多
In the present study,we optimized the ceftriaxone dosing regimens based on pharmacokinetic/pharmacodynamic(PK/PD)principles using Monte Carlo simulation(MCS).Based on PK/PD theory,MCS was performed using Crystal Ball ...In the present study,we optimized the ceftriaxone dosing regimens based on pharmacokinetic/pharmacodynamic(PK/PD)principles using Monte Carlo simulation(MCS).Based on PK/PD theory,MCS was performed using Crystal Ball software combining PK and PD parameters with 10000 simulation runs to calculate the probability of target attainment(PTA)and cumulative fraction of response(CFR)for the seven clinically common dosing regimens of ceftriaxone(1 g qd,1.5 g qd,1 g bid,2 g qd,1 g tid,1.5 g bid,and 2 g bid).A%fT≥50 as the target value expected to achieve satisfactory clinical efficacy and a dosing regimen with an obtained CFR≥90%or the ability to achieve the highest PTA was used as a reasonable choice for empirical antimicrobial therapy,i.e.the clinically optimal regimen.All eight pathogenic bacteria had a CFR>90%when the dosing regimen was 2 g bid and 1 g tid,seven pathogenic bacteria had a CFR>90%when the dosing regimen was 1 g bid and 1.5 g bid,except for Pseudomonas aeruginosa,and all pathogenic bacteria had a CFR<90%when the dosing regimen was 1 g qd and 1.5 g qd.The dosing regimens of 2 g bid and 1 g tid were effective against all eight pathogenic bacteria infections,and 1 g bid and 1.5 g bid dosing regimens were effective against the other seven pathogenic bacteria except for Pseudomonas aeruginosa.展开更多
提出了一种新的近场动力学-有限元方法(peridynamics-finite element method,PD-FEM)混合模型.该模型用于求解材料热力耦合损伤问题,将求解域划分为近场动力学(PD)区域和有限元方法(FEM)区域,通过FEM节点与PD物质点构成的混合键连接各...提出了一种新的近场动力学-有限元方法(peridynamics-finite element method,PD-FEM)混合模型.该模型用于求解材料热力耦合损伤问题,将求解域划分为近场动力学(PD)区域和有限元方法(FEM)区域,通过FEM节点与PD物质点构成的混合键连接各个子区域.采用该模型对氧化铝陶瓷板在热冲击载荷作用下的损伤行为进行了模拟分析,计算结果表明,采用该混合模型获得的裂纹萌生及扩展与实验研究结果吻合良好,验证了该模型的正确性.该PD-FEM混合模型继承了PD处理不连续问题的优势,同时,由于FEM的引入,大大提高了PD方法在研究材料热力耦合损伤问题时的求解效率.展开更多
目的:探讨粪菌移植(fecal microbiota transplantation,FMT)能否提高抗程序性细胞死亡蛋白1(anti-programmed cell death protein 1,PD-1)疗法治疗卵巢癌荷瘤小鼠的效果及可能的作用机制。方法:随机将20只5周龄的C57bl/6 SPF雌鼠分为4组...目的:探讨粪菌移植(fecal microbiota transplantation,FMT)能否提高抗程序性细胞死亡蛋白1(anti-programmed cell death protein 1,PD-1)疗法治疗卵巢癌荷瘤小鼠的效果及可能的作用机制。方法:随机将20只5周龄的C57bl/6 SPF雌鼠分为4组,每组5只,分别为对照组(NC组)、FMT组、PD-1组、联合治疗(FMT联合PD-1)组。每组小鼠予广谱抗生素统一处理2周,构建假无菌小鼠模型。第0天,腹腔注射ID8-luc细胞,构建卵巢癌荷瘤小鼠模型。在药物治疗前后,分别给小鼠进行1次动物活体成像(in-vivo imaging system,IVIS),评价治疗效果。第30天即实验结束后,小鼠脱颈处死,取腹膜肿瘤组织进行HE和免疫组化染色,观察肿瘤组织病理变化。结果:联合治疗组比PD-1组治疗卵巢癌荷瘤小鼠效果更好,并且降低了肿瘤细胞PD-L1表达(P<0.05)和增加了肿瘤微环境(the tumor microenvironment,TME)中CD8+T细胞浸润(P<0.05)。结论:FMT通过增加肿瘤微环境中CD8+T细胞的浸润来提高PD-1单抗治疗卵巢癌荷瘤小鼠的效果。展开更多
文摘目的应用蒙特卡洛模拟评价奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌和大肠埃希菌感染的疗效。方法结合药动学参数和药效学参数,以AUC/MIC为PK/PD模型进行蒙特卡洛模拟,得到6种给药方案对上述3种病原菌的达标概率(PTA)及累积反应分数(CFR)。结果奥马环素等6种给药方案对肺炎链球菌、金黄色葡萄球菌(抑菌靶值下模拟),都能达到CFR>90%;对于金黄色葡萄球菌(杀菌靶值下模拟),仅600 mg po q24h和多剂量C组(负荷剂量450 mg po q12h,维持剂量450 mg poq24h)达到CFR>90%;但对大肠埃希菌,所有给药方案的CFR均不达标。结论奥马环素的说明书推荐给药方案(负荷剂量200 mg iv,维持剂量300 mg po q24h)对肺炎链球菌、金黄色葡萄球菌有较好的治疗效果;但对大肠埃希菌,6种给药方案均达不到预期疗效。
文摘目的基于药动/药效(pharmacokinetic/pharmacodynamic,PK/PD)理论,应用蒙特卡洛模拟(Monte Carlo simulation,MCS)评价及优化不同病原菌感染时帕珠沙星的给药方案。方法将12名健康志愿受试者分为3组,分别给予300、500和1000 mg3种不同剂量的帕珠沙星,以高效液相色谱法测得血药浓度,进而求出PK参数。用琼脂二倍稀释法确定大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、金黄色葡萄球菌、表皮葡萄球菌和肺炎链球菌6种临床分离菌株物的最低抑菌浓度以进行PD研究。根据PK/PD研究结果,以AUC_(0-24)/MIC作为帕珠沙星的PK/PD指数(靶值为30、100和125),通过蒙特卡洛模拟得出不同给药方案的达标概率(probability of target attainment,PTA)和累积响应百分率(cumulative fraction of response,CFR),评价出最佳给药方案。结果以CFR>90%的给药方案作为临床最佳给药方案,蒙特卡洛模拟10000次的结果得出,帕珠沙星在1000 mg的给药剂量下对肺炎链球菌的CFR可达到92.33%,在500和1000 mg的给药剂量下对表皮葡萄球菌的CFR可达到90.11%和93.79%;对大肠埃希菌、肺炎克雷伯菌、金黄色葡萄球菌和铜绿假单胞菌的CFR均小于90%。结论在表皮葡萄球菌感染时推荐使用500 mg qd的帕珠沙星;在日剂量为1000 mg时帕珠沙星对肺炎链球菌的感染有很好的效果,对大肠埃希菌、肺炎克雷伯菌、金黄色葡萄球菌和铜绿假单胞菌的抑制效果不佳,可作为辅佐治疗药物。不同致病菌感染时所需要的给药剂量存在明显差异,根据PK/PD理论以及蒙特卡洛模拟可为帕珠沙星临床最佳给药方案的制定提供依据。
文摘In this study,we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic(WB-PBPK)/pharmacodynamic(PD)model for saxagliptin,simulate its pharmacokinetic and pharmacodynamic properties in healthy adults and patients with hepatic function impairment,and provide a new method for the research to the clinical pharmacy of special patients.Based on the drug-specific properties,such as log D,plasma protein binding collected by the published literature,the WB-PBPK model and the PD model were established.After comparing the simulated concentration-time profiles and the pharmacokinetic parameters with data in healthy adults from oral and intravenous clinical investigation,the WB-PBPK model could be optimized.After comparing the simulated DPP-4 inhibition profile with the observed pharmacodynamic in healthy subjects,the PD model could be optimized.The PK/PD model was utilized to predict the mean and variability of the pharmacokinetic and pharmacodynamic profiles in subjects with different hepatic impairment.All of the predicted pharmacokinetic curves were comparable to the observed curves both in healthy subjects and hepatic impairment subjects(Cmax and AUC were less than 1.3-fold).The predicted pharmacodynamic curves were comparable to the observed ones in different oral dosage after optimization,and pharmacodynamics of saxagliptin in hepatic impairment subjects were predicted successfully.The WB-PBPK/PD model can accurately simulate the pharmacokinetics and pharmacodynamics of saxagliptin in normal adults and different hepatic impaired patients.
文摘Peptides play multiple functions in cellular processes and are considered an attractive paradigm for the development of novel drugs and therapeutic approaches. However, the complexity of their pharmacokinetics/pharmacodynamics and physicochemical properties presents challenges in their development. Currently, there is no single analytical method that fully meets the requirements for studying peptide drug pharmacokinetics. Interdisciplinary teams and multiple technical platforms are required to address these challenges. This article explores the pharmacokinetics, bioanalytical methods, challenges, and strategies in the development of peptide drugs. As our understanding of peptide drug pharmacokinetics and bioanalytical characteristics deepens, it will facilitate their development and provide scientific evidence for rational clinical use.
基金2019 Second Hospital of Hebei Medical University Pro ject(Grant No.2h2019042)。
文摘In the present study,we optimized the ceftriaxone dosing regimens based on pharmacokinetic/pharmacodynamic(PK/PD)principles using Monte Carlo simulation(MCS).Based on PK/PD theory,MCS was performed using Crystal Ball software combining PK and PD parameters with 10000 simulation runs to calculate the probability of target attainment(PTA)and cumulative fraction of response(CFR)for the seven clinically common dosing regimens of ceftriaxone(1 g qd,1.5 g qd,1 g bid,2 g qd,1 g tid,1.5 g bid,and 2 g bid).A%fT≥50 as the target value expected to achieve satisfactory clinical efficacy and a dosing regimen with an obtained CFR≥90%or the ability to achieve the highest PTA was used as a reasonable choice for empirical antimicrobial therapy,i.e.the clinically optimal regimen.All eight pathogenic bacteria had a CFR>90%when the dosing regimen was 2 g bid and 1 g tid,seven pathogenic bacteria had a CFR>90%when the dosing regimen was 1 g bid and 1.5 g bid,except for Pseudomonas aeruginosa,and all pathogenic bacteria had a CFR<90%when the dosing regimen was 1 g qd and 1.5 g qd.The dosing regimens of 2 g bid and 1 g tid were effective against all eight pathogenic bacteria infections,and 1 g bid and 1.5 g bid dosing regimens were effective against the other seven pathogenic bacteria except for Pseudomonas aeruginosa.
文摘提出了一种新的近场动力学-有限元方法(peridynamics-finite element method,PD-FEM)混合模型.该模型用于求解材料热力耦合损伤问题,将求解域划分为近场动力学(PD)区域和有限元方法(FEM)区域,通过FEM节点与PD物质点构成的混合键连接各个子区域.采用该模型对氧化铝陶瓷板在热冲击载荷作用下的损伤行为进行了模拟分析,计算结果表明,采用该混合模型获得的裂纹萌生及扩展与实验研究结果吻合良好,验证了该模型的正确性.该PD-FEM混合模型继承了PD处理不连续问题的优势,同时,由于FEM的引入,大大提高了PD方法在研究材料热力耦合损伤问题时的求解效率.
