伏立康唑的抗真菌机制与治疗药物监测进展

目的:为伏立康唑合理应用提供参考。方法:阐述伏立康唑的代谢、药物相互作用、毒副反应及其疗效与药物浓度的相互关系,就伏立康唑的血药浓度监测的研究进展进行综述,特别针对安全性方面进行阐述。结果与结论:伏立康唑广泛应用于侵袭性真菌感染的治疗,特别是侵袭性曲霉菌感染。伏立康唑主要由肝脏代谢,容易发生药物相互作用。由于在吸收、代谢和排泄等方面的差异和合并用药的影响,伏立康唑血药浓度的个体差异大。现有研究结果表明,伏立康唑血药浓度与疗效有相关性,与毒副作用也有相关性。     

雷贝拉唑的药效学与药动学特点

新一代质子泵抑制药雷贝拉唑为苯并咪唑衍生物，具有较高的pKa值，口服后可在体内快速活化，与质子泵结合发挥抑酸作用。雷贝拉唑在抗分泌作用、抗幽门螺杆菌作用、药物的相互作用、药物的安全性及代谢的多态性等方面与第一代质子泵抑制药相比具有明显的优点。     

儿童患者伏立康唑治疗药物监测研究进展

伏立康唑在成人体内呈现非线性药动学特征,主要在肝脏中代谢,受基因多态性和药物相互作用的影响,个体间及个体内差异较大.因此,治疗药物监测在伏立康唑临床应用中发挥重要作用.相比成人,儿童患者的药动学更加复杂,目前针对儿童群体的研究数据相对较少,对于儿童目标浓度范围及剂量的调整策略尚存在争议,故该群体使用伏立康唑存在较大风险...     

伏立康唑在肾移植患者中的群体药动学研究

目的：建立肾移植患者服用伏立康唑的群体药动学（PopPK）特征,探究影响伏立康唑药动学参数的因素,为临床个体化给药提供依据。方法：回顾性收集84例肾移植患者进行治疗药物监测的谷浓度和生理病理资料,利用Phoenix NLME软件建模,并用VPC法和Bootstrap法进行内部验证。结果：肾移植患者的伏立康唑的药动学特征符合一级消除一室模型,最终PopPK模型为：表观分布容积V（L）=183.69×[1+（HGB-98）×0.016]×exp（η_V）,清除率CL（L·h^-1）=7.24×[1+（ALB-36）×0.037]×exp（η_CL）。结论：血红蛋白（HGB）对V有显著影响,白蛋白（ALB）对CL有显著影响,所建PopPK模型较稳定,可以较好地描述肾移植患者伏立康唑的药动学特征。     

伏立康唑及其临床应用

伏立康唑是最新上市的第2代三唑类广谱抗真菌药物,能有效抑制真菌羊毛甾醇14α去甲基化酶,阻断麦角甾醇生物合成,从而影响细胞膜的流动性、通透性,在体内、外具有广泛的抗真菌活性临床研究结果表明,伏立康唑可用于念珠菌感染和其他药物治疗无效的克柔念珠菌及烟曲菌感染。本文综述了伏立康唑的药效学、药动学特性及临床应用等研究进展。     

新型抗真菌药伏立康唑

伏立康唑 (voriconazole)是第 2代三唑类抗真菌药 ,具有抗菌谱广、抗菌效力强的特点 ,尤其对于侵袭性曲霉菌侵润所致感染疗效好。本品口服吸收好 ,病人也有很好的耐受性。本文对其药效学、药动学、药物相互作用、临床应用、不良反应等研究作一综述。     

伏立康唑对家兔体内环孢素A的药动学影响

目的:研究伏立康唑对家兔体内环孢素A（CsA）药动学的影响。方法:测定6只家兔单用CsA及合用伏立康唑后CsA的血药浓度,并进行药动学参数的计算与比较结果:与合用前比较,合用伏立康唑后CsA的t_1/2显著延长[（16.31±9.80）和（46.77±19.36）h,（P<0.05）],AUC_0-24h显著增加[（18.25±4.67）和（25.48±2.39）mg·h·L^-1,（P<0.01）],CL显著降低[（2.29±0.62）和（1.43±0.17）L·h^-1·kg^-1,（P<0.01）],其余药动学参数无显著变化。结论:合用伏立康唑后CsA的半衰期延长,临床上两者合用需调整CsA的剂量并监测血药浓度,以保证治疗的安全有效。     

伏立康唑的体外及体内药动学研究进展

目的:为伏立康唑的临床应用提供理论依据和指导。方法:采用文献综述法,对伏立康唑临床前和临床药动学研究所涉及的生物样品预处理技术、动物和人体内分析方法、临床前和临床药动学予以综述。结果与结论:样品预处理与体内分析的新方法、新技术联用,提高了伏立康唑体内定性、定量分析和检测的灵敏度、选择性,确保了药动学参数的准确性和可靠性,对设计更合理的给药途径、给药剂量和临床应用具有指导意义。     

泊沙康唑的药动和药效学评价

目的:综述介绍泊沙康唑的药动和药效学评价。方法:检索10余年来的相关文献,介绍其药学相关信息。结果:泊沙康唑的口服制剂吸收在一定范围内与剂量相关,且明显受食物摄入的影响,相对生物利用度与给药方案相关,分次服用有助于提高其生物利用度(BA),主要通过葡萄糖醛酸转移酶(UDP)酶代谢,该酶的诱导或抑制剂会影响药物的浓度。结论:泊沙康唑是近年来新的三唑类抗真菌药,充分了解药品的药理、药动和药效学信息,有助于临床合理选药、用药。     

手性药物的药动学、药效学及不良反应

本文探讨手性药物的代谢动力学及药效学特征,阐明其药理活性和不良反应实质。结果表明有些手性药物在临床上的应用是有益的,有些则会造成不良后果。因此,通过对手性药物的深入研究,对临床合理应用手性药物具有重要的意义。     

伏立康唑血药浓度监测及其影响因素分析

目的：讨论伏立康唑体内血药浓度个体差异大的影响机制,为临床合理使用伏立康唑提供依据。方法：回顾性分析109名使用伏立康唑的患者,分析其CYP2C19基因型,测定血中伏立康唑及其主要代谢物浓度,统计分析性别,年龄,溶媒,CYP2C19基因型、C反应蛋白,药物相互作用对伏立康唑血药浓度的影响,并统计分析使用伏立康唑前后肝酶指标的情况。结果：性别、年龄及临床常用溶媒对伏立康唑血药浓度无显著性影响;不同基因型之间,伏立康唑血药浓度及代谢物浓度之间无显著性差异,代谢率（代谢物浓度与原药浓度比值）有显著性差异;随着C反应蛋白增加,伏立康唑浓度升高,并在<40,40~200、>200组间具有显著性差异。质子泵抑制剂能显著性影响伏立康唑浓度,其他利尿剂、激素对伏立康唑血药浓度无显著性差异。结论：伏立康唑血药浓度受影响因素较多,对于临床重症患者更应该加强血药浓度监测。     

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.     

儿童伏立康唑治疗药物浓度监测的临床意义

目的：本研究拟评估伏立康唑治疗药物浓度监测在儿童侵袭性真菌感染治疗中的作用。方法：采集76例以常规推荐剂量静脉滴注或口服伏立康唑治疗侵袭性真菌感染患儿的血液标本共99份,应用高效液相色谱-质谱联用技术检测谷浓度。结果：测定伏立康唑谷浓度中位值为0.784 μg·mL^-1（0.025~9.910 μg·mL^-1）,其中44例（44.4%）达到目标浓度范围（1~5.5 μg·mL^-1）,给药剂量与血药浓度之间缺乏相关性（r=0.252,P=0.315）。个体间和个体内血药浓度变异系数分别为97.0%和69.6%。患儿年龄分布2个月~14岁,年龄<6岁的患儿与年龄>6岁的患者相比,谷浓度要达到目标范围需要给予更高剂量的伏立康唑（6.1 mg·kg^-1/次vs. 4.55 mg·kg^-1/次,P<0.05）。谷浓度<1 μg·mL^-1的患儿治疗失败率高于成功率（58.8%vs. 46.5%）,但差异无统计学意义（P=0.390）。5名患儿治疗中监测谷浓度<1 μg·mL^-1且疗效不佳,通过提高给药剂量使谷浓度达1 μg·mL^-1以上,最终治疗有效。2例谷浓度≥ 5.5 μg·mL^-1的患儿均出现肝功能异常。结论：采用常规推荐剂量给药部分儿童难以达到伏立康唑的目标浓度。伏立康唑血药浓度在个体间和个体内均有较大的差异。低龄儿童要达到有效的伏立康唑血药浓度,往往需给予更高的用药剂量。开展伏立康唑药物浓度监测不仅可以保障患儿用药的安全性和有效性,同时可为合理制订我国儿童的伏立康唑初始治疗方案提供研究数据。     

Pharmacokinetics/pharmacodynamics and the stages of drug development: Role of modeling and simulation

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation (M&S) are well-recognized powerful tools that enable effective implementation of the learn-and-confirm paradigm in drug development. The impact of PK/PD M&S on decision making and drug development risk management is dependent on the question being asked and on the availability and quality of data accessible at a particular stage of drug development. For instance, M&S methodologies can be used to capture uncertainty and use the expected variability in PK/PD data generated in preclinical species for projection of the plausible range of clinical dose; clinical trial simulation can be used to forecast the probability of achieving a target response in patients based on information obtained in early phases of development. Framing the right question and capturing the key assumptions are critical components of the "learn-and-confirm" paradigm in the drug development process and are essential to delivering high-value PK/PD M&S results. Selected works of PK/PD modeling and simulation from preclinical to phase III are presented as case examples in this article.     

Pharmacokinetics and pharmacodynamics of azosemide

Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.     

伏立康唑的治疗药物浓度监测影响因素的研究进展

伏立康唑是多种深部真菌感染的有效治疗药物,但其药动学复杂、治疗窗窄、个体差异大,且其血药浓度易受CYP2C19基因多态性、性别、年龄、联合用药等多种因素影响,因此为提高疗效、减少不良反应,进行治疗药物浓度监测十分重要.就伏立康唑治疗药物浓度监测的影响因素如个体差异大、CYP2C19基因多态性、药物间相互作用多、年龄因素...     

喹诺酮类抗菌药物的药动学和药效学研究进展

喹诺酮类是目前临床普遍使用的一类抗菌药物.现从体外实验、动物实验和人体试验等方面对其药动学/药效学(PK/PD)研究进行了综述,并对PK/PD与细菌耐药及其在临床上的应用进行了简介.     

抗肿瘤药物的治疗药物监测研究

尽管治疗药物监测(TDM)已广泛应用于多个疾病治疗领域,但在抗肿瘤药物方面的应用仍较为局限。近年来,抗肿瘤药物的暴露量与其疗效和药物不良反应之间的相关性研究越来越多,这有利于抗肿瘤药物个体化精准给药。本文综述了细胞毒类和靶向性(小分子和大分子)抗肿瘤药物的治疗药物监测现状,为肿瘤药物个体化用药提供参考。     

HPLC法测定人血浆中伏立康唑及其代谢物的浓度

目的 建立一种快速、灵敏、准确、稳定的测定人血浆中伏立康唑及其代谢物浓度的方法,用于伏立康唑临床治疗药物监测。方法 采用高效液相色谱（HPLC）-紫外（UV）检测法,以罂粟碱为内标,乙腈蛋白沉淀法处理血浆样品。色谱柱为ACE5C₁₈-AR （150 mm×4.6 mm）,流动相为0.025 mol/L磷酸二氢钠（含三乙胺400 μl/L,用0.25 mol/L的氢氧化钠调至pH=7.0）-乙腈（67：33）,流速为l ml/min,柱温为40℃,检测波长为255、276 nm （双波长检测）,进样量为20 μl。结果 伏立康唑氮氧化物、伏立康唑和罂粟碱的保留时间分别为4.5、11.3、13.7 min;血浆中伏立康唑、伏立康唑氮氧化物线性范围均为0.5~20.0 μg/ml （r=0.999 5）,定量下限均为0.5 μg/ml,批内、批间RSD均<11%,定量下限、低、中、高梯度浓度提取回收率在90.3%~109.9%之间。结论 该方法操作简便,结果准确,适用于伏立康唑的临床治疗药物监测和对其主要代谢物的测定。