临床药师参与1例伏立康唑浓度异常升高致肝功能损伤分析

摘要：伏立康唑在体内呈非线性药动学特征,血药浓度易受多种因素影响。本文通过对1例肾移植术后患者伏立康唑浓度异常升高致肝功能损伤的病例进行药学监护,查阅文献分析伏立康唑浓度异常升高的影响因素,结合患者的生理病理因素,血药浓度监测及药物基因检测结果综合分析,为临床提供剂量调整建议,从而保证伏立康唑临床应用的疗效和安全性。     

基于群体药动学的利奈唑胺个体化给药研究进展

利奈唑胺是一种治疗多重耐药革兰氏阳性菌感染的抗菌药物,目前在临床广泛使用。但其在患者体内的药动学特征存在较大的个体差异,按说明书常规剂量给药较难获得最佳疗效。因此,有必要对利奈唑胺进行治疗药物监测（TDM）,并利用群体药动学（PPK）和药效学原理指导和优化其抗菌治疗方案。本文总结了利奈唑胺在各种人群中的PPK变化及个体化给药研究进展,建议临床使用利奈唑胺时,应通过TDM将患者稳态血药浓度保持在2～8 mg/mL;对于肝肾功能不全的患者,应适当降低利奈唑胺给药剂量,而对于肥胖、烧伤、儿童患者应适当增加利奈唑胺给药剂量,并在用药过程中提供药学监护,以促进合理用药。     

伏立康唑对儿童肾移植患者他克莫司血药浓度影响的案例分析

目的 ：探讨伏立康唑对儿童肾移植患者他克莫司血药浓度的影响。方法 ：1例儿童肾移植患者,长期口服他克莫司抗排异治疗后继发真菌感染,给予伏立康唑注射液治疗后导致他克莫司血药浓度升高,临床药师结合治疗药物监测结果对他克莫司剂量进行调整,使其血药浓度维持在目标浓度范围内。结果 ：治疗药物监测有助于儿童肾移植患者的临床预后。结论 ：长期服用他克莫司的儿童肾移植患者,合用伏立康唑治疗时,他克莫司的剂量应调整为原来的1/2,后续根据血药浓度调整给药剂量。     

伏立康唑的药动学/药效学及其药物监测

伏立康唑为新一代三唑类抗真菌药,抗菌谱广,抗菌作用强,主要用于治疗患有进展性、可能威胁生命的真菌感染的患者。其药动学呈非线性,个体差异大。本文对伏立康唑药动学影响因素,药动学/药效学特性,血药浓度与治疗效果、不良反应间关系以及不同类患者伏立康唑药物监测作一综述,以指导临床制定个性化给药方案,提高药物治疗效果。     

伏立康唑与血液病患者常用药的药物相互作用研究

目的探讨伏立康唑与血液病患者常用药间的药物相互作用,指导伏立康唑个体化用药。方法收集2015-2017年天津市第一中心医院应用伏立康唑预防或治疗侵袭性真菌感染的血液病患者的血药浓度资料,应用非线性混合效应模型法,考察血液病患者常用药物与伏立康唑联用时的相互作用。结果伏立康唑清除率和表观分布容积的群体典型值分别为8.24 L·h^-1和163 L。群体药动学模型显示碱性磷酸酶对伏立康唑的清除率有显著影响(P<0.005)。联用兰索拉唑或环孢素时,伏立康唑的清除率分别降低33.4%、32.8%,而联用地塞米松使伏立康唑的清除率增加41.0%。结论临床上伏立康唑与兰索拉唑、环孢素或地塞米松联用时,需注意相互作用的产生,并合理调整用药剂量。     

造血干细胞移植中儿童白消安群体药动学模型的建立及在治疗药物监测中的应用

作为造血干细胞移植预处理的重要药物之一,白消安已被广泛应用于临床。由于白消安口服较静脉途径的药动学参数变化更大,临床目前以静脉途径更常用。但静脉输注白消安仍具有治疗窗窄、不良反应大、个体间与个体内的药动学差异较大等特点。基于群体药动学模型的治疗药物监测方法可以优化白消安的给药方案,实现个体化给药,使患者达到目标暴露量。该综述对儿童白消安群体药动学模型的建立与其在治疗药物监测中的应用进行总结,为开展相关研究提供参考。     

伏立康唑个体化给药研究进展

伏立康唑是目前临床用于治疗一些真菌感染的首选药物,其药动学复杂多变且受多种因素的影响。本文阐述了影响伏立康唑代谢的重要因素,包括药物相互作用、CYP2C19的基因多态性、炎症状态;总结了各国指南中对伏立康唑TDM指征、有效浓度范围、剂量调整等方面的推荐;并对不同人群中伏立康唑应用的研究进行了探讨。本文旨在推进伏立康唑个体化给药。     

危重患者ECMO生命支持期间抗真菌药物TDM与剂量调整

目的： 分析危重患者体外膜肺氧合（ECMO）生命支持期间治疗药物监测（TDM）的意义,提供抗真菌药物剂量调整方案。方法： 检索PubMed、Cochrane Library至今有关ECMO期间抗真菌药物TDM相关文献进行分析综述。结果： ECMO对伏立康唑、泊沙康唑、艾沙康唑、两性霉素B脂质体的药动学影响明显,TDM结果显示,ECMO支持期间药物暴露明显降低,需要增加剂量以达到预期临床效果,推荐依据TDM结果进行个体化药物治疗方案调整;氟康唑、阿尼芬净、两性霉素B脱氧胆酸盐受ECMO影响小,可使用常规剂量并进行必要的TDM;TDM有助于提高抗真菌治疗的成功率。结论： ECMO支持期间抗真菌药物的药动学呈现复杂变化,推荐进行TDM并依次调整临床药物治疗方案。     

肾移植术后抗感染治疗期间环孢素血药浓度监测与剂量调整1例

目的:分享肾移植术后患者抗感染治疗期间环孢素剂量调整的经验。方法:通过1例实际病例,并结合文献复习,总结肾移植术后使用阿奇霉素、伏立康唑抗感染治疗期间环孢素血药浓度监测与剂量调整的经验。结果:肾移植术后抗感染治疗时,大环内酯类药物如果无法代替,选用阿奇霉素可能是恰当的选择,必要时需要通过环孢素血药浓度监测来调整药物剂量;伏立康唑与环孢素的相互作用明确,两药联用时,必须通过环孢素血药浓度监测来调整其剂量。结论:肾移植术后,患者使用环孢素治疗期间,临床药师应该从与其有相互作用的药物中选择影响相对较小的药物;在药物剂量调整时,应该在抗感染药物和环孢素之间确定调整的目标药物,从而给临床医师提供合理建议。     

临床药师参与伏立康唑引起骨痛的病例分析及文献回顾

摘要：本文报道临床药师参与慢性阻塞性肺疾病合并曲霉菌感染使用伏立康唑导致骨痛的患者治疗过程。患者在治疗过程中突然出现骨痛,临床药师综合考虑建议检测患者CYP2C19基因型,监测伏立康唑血药浓度。检测结果提示患者为CYP2C19*2/*2（636GG,681AA）基因型,伏立康唑血药浓度为6.2 mg·L-1。临床药师进一步建议将伏立康唑的给药剂量减半,并于治疗后第2天、第3天监测血药浓度。患者在剂量调整后的第2天骨痛明显好转,临床医生采纳药师建议后,持续使用伏立康唑联合其他抗菌药物2周后患者的症状明显好转,未再出现骨痛发作,好转出院。     

Therapeutic drug monitoring of voriconazole and posaconazole

Despite the availability of newer antifungal agents, invasive fungal diseases remain a leading cause of morbidity and mortality in immunocompromised patients. Voriconazole and posaconazole are two extended-spectrum triazoles indicated for treatment and prophylaxis of invasive fungal diseases. Recently, there has been increased interest in the utility of therapeutic drug monitoring to optimize safety and efficacy of antifungals in an attempt to improve patient outcomes. We reviewed the pharmacokinetic and pharmacodynamic characteristics of voriconazole and posaconazole in the context of clinical indications for therapeutic drug monitoring. In addition, the most recent evidence examining the relationship between serum concentrations of voriconazole and posaconazole and their efficacy or toxicities was evaluated. This information was then integrated to formulate recommendations for use of therapeutic drug monitoring in clinical settings.     

Therapeutic drug monitoring of voriconazole

Voriconazole is a triazole antifungal developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi, and opportunistic molds. Voriconazole has a nonlinear pharmacokinetic profile with a wide inter- and intraindividual variety. This variability is caused by many factors such as gender, age, genotypic variation, liver dysfunction, the presence of food, and so on. Another important factor influencing voriconazole's pharmacokinetic profile is drug-drug interactions with CYP450 inhibitors as well as inducers. Variability in plasma concentrations, as a result of the previously mentioned aspects, may lead to variability in efficacy or toxicity. Determination of plasma concentrations is indicated in situations to guide dosing and to individualize and improve the treatment options resulting in better therapeutic outcome or fewer side effects. In this article, we review factors influencing voriconazole pharmacokinetic profile, the data supporting exposure-effect and exposure-toxicity relationships, review the gaps in current knowledge, which make broad recommendations for therapeutic drug monitoring difficult for voriconazole, provide the indications in which therapeutic drug monitoring is reasonable based on currently available data (eg, children), and outline the ways in which this problem could be solved. We provide a summary of the problem so that further research can be conducted to address this are of clinical need.     

Triazole antifungal agents in invasive fungal infections: a comparative review

Invasive fungal disease continues to be a problem associated with significant morbidity and high mortality in immunocompromised and, to a lesser extent, immunocompetent individuals. Triazole antifungals have emerged as front-line drugs for the treatment and prophylaxis of many systemic mycoses. Fluconazole plays an excellent role in prophylaxis, empirical therapy, and the treatment of both superficial and invasive yeast fungal infections. Voriconazole is strongly recommended for pulmonary invasive aspergillosis. Posaconazole shows a very wide spectrum of activity and its primary clinical indications are as salvage therapy for patients with invasive aspergillosis and prophylaxis for patients with neutropenia and haematopoietic stem-cell transplant recipients. Itraconazole also has a role in the treatment of fungal skin and nail infections as well as dematiaceous fungi and endemic mycoses. Fluconazole and voriconazole are well absorbed and exhibit high oral bioavailability, whereas the oral bioavailability of itraconazole and posaconazole is lower and more variable. Posaconazole absorption depends on administration with a high-fat meal or nutritional supplements. Itraconazole and voriconazole undergo extensive hepatic metabolism involving the cytochrome P450 system. The therapeutic window for triazoles is narrow, and inattention to their pharmacokinetic properties can lead to drug levels too low for efficacy or too high for good tolerability or safety. This makes these agents prime candidates for therapeutic drug monitoring (TDM). Target drug concentrations for voriconazole and itraconazole should be >1?μg/mL and for posaconazole >1.5?μg/mL for treatment. Blood should be drawn once the patient reaches steady state, which occurs after 5 and 7 days of triazole therapy. Routine TDM of fluconazole is not required given its highly favourable pharmacokinetic profile and wide therapeutic index. The aim of this review is to provide a brief update on the pharmacology, activity, clinical efficacy, safety and cost of triazole agents (itraconazole, fluconazole, voriconazole and posaconazole) and highlight the clinical implications of similarities and differences.     

临床药师参与1例肺曲霉菌感染合并癫痫治疗药学实践

目的探讨临床药师参与药学实践对促进临床合理用药的作用。方法临床药师通过建议监测肺曲霉菌感染合并癫痫患者静脉序贯口服伏立康唑后的血药浓度,予以增加剂量和检测相关代谢酶的基因多态性,并分析抗感染疗效不佳的原因,参与临床治疗。结果第1次监测时伏立康唑体内血药浓度较低,临床药师建议将剂量加倍后仍较低;考虑受CYP2C19基因多态性影响,临床药师建议进行基因检测,但结果与血药浓度监测结果相悖;血药浓度偏低可能由卡马西平与伏立康唑间的相互作用所致,临床药师建议停用伏立康唑,改用卡泊芬净,临床症状明显改善。结论临床药师借助专业知识参与临床治疗,对患者进行药学监护,可促进临床合理用药。     

Role of therapeutic drug monitoring of voriconazole in the treatment of invasive fungal infections

Background:

Voriconazole is a broad-spectrum, second-generation triazole antifungal agent with demonstrated efficacy in the treatment of invasive fungal infections caused by Aspergillus spp. and Candida spp. Given the characteristically poor prognosis of patients with invasive fungal infections and the protracted duration of treatment required, therapeutic monitoring of voriconazole is, in theory, an attractive method to optimize antifungal therapy.

Objective:

To determine the utility of therapeutic drug monitoring for voriconazole.

Methods:

A previously published decision-making algorithm was used to assess the currently available literature on therapeutic drug monitoring of voriconazole.

Results:

Several analytical methods can be used to quantify plasma or serum concentrations of voriconazole. Reasons for therapeutic monitoring of this drug include wide variability both within and between individuals secondary to drug properties, drug–drug interactions, and disease states. Furthermore, voriconazole follows nonlinear pharmacokinetics with saturable hepatic clearance. Another potential factor in favour of therapeutic drug monitoring for voriconazole is genetic polymorphism of CYP2C19, whereby patients who are homozygous for poor metabolism (about 19% of non-Indian Asians) can have 4-fold greater exposure to voriconazole. The concentrations of this drug are also greater in patients with hepatic impairment. Drug–drug interactions with other substrates of CYP2C9, CYP2C19, and CYP3A4 can also alter voriconazole concentrations. However, the correlations between plasma concentrations of voriconazole and its efficacy and toxicity are not well defined. Although lower and upper target thresholds of 0.25–2 mg/L and 4–6 mg/L, respectively, have been suggested, studies to date have not been appropriately designed or powered to reveal any definitive association.

Conclusions:

Routine therapeutic drug monitoring of voriconazole is not recommended except in certain circumstances, such as lack of response to therapy or evidence of toxicity, in which case selective monitoring of voriconazole concentrations may be of clinical utility.     

Written consent to use the drug in children: the problem of off-label drugs

Cardiac arrhythmias in pediatric patients have different mechanisms and frequencies compared to adult patients. There are many physiological differences between children and adults that may affect the pharmacodynamic and pharmacokinetic of the antiarrhythmic drugs in pediatric population. Children, and specially breast feeding children, cannot be considered low weighted adults to select antiarrhythmic drug doses. Although radiofrequency ablation has experienced great technological advances, it is performed in selected pediatric patients. Therefore, the main therapeutic strategy is the use of antiarrhythmic drugs in children. The medical management of arrhythmias in pediatric patients is challenging and complex. There are few clinical guidelines. There is scarce and incomplete information about the efficacy and safety of antiarrhythmic drugs in pediatric population. Most of the doses and drug administration intervals are extrapolated from adult population and applied to children. Antiarrhythmic drug doses have been extensively studied in adult population. However, in pediatric population, there are very few clinical trials and the safety of these drugs is not well known. In general, dose regimens are based on small uncontrolled studies, extrapolation of drug doses from studies performed in the adult population or physician experience. As a consequence, there is a need for further studies to assess the most effective antiarrhythmic drug regimens in children reducing the risk of side effects. Evidence suggests that medical research in pediatric population is necessary and morally valuable. But investigators involved must take care of moral and ethical values, including the respect for the child-subject and his parents or legal representatives, and this respect compels them to consider the patient and family in the decision making process. The participation request and the informed consent must be obtained according to the competitions the patient exhibits, trying to anticipate information about benefits and possible damages derived from the investigation in an understandable language for him. In our opinion the pharmacologic clinical investigation of antiarrhythmic treatments in pediatrics is necessary. More clinical studies must be carried out under rigorous scientific rules that contemplate the particular ethical dilemmas this population faces.     

伏立康唑血药浓度监测在儿童血液病的临床应用

目的:探讨伏立康唑血药浓度监测在儿童血液病临床治疗中的作用。方法:收集2019年2月至2020年8月接受伏立康唑治疗的62例血液病患儿的临床资料,应用高效液相色谱法测定伏立康唑谷浓度。根据伏立康唑剂量将患儿分为3组,分别为<4.0 mg/kg组,4.0～6.0 mg/kg组,>6.0 mg/kg组,比较其临床特点。结果:总体血药浓度达标率为57.5%。伏立康唑剂量>6.0 mg/kg组患儿的年龄、体质量、身高明显低于其他两组。联用糖皮质激素降低伏立康唑浓度,而联用美罗培南升高伏立康唑浓度。伏立康唑肝损伤发生率为12.3%,肝功能异常患儿的伏立康唑血药浓度与肝功能正常的患儿比较差异无统计学意义。结论:血液病儿童伏立康唑血药浓度达标率较低。小龄儿更易出现伏立康唑浓度偏低,需更大的体质量剂量达到治疗浓度。临床中合并用药时会影响伏立康唑血药浓度,伏立康唑血药浓度监测有利于指导血液病儿童个体化用药。     

基于伏立康唑血药浓度监测的药物相互作用研究

目的 临床药师通过治疗药物监测(TDM)手段，研究利福平和伏立康唑之间的药物相互作用。方法 基于利福平和伏立康唑联用，及停用利福平后使用伏立康唑这两类患者的伏立康唑血药浓度监测情况，揭示利福平和伏立康唑间的药物相互作用强度与持续时间。结果 18例利福平和伏立康唑联用患者，94.44%患者的伏立康唑血药浓度低于有效治疗浓度范围下限(1.0mg/L)，其中72.22%患者低于定量下限0.16mg/L；19例停用利福平后再使用伏立康唑的标本中，停药6d内伏立康唑血药浓度小于1.0mg/L共12例，占总例数的63.16%，占停药6d内例数的91.67%；停药7d及以上伏立康唑血药浓度大于1mg/L的5例，占总例数的26.32%，占停药7d及以上例数的83.33%。结论 利福平会严重降低伏立康唑血药浓度，在停用利福平第7d起伏立康唑血药浓度很可能才上升有效浓度范围，因此临床上应避免伏立康唑与利福平联用。临床药师借助TDM成功干预了有临床意义的药物相互作用，TDM是临床药师参与药物治疗的有效技术手段。     

Target concentration intervention: beyond Y2K

Target concentration intervention (TCI) is proposed as an alternative conceptual strategy to therapeutic drug monitoring (TDM). It is argued that the idea of a therapeutic range has limited the interpretation of measured drug concentrations and diminished the anticipated clinical benefit to patients by use of an oversimplified pharmacodynamic model. TCI on the other hand embraces pharmacokinetic and pharmacodynamic concepts and uses the idea of a target effect and associated target concentration to make rational individual dose decisions.