伏立康唑血药浓度影响因素探讨
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摘要
目的探讨静脉用伏立康唑血药浓度的影响因素,以指导临床制订个体化给药方案,实现精准化治疗。方法共纳入154例患者的154个伏立康唑初始稳态谷浓度(C_(trough))。患者根据年龄段分为婴幼儿组(<2岁)、儿童组(2～17岁)和成人组(≥18岁)。根据2017年中国药理学会治疗药物监测研究专业委员会发布的《伏立康唑个体化用药指南》中推荐的伏立康唑C_(trough)范围为0.5～5 mg·L~(-1),在考察影响有效血药浓度因素时分为<0.5 mg·L~(-1)组和≥0.5 mg·L~(-1)组;在考察影响安全血药浓度因素时分为≤5 mg·L~(-1)组和> 5 mg·L~(-1)组。分别考察不同年龄组患者伏立康唑有效浓度和安全浓度的影响因素。结果婴幼儿组、儿童组和成人组伏立康唑C_(trough)达标率分别为60.00%、55.10%、79.00%。影响儿童组有效血药浓度的因素有苯妥英钠(用药前1周内)(OR:0.057,95%CI:0.013～0.246,P=0.000)、泮托拉唑(OR:0.169,95%CI:0.030～0.945,P=0.043),未发现儿童组安全血药浓度影响因素。影响成人组有效血药浓度的因素为艾司奥美拉唑(OR:0.140,95%CI:0.020～0.962,P=0.046),影响成人组安全血药浓度的因素为谷草转氨酶(OR:1.036,95%CI:1.011～1.060,P=0.004)。结论儿童患者和成人患者伏立康唑有效血药浓度、安全血药浓度影响因素有差异,需要根据患者的具体病例情况和联合用药情况制定伏立康唑用药方案。
Objective To determine the influencing factors of voriconazole serum concentration in patients, and to guide the clinical formulation of individualized dosage regimen for accurate treatment. Methods Totally the voriconazole initial steady-state trough concentrations(C_(trough)) of 154 patients were included. The patients were divided into 3 groups: an infant group( < 2 years), a child group(2-17 years) and an adult group( ≥ 18 years).According to the 2017 Guidelines for the Individualized Use of Voriconazole issued by the Chinese Pharmacological Society's Therapeutic Drug Monitoring Research Committee, the recommended voriconazole C_(trough) range was0.5-5 mg·L~(-1). Voriconazole serum concentrations were divided into the < 0.5 mg·L~(-1) group and the ≥ 0.5 mg·L~(-1) group when investigating the factors affecting the effective serum concentrations. When the factors affecting the safe serum concentrations were investigated, it was divided into the ≤ 5 mg·L~(-1) group and the >5 mg·L~(-1) group. The influencing factors of effective concentration and safe concentration of voriconazole in different age groups were investigated. Results The compliance rates of voriconazole C_(trough) in the infant group,the child group, and the adult group were 60.00%, 55.10% and 79.00%, respectively. Factors affecting the effective serum concentration of the child group included phenytoin(one week before the administration)(OR:0.057,95%CI:0.013-0.246, P = 0.000) and pantoprazole(OR:0.169, 95%CI:0.030-0.945, P = 0.043). No factors affecting safe serum concentration in the child group were found. Esomeprazole(OR:0.140, 95%CI:0.020-0.962, P = 0.046) and AST(OR:1.036, 95%CI:1.011-1.060, P = 0.004) were the influencing factors for effective and safe serum drug concentration in the adult group. Conclusion Factors affecting the effective serum concentration and safe serum concentration of voriconazole in children and adults are different. It is necessary to formulate the voriconazole medication plan according to specific patients before combining medications.
Objective To determine the influencing factors of voriconazole serum concentration in patients, and to guide the clinical formulation of individualized dosage regimen for accurate treatment. Methods Totally the voriconazole initial steady-state trough concentrations(C_(trough)) of 154 patients were included. The patients were divided into 3 groups: an infant group( < 2 years), a child group(2-17 years) and an adult group( ≥ 18 years).According to the 2017 Guidelines for the Individualized Use of Voriconazole issued by the Chinese Pharmacological Society's Therapeutic Drug Monitoring Research Committee, the recommended voriconazole C_(trough) range was0.5-5 mg·L~(-1). Voriconazole serum concentrations were divided into the < 0.5 mg·L~(-1) group and the ≥ 0.5 mg·L~(-1) group when investigating the factors affecting the effective serum concentrations. When the factors affecting the safe serum concentrations were investigated, it was divided into the ≤ 5 mg·L~(-1) group and the >5 mg·L~(-1) group. The influencing factors of effective concentration and safe concentration of voriconazole in different age groups were investigated. Results The compliance rates of voriconazole C_(trough) in the infant group,the child group, and the adult group were 60.00%, 55.10% and 79.00%, respectively. Factors affecting the effective serum concentration of the child group included phenytoin(one week before the administration)(OR:0.057,95%CI:0.013-0.246, P = 0.000) and pantoprazole(OR:0.169, 95%CI:0.030-0.945, P = 0.043). No factors affecting safe serum concentration in the child group were found. Esomeprazole(OR:0.140, 95%CI:0.020-0.962, P = 0.046) and AST(OR:1.036, 95%CI:1.011-1.060, P = 0.004) were the influencing factors for effective and safe serum drug concentration in the adult group. Conclusion Factors affecting the effective serum concentration and safe serum concentration of voriconazole in children and adults are different. It is necessary to formulate the voriconazole medication plan according to specific patients before combining medications.
引文
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[8]肖桂荣,徐珽,吕晓菊.遵循指南推广伏立康唑血浓度监测[J].中国合理用药探索,2017,14(2):71-77.
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[11]Wang T,Yan M,Tang D,et al.Therapeutic drug monitoring and safety of voriconazole therapy in patients with Child-Pugh class B and C cirrhosis:A multicenter study[J].Int J Infect Dis,2018,72:49-54.
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[13]Shin JM,Kim N.Pharmacokinetics and pharmacodynamics of the proton pump inhibitors[J].J Neurogastroenterol Motil,2013,19(1):25-35.
[14]Yan M,Wu ZF,Tang D,et al.The impact of proton pump inhibitors on the pharmacokinetics of voriconazole in vitro and in vivo[J].Biomed Pharmacother,2018,108:60-64.
[15]Ogilvie BW,Yerino P,Kazmi F,et al.The proton pump inhibitor,omeprazole,but not lansoprazole or pantoprazole,is a metabolism-dependent inhibitor of CYP2C19:implications for coadministration with clopidogrel[J].Drug Metab Dispos,2011,39(11):2020-2033.
[16]Cojutti P,Candoni A,Forghieri F,et al.Variability of voriconazole trough levels in haematological patients:influence of comedications with cytochrome P450(CYP)Inhibitors and/or with CYP inhibitors plus CYP inducers[J].Basic Clin Pharmacol Toxicol,2016,118(6):474-479.
[17]Gautier-Veyret E,Fonrose X,Tonini J,et al.Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation:impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels[J].Antimicrob Agents Chemother,2015,59(4):2305-2314.
[18]Li X,Yu C,Wang T,et al.Effect of cytochrome P450 2C19 polymorphisms on the clinical outcomes of voriconazole:a systematic review and meta-analysis[J].Eur J Clin Pharmacol,2016,72(10):1185-1193.
[19]Moriyama B,Obeng AO,Barbarino J,et al.Clinical pharmacogenetics implementation consortium(CPIC)Guidelines for CYP2C19 and voriconazole therapy[J].Clin Pharmacol Ther,2016,102(1):45-51.
[20]Moriyama B,Kadri S,Henning SA,et al.Therapeutic Drug Monitoring and Genotypic Screening in the Clinical Use of Voriconazole[J].Curr Fungal Infect Rep,2015,9(2):74-87.
[21]Zhong X,Tong X,Ju Y,et al.Interpersonal factors in the pharmacokinetics and pharmacodynamics of voriconazole:Are CYP2C19 genotypes enough for us to make a clinical decision?[J].Curr Drug Metab,2018,19(1):1-7.
[2]Girmenia C,Annino L,Bertaina A,et al.Voriconazole treatment in adults and children with hematological diseases:can it be used without measurement of plasma concentration?[J].Med Mycol,2018,56(3):263-278.
[3]陈恳,李光耀,翟所迪.伏立康唑治疗药物监测有效性和安全性的系统评价[J].中国临床药理学杂志,2017,33(1):80-83.
[4]Chau MM,Kong DC,van Hal SJ,et al.Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy,2014[J].Intern Med J,2014,44(12b):1364-1388.
[5]Phillips CJ,McKinnon RA,Woodman RJ,et al.Sustained improvement in vancomycin dosing and monitoring post-implementation of guidelines:Results of a three-year follow-up after a multifaceted intervention in an Australian teaching hospital[J].J Infect Chemother,2018,24(2):103-109.
[6]中国药理学会治疗药物监测研究专业委员会中.伏立康唑个体化用药指南[EB/OL].(2017-5-25)[2018-05-09].http://www.tdmchina.org/portal.php?mod=view&aid=467.
[7]郭一萌,安琳娜,陈恳,等.伏立康唑在不同年龄段使用中安全性和有效性以及药代动力学差异的系统评价[J].中国临床药理学杂志,2016,32(3):261-263.
[8]肖桂荣,徐珽,吕晓菊.遵循指南推广伏立康唑血浓度监测[J].中国合理用药探索,2017,14(2):71-77.
[9]Han K,Bies R,Johnson H,et al.Population pharmacokinetic evaluation with external validation and Bayesian estimator of voriconazole in liver transplant recipients[J].Clin Pharmacokinet,2011,50(3):201-214.
[10]You H,Dong Y,Zou Y,et al.Voriconazole therapeutic drug monitoring:Factors associated with supratherapeutic and subtherapeutic voriconazole concentrations[J].Int JClin Pharmacol Ther,2018,56(5):239-246.
[11]Wang T,Yan M,Tang D,et al.Therapeutic drug monitoring and safety of voriconazole therapy in patients with Child-Pugh class B and C cirrhosis:A multicenter study[J].Int J Infect Dis,2018,72:49-54.
[12]Theuretzbacher U,Ihle F,Derendorf H.Pharmacokinetic/pharmacodynamic profile of voriconazole[J].Clin Pharmacokinet,2006,45(7):649-663.
[13]Shin JM,Kim N.Pharmacokinetics and pharmacodynamics of the proton pump inhibitors[J].J Neurogastroenterol Motil,2013,19(1):25-35.
[14]Yan M,Wu ZF,Tang D,et al.The impact of proton pump inhibitors on the pharmacokinetics of voriconazole in vitro and in vivo[J].Biomed Pharmacother,2018,108:60-64.
[15]Ogilvie BW,Yerino P,Kazmi F,et al.The proton pump inhibitor,omeprazole,but not lansoprazole or pantoprazole,is a metabolism-dependent inhibitor of CYP2C19:implications for coadministration with clopidogrel[J].Drug Metab Dispos,2011,39(11):2020-2033.
[16]Cojutti P,Candoni A,Forghieri F,et al.Variability of voriconazole trough levels in haematological patients:influence of comedications with cytochrome P450(CYP)Inhibitors and/or with CYP inhibitors plus CYP inducers[J].Basic Clin Pharmacol Toxicol,2016,118(6):474-479.
[17]Gautier-Veyret E,Fonrose X,Tonini J,et al.Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation:impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels[J].Antimicrob Agents Chemother,2015,59(4):2305-2314.
[18]Li X,Yu C,Wang T,et al.Effect of cytochrome P450 2C19 polymorphisms on the clinical outcomes of voriconazole:a systematic review and meta-analysis[J].Eur J Clin Pharmacol,2016,72(10):1185-1193.
[19]Moriyama B,Obeng AO,Barbarino J,et al.Clinical pharmacogenetics implementation consortium(CPIC)Guidelines for CYP2C19 and voriconazole therapy[J].Clin Pharmacol Ther,2016,102(1):45-51.
[20]Moriyama B,Kadri S,Henning SA,et al.Therapeutic Drug Monitoring and Genotypic Screening in the Clinical Use of Voriconazole[J].Curr Fungal Infect Rep,2015,9(2):74-87.
[21]Zhong X,Tong X,Ju Y,et al.Interpersonal factors in the pharmacokinetics and pharmacodynamics of voriconazole:Are CYP2C19 genotypes enough for us to make a clinical decision?[J].Curr Drug Metab,2018,19(1):1-7.