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。     

造血干细胞移植患者中伏立康唑与环孢素及他克莫司的相互作用

目的 通过监测造血干细胞移植患者伏立康唑和免疫抑制剂（环孢素A、他克莫司）的稳态血药谷浓度,探讨伏立康唑与环孢素及他克莫司之间的作用。方法 回顾性分析2016年6月-12月于宁波市第一医院血液科住院治疗的造血干细胞移植患者的伏立康唑、环孢素A以及他克莫司的稳态血药浓度数据。结果 伏立康唑与环孢素A合用后,环孢素A稳态谷浓度升高41.55%（P<0.05）,伏立康唑稳态谷浓度下降23.31%;伏立康唑与他克莫司合用后,他克莫司稳态谷浓度升高17.52%,伏立康唑稳态谷浓度下降29.45%（P<0.05）。结论 伏立康唑联用环孢素A或他克莫司时,建议诊疗过程严密监测免疫抑制剂及伏立康唑的血药浓度,以便及时调整治疗药物剂量,保障安全、有效、合理用药。     

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。     

本院住院患者注射用兰索拉唑用药合理性分析

目的分析本院住院患者注射用兰索拉唑临床应用的合理性。方法制定质子泵抑制剂用药评价标准,抽取本院2013年5月住院患者使用注射用兰索拉唑的病例225份,对病例中注射用兰索拉唑的适应证、用法用量、联合用药等进行回顾性统计分析。结果 225份病例中存在不合理用药病例97例,合格率为56.89%。主要存在无适宜证用药和用药疗程过长等。结论本院住院患者注射用兰索拉唑在临床应用过程中存在一些不合理现象,医院应尽早制定注射用兰索拉唑的使用标准或规范,加强对医务人员合理用药知识的培训,以提高药物使用的合理性。     

兰索拉唑临床联合用药研究进展

目的：总结兰索拉唑联合药物治疗消化系统疾病以及与其他药物间相互作用的现状并对相关问题进行思考,为提高兰索拉唑联合用药的安全性和有效性提供文献支撑。方法：本文对兰索拉唑联合西药治疗消化系统疾病及其相互作用机制研究进行文献检索、分析与归纳。结果：兰索拉唑主要通过抑酸作用治疗多种消化系统疾病,并可通过细胞色素P450、P-糖蛋白等多种机制影响联合用药药物的生物利用度。 结论：今后需着重研究LPZ联合用药的作用机制、药效学评价和个体化用药差异,以确保联合用药的安全性和科学性。     

雷贝拉唑、兰索拉唑与奥美拉唑不同用药方案治疗消化性溃疡的疗效观察

目的探讨雷贝拉唑、兰索拉唑、奥美拉唑3种不同药物治疗消化性溃疡的临床疗效。方法将135例消化性溃疡患者随机分为雷贝拉唑组、兰索拉唑组、奥美拉唑组,3组分别给予雷贝拉唑、兰索拉唑、奥美拉唑治疗,同时给予甲硝唑片+阿莫西林治疗,对比分析3组患者的临床疗效及治疗成本。结果雷贝拉唑组、兰索拉唑组、奥美拉唑组的总有效率分别为95.56%、93.33%、91.11%,幽门螺杆菌清除清除率分别为93.33%、91.11%、88.89%,差异无统计学意义(P>0.05);3组患者药物总成本分别为391.23元、816.48元、412.51元,差异存在统计学意义(P<0.05)。结论雷贝拉唑、兰索拉唑与奥美拉唑治疗消化性溃疡,均取得理想的疗效,但雷贝拉唑与奥美拉唑的治疗成本低于兰索拉唑。     

环孢素与伏立康唑联合应用引起的高血钾症

在2例恶性血液病合并真菌感染患者的治疗中发现,环孢素与伏立康唑联用导致环孢素血药浓度升高,引起高血钾症。在治疗过程中应减少环孢素给药剂量并监测其血药浓度,根据监测结果及时调整剂量。     

在本院患者中建立伏立康唑群体药物代谢动力学模型的初步探索

目的利用非线性混合效应模型(NONMEM)法建立伏立康唑的群体药物代谢动力学(Pop PK)模型,探索影响伏立康唑体内处置的生理病理因素,为伏立康唑的临床个体化用药提供依据。方法回顾性地收集2014年5月到2015年4月中南大学湘雅二医院药学部治疗药物监测室监测的患者资料,从中挑选出55名患者,收集86个血药浓度数据点及其生理病理数据(包括人口学数据、实验室数据与合并用药情况),收集的数据使用Phoenix软件构建模型。结果 Pop PK研究最终得到的模型是:CL(m L·min-1)=1.63×[1+(Age-47)×(-0.01)]×[(1+(ALT-42)×0.001]×exp(0.05),V(L)=6.93×exp(1.37×10-7)。结论本研究得到的模型提示老年患者比年轻成年患者有着更低的伏立康唑清除率,丙氨酸转氨酶浓度较高的患者清除率较高,这一结果还需进一步验证。     

兰索拉唑防治化疗药物所致消化道反应的临床研究

目的 观察兰索拉唑在化疗药物所致消化道反应防治中的有效性和安全性.方法 将127例恶性肿瘤化疗患者完全随机分为3组,兰索拉唑组(41例)应用"兰索拉唑+格拉司琼+地塞米松"方案防治消化道反应,奥美拉唑组(44例)应用"奥美拉唑+格拉司琼+地塞米松"方案,常规对照组(42例)应用"格拉司琼+地塞米松"方案,比较3组的临床疗效与不良反应.结果 在防治呕吐、恶心、食欲不振方面,兰索拉唑组和奥美拉唑组的总有效率[92.7%(38例)、87.8%(36例)、58.5%(24例),91.0%(40例)、88.6%(39例)、59.1%(26例)]明显优于常规对照组[71.5%(30例)、69.1%(29例)、35.7%(15例)],差异有统计学意义(均P<0.05),而兰索拉唑组与奥美拉唑组比较差异无统计学意义(均P>0.05).不良反应方面,兰索拉唑组1例(2.4%)发生轻微皮疹反应,未经处理症状消失;奥美拉唑组有1例(2.3%)发生轻度肌痛反应,患者可耐受;常规对照组未出现不良反应,3组比较差异无统计学意义(均P>0.05).结论 兰索拉唑对化疗药物所引起的消化道反应和奥美拉唑一样具有明显的预防及抑制作用,且安全性高,值得临床推广.     

兰索拉唑与奥美拉唑治疗酒精型消化性溃疡的临床疗效比较

目的对比分析兰索拉唑与奥美拉唑治疗酒精型消化性溃疡的临床疗效。方法将126例酒精型消化性溃疡患者随机分入兰索拉唑组与奥美拉唑组,兰索拉唑组给予兰索拉唑+阿莫西林+克拉霉素治疗,奥美拉唑组给予奥美拉唑+阿莫西林+克拉霉素治疗,两组疗程均为4周。比较两组的临床疗效、幽门螺杆菌(Hp)清除率及不良反应发生率。结果兰索拉唑组与奥美拉唑组临床治疗总有效率分别为95.5%和95.0%,两组比较差异无统计学意义(P>0.05);两组患者治疗前后临床症状比较差异无统计学意义(P>0.05);兰索拉唑组Hp清除率显著高于奥美拉唑组(90.9%vs.78.3%,P<0.05);兰索拉唑组与奥美拉唑组不良反应发生率比较差异无统计学意义(7.6%vs.13.4%,P>0.05)。结论兰索拉唑治疗酒精型消化性溃疡Hp清除率高,不良反应少。     

Apparent clearance of sirolimus in heart transplant recipients: impact of primary diagnosis and serum lipids

The study was aimed to identify factors affecting sirolimus apparent clearance (CL/F) in de novo heart transplant recipients using a population pharmacokinetic approach. A total of 31 patients (7 female and 24 male) originally included in a formal clinical trial, contributed 524 sirolimus blood concentrations with the time after dose ranging from 11.08 to 31.83 hours. Sirolimus concentrations were measured using liquid chromatography-tandem mass spectrometry and data analysis was carried out using NONMEM (Globomax LLC, Hanover, MD) software. Factors screened included age, weight, gender, primary diagnosis, biochemical and hematological indices, cyclosporine dose, days post-transplant and potential interacting medications. The predictive performance of the final model was evaluated using a data-splitting method. Sirolimus apparent clearance (CL/F) was decreased by 20.8% for every 100 mg increase in cyclosporine daily dose and was 62.1% lower in patients with primary diagnosis of ischemic heart disease (IHD). Sirolimus apparent clearance was 37.8% lower when triglyceride was greater than 2 mmol/L. Based on the final model, the average values for sirolimus CL/F and apparent volume of distribution were 7.09 and 1350 L/h, respectively. Inter-subject variability in CL/F was 27.5% and residual random error was 24.1%. This study identified cyclosporine dose, hypertriglyceridemia and primary diagnosis of IHD as the most important factors affecting sirolimus CL/F. This information may assist in dose individualization of sirolimus in heart transplant recipients.     

Apparent clearance of sirolimus in heart transplant recipients: impact of primary diagnosis and serum lipids

The study was aimed to identify factors affecting sirolimus apparent clearance (CL/F) in de novo heart transplant recipients using a population pharmacokinetic approach. A total of 31 patients (7 female and 24 male) originally included in a formal clinical trial, contributed 524 sirolimus blood concentrations with the time after dose ranging from 11.08 to 31.83 hours. Sirolimus concentrations were measured using liquid chromatography-tandem mass spectrometry and data analysis was carried out using NONMEM (Globomax LLC, Hanover, MD) software. Factors screened included age, weight, gender, primary diagnosis, biochemical and hematological indices, cyclosporine dose, days post-transplant and potential interacting medications. The predictive performance of the final model was evaluated using a data-splitting method. Sirolimus apparent clearance (CL/F) was decreased by 20.8% for every 100-mg increase in cyclosporine daily dose and was 62.1% lower in patients with primary diagnosis of ischemic heart disease (IHD). Sirolimus apparent clearance was 37.8% lower when triglyceride was greater than 2 mmol/L. Based on the final model, the average values for sirolimus CL/F and apparent volume of distribution were 7.09 and 1,350 L/h, respectively. Inter-subject variability in CL/F was 27.5% and residual random error was 24.1%. This study identified cyclosporine dose, hypertriglyceridemia and primary diagnosis of IHD as the most important factors affecting sirolimus CL/F. This information may assist in dose individualization of sirolimus in transplant recipients.     

多因素致治疗肾移植术后肺部真菌感染的伏立康唑血药浓度升高 1例

目的 分析导致病人伏立康唑血药浓度升高可能原因,并指导临床用药.方法 回顾病例资料,从遗传因素、药物相互作用、疾病状态等角度出发,查阅相关文献报道,探讨各因素与伏立康唑血药浓度过高之间的相关性.结果 CYP2C19基因型,与艾司奥美拉唑、环孢素、美罗培南之间的相互作用,以及肝功能异常、发热两种疾病状态均可能在一定程度上导致病人的伏立康唑浓度偏高.结论 临床药师应从遗传因素、疾病状态多角度出发,筛查存在慢代谢基因的高危人群,及时给医生提出建议,减少不良反应的发生,促进临床用药安全.     

再生障碍性贫血患儿的环孢素群体药动学研究

目的：建立环孢素在再生障碍性贫血患儿中的群体药动学模型,为其临床个体化用药提供依据。方法：回顾性收集94例再生障碍性贫血患儿的194份血药浓度常规监测数据,应用NONMEM（7.2.0）软件建立药动学模型,用一级条件估计及交互作用（FOCE-Ⅰ）估算药动学参数和个体间、个体内变异。定量考察人口学特征、生化指标、血常规指标、合并用药及CYP3A4＊18B、CYP3A5＊3基因多态性等协变量对药动学参数的影响,采用自举法对最终模型的稳定性进行评价。结果：基础模型选用一房室、一级吸收和一级消除模型。环孢素的群体药动学参数：表观清除率（CL/F）为（29.5±1.3）L/h,表观分布容积（V/F）为（419.4±52.2）L。CL/F和V/F的个体间变异分别为27.8%和0.14%,个体内变异为36.4%和70ng/ml。按照最终模型,仅有年龄对CL/F有显著影响。自举法验证结果表明模型较稳定。结论：本研究建立的再生障碍性贫血患儿的环孢素群体药动学模型可为该群体的临床个体化用药提供依据。     

Pharmacoepidemiologic investigation of clonazepam relative clearance by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients.

The effects of drug-drug interactions on clonazepam clearance were examined through a retrospective analysis of serum concentration data from pediatric and adult epileptic patients. Patients received clonazepam as monotherapy or in combination with other antiepileptic drugs. A total of 259 serum clonazepam concentrations gathered from 137 patients were used in a population analysis of drug-drug interactions on clonazepam clearance. Data were analyzed using a nonlinear mixed-effects modeling (NONMEM) technique. The final model describing clonazepam clearance was CL = 152 x TBW(-0.181) x DIF, where CL is clearance (ml/kg/h), TBWis total body weight (kg), and DIF (drug interaction factor) is a scaling factor for concomitant medication with a value of 1 for patients on clonazepam monotherapy, 1.18 for those patients receiving concomitant administration of clonazepam and one antiepileptic drug (carbamazepine or valproic acid), and 2.12 x TBW(-0.119) for those patients receiving concomitant administration of clonazepam and more than two antiepileptic drugs. Clonazepam clearance decreased in a weight-related fashion in children, with minimal changes observed in adults. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance. Concomitant administration of clonazepam and valproic acid resulted in a 12% increase in clonazepam clearance. Concomitant administration of clonazepam with two or more antiepileptic drugs resulted in a 23% to 75% increase in clonazepam clearance.     

Choice of antiepileptic drugs for the elderly: possible drug interactions and adverse effects

INTRODUCTION: Antiepileptic drugs are prescribed to patients of all ages and are commonly prescribed to patients over the age of 65. When prescribing these drugs to patients of this age bracket, treatment should be based not only on the diagnosis and seizure type but also on the propensity of the drugs for adverse effects and their drug-drug interactions. AREAS COVERED: This article reviews antiepileptic drugs currently used for treating the elderly and highlights the adverse effects and potential drug-drug interactions for these treatments. The article was complied through literature searches of the Cochrane database of systematic reviews, MEDLINE and SCindeks. EXPERT OPINION: In elderly patients who have hepatic diseases, antiepileptic drugs that are not metabolized in the liver, such as levetiracetam, are preferred; in patients with moderate and severe renal failure, carbamazepine and valproic acid are the preferred antiepileptic drugs. Phenytoin, fosphenytoin, carbamazepine, oxcarbazepine and lamotrigine should not be prescribed in elderly patients with cardiac conduction abnormalities or a history of ventricular arrhythmia. While the majority of antiepileptic drugs interact with other drugs, hepatic enzymes and plasma proteins, a few newer antiepileptic drugs are free from such interactions (e.g., gabapentin, levetiracetam and tiagabine), which make them suitable candidates for elderly patients. However, in order to make further recommendations regarding the choice and dosing regimens of antiepileptic drugs in elderly patients, more extensive clinical research in this specific population is necessary.     

Drug-drug interaction of antifungal drugs

This article reviews the in vitro metabolic and the in vivo pharmacokinetic drug-drug interactions with antifungal drugs, including fluconazole, itraconazole, micafungin, miconazole, and voriconazole. In the in vitro interaction studies, the effects of antifungal drugs on specific activities of cytochrome P450s (CYPs), including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, in human liver microsomes are compared to predict the possibility of drug interactions in vivo. Fluconazole, micafungin, and voriconazole have lower inhibitory effects on CYP3A4 activities than itraconazole and miconazole, and IC(50) and/or K(i) values against CYP2C9 and CYP2C19 activities are the lowest for miconazole, followed by voriconazole and fluconazole. In in vivo pharmacokinetic studies, it is well known that itraconazole is a potent clinically important inhibitor of the clearance of CYP3A4 substrates, and fluconazole and voriconazole are reported to increase the blood or plasma concentrations of not only midazolam and cyclosporine (CYP3A4 substrates) but also of phenytoin (CYP2C9 substrate) and/or omeprazole (CYP2C19/CYP3A4 substrate). On the other hand, no inhibition of CYP activities except for CYP3A4 activity by micafungin is observed in vitro, and the blood concentrations of cyclosporine and tacrolimus are not affected by coadministration of micafungin in vivo, suggesting that micafungin would not cause clinically significant interactions with drugs that are metabolized by CYPs via the inhibition of metabolism. Miconazole is a potent inhibitor of all CYPs investigated in vitro, although there are few detailed studies on the clinical significance of this except for CYP2C9. Therefore the differential effects of these antifungal drugs on CYP activities must be considered in the choice of antifungal drugs in patients receiving other drugs.     

Safety and interactions of new antifungals in stem cell transplant recipients

Introduction: Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Considerable progress in treating IFDs has been achieved over the last years, through the availability of new, effective drugs. However, many of these newer antifungal agents have some limitations, such as their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions. Areas covered: This article reviews the literature evaluating the safety profile of the lipid formulations of Amphotericin B, echinocandins, and second-generation triazoles. It also discusses the possible drug-drug interactions with some drugs commonly used in allogeneic HSCT. Expert opinion: Nephrotoxicity is the most frequent side effect of lipid formulations of Amphotericin B, which may cause a reduced clearance of the renally eliminated calcineurin inhibitors used for the control of Graft Versus Host Disease. Second-generation triazoles are characterized by a limited toxicity profile, but also by frequent drug-drug interactions with other drugs metabolized by the hepatic enzymes. The echinocandins are characterized by a very low toxicity profile and negligible interactions with other drugs. Such pharmacological knowledge is crucial in the daily care of allogeneic HSCT patients.     

Identification and relative contributions of human cytochrome P450 isoforms involved in the metabolism of glibenclamide and lansoprazole: evaluation of an approach based on the in vitro substrate disappearance rate

1. The identification and relative contributions of human cytochrome P450 (CYP) enzymes involved in the metabolism of glibenclamide and lansoprazole in human liver microsomes were investigated using an approach based on the in vitro disappearance rate of unchanged drug. 2. Recombinant CYP2C19 and CYP3A4 catalysed a significant disappearance of both drugs. When the contribution of CYPs to the intrinsic clearance (CL(int)) of drugs in pooled human microsomes was estimated by relative activity factors, contributions of CYP2C19 and CYP3A4 were determined to be 4.6 and 96.4% for glibenclamide, and 75.1 and 35.6% for lansoprazole, respectively. 3. CL(int) of glibenclamide correlated very well with CYP3A4 marker activity, whereas the CL(int) of lansoprazole significantly correlated with CYP2C19 and CYP3A4 marker activities in human liver microsomes from 12 separate individuals. Effects of CYP-specific inhibitors and anti-CYP3A serum on the CL(int) of drugs in pooled human liver microsomes reflected the relative contributions of CYP2C19 and CYP3A4. 4. The results suggest that glibenclamide is mainly metabolized by CYP3A4, whereas lansoprazole is metabolized by both CYP2C19 and CYP3A4 in human liver microsomes. This approach, based on the in vitro drug disappearance rate, is useful for estimating CYP identification and their contribution to drug discovery.     

Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach

Voriconazole is a broad‐spectrum antifungal agent commonly used to treat invasive fungal infections. Voriconazole has significant intraindividual and interindividual pharmacokinetics variability in different patient populations. Pharmacokinetic data of voriconazole in patients with liver dysfunction were limited. The aims of this study were to evaluate the population pharmacokinetics of voriconazole in patients with liver dysfunction and to identify the factors that affect voriconazole pharmacokinetics. A total of 166 samples taken from 57 patients with liver dysfunction were included in the study. A one‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. Voriconazole clearance (CL) was 0.58 L/h, the volume of distribution (V_d) was 134 L, and oral bioavailability (F) was 80.8%. This study showed that platelet count was significantly associated with voriconazole pharmacokinetic parameters. CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. Voriconazole CL was significantly decreased in patients with liver dysfunction. This study provides useful pharmacokinetics information for patients with liver dysfunction while highlighting the value of therapeutic drug monitoring in adjusting doses.