Interactions between oral antineoplastic agents and concomitant medication: a systematic review

Introduction: In recent years, the number of oral antitumoral agents has considerably increased. Oral administration increases the risk of interactions, because most oral anticancer drugs are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Many antitumoral drugs undergo enzymatic metabolism by cytochrome P450. As some act as inducers or inhibitors of one or more isoenzymes, they can lead to decreases or increases in plasma concentrations of concomitant drugs. Hence, cytostatic drugs can act not only as victims but also as perpetrators. P-glycoprotein, an efflux transporter, can also be involved in pharmacokinetic interactions.

Areas covered: A Medline search was performed to summarize the available evidence of the most clinically relevant interactions between oral chemotherapy agents and other drugs. The search covered the period from 1966 until August 2012 for each antitumoral drug using the medical subject headings ‘Drug Interactions' OR ‘Pharmacokinetics'. While the present review is not exhaustive, it aims to increase clinicians' awareness of potential drug–drug interactions.

Expert opinion: As cancer patients are often polymedicated and treated by different physicians, the risk of drug interactions between antitumoral agents and other medications is high. More clinical interaction studies are encouraged to ensure appropriate antineoplastic pharmacokinetics in clinical practice.     

Oral antineoplastic agents: assessment of safety and dose adjustments in clinical practice

Objectives: Although the safety profile of oral antineoplastic agents (OAAs) is better than that of classic chemotherapy, the rate of severe adverse events (AEs) is high. The objective was to assess the reasons for adjustments to treatment with OAAs during the first 100 days of treatment.

Methods: The authors performed a prospective observational study of cancer outpatients who initiated OAAs between November 2015 and October 2017. Dose reductions and treatment interruptions were closely followed-up during the first 100 days after the beginning of treatment with an OAA. The authors described the different safety profile of different OAA classes.

Results: The authors included 443 patients (31 different OAA assessed), of whom 53.0% required their OAA to be adjusted during the first 100 days of treatment. A total of 151 patients required dose reductions and/or interruptions of OAAs owing to AEs. The authors identified 203 AEs in these patients. Treatment with sorafenib, lower ECOG performance status, and first-line treatment were associated with a higher proportion of treatment adjustments due to AEs.

Conclusion: These results in clinical practice could be a first approach to help healthcare professionals to design patient monitoring programs by identifying priority patients and drugs, and remarks the importance of pharmacovigilance in OAAs.     

某院抗肿瘤药静脉输液过程调查分析

目的：调查某院抗肿瘤静脉输液过程,为制定某院抗肿瘤药静脉输液管理规范奠定基础。方法：收集某院2015年10月-2016年1月肿瘤科及放疗科住院化疗患者共1 093袋抗肿瘤药静脉输液信息,就给药顺序、预处理时机、滴注时间、冲管、稳定性、水化等方面进行汇总分析。结果：仅有1例联合用药顺序错误;预处理时机达标情况为紫杉醇脂质体43.29%、多西他赛100%;滴注时间达标情况为紫杉醇脂质体14.20%、多西他赛2.26%、奥沙利铂85.82%、奈达铂99.59%、依托泊苷100%、伊立替康38.64%、培美曲塞100%、吉西他滨13.04%;冲管达标情况为紫杉醇脂质体20.45%、多西他赛8.47%、奥沙利铂5.22%、奈达铂19.50%、伊立替康0%、培美曲塞14.59%、吉西他滨0%;多西他赛成品输液在4 h内用完的占40%;奈达铂输液结束后继续点滴输液量达1 000 mL以上的占47.58%。结论：某院抗肿瘤药静脉输液过程中还存在一定不足之处,需要医、药、护三方共同协作,制定管理规范。     

抗肿瘤药物不良反应信息评价与分析

目的:评价药物不良反应(ADR)报告质量,分析抗肿瘤药物使用中发生ADR患者临床资料,为指导临床合理用药提供参考。方法:收集某院2015年1月1日-12月31日上报的住院患者ADR报告,收集2014年、2015年住院患者使用抗肿瘤药发生ADR肿瘤患者病历资料。符合纳入标准的ADR报告,按患者性别、药品种类、给药途径、ADR类型进行回顾性分析。对2014年、2015年住院患者使用抗肿瘤药发生ADR病历资料进行危险因素分析。结果:2015年合格ADR报告共1 053份,男487例(46.25%)、女566例(53.75%);药品种类涉及20类,排名前5位的分别是心血管系统药、抗微生物药、电解质酸碱平衡及营养药、抗肿瘤用药、诊断用药;静脉滴注给药引发ADR例数最多,共529例(50.24%);新的ADR有30例(2.80%),严重ADR有90例(8.39%)。2014年和2015年抗肿瘤药合格ADR报告186例,严重ADR有25例(13.44%)。ADR主要临床表现为恶心呕吐、骨髓抑制等。抗肿瘤药致ADR发生的单因素分析影响因素共有3个指标,分别是:中性粒细胞数、血小板数、谷草转氨酶量;抗肿瘤药致ADR发生的多因素分析危险因素共有2个指标,分别是:中性粒细胞数的降低和血小板数的减少。结论:医疗机构需重视ADR监测、加强上报ADR报告质量管理;临床观察用药过程中患者的临床表现、临床指标、抗肿瘤药检测危险因素,以便及时得到预警信息,为合理指导用药,保障用药安全服务。     

上海市2007-2009年抗肿瘤药物用药分析

目的：分析上海市2007-2009年抗肿瘤药的用药情况。方法：收集上海市105家抽样医院的用药数据,计算抗肿瘤药的总用药金额,对用药金额领先的药物的用药金额、用药量等进行统计,并对用药趋势进行分析。结果：上海市2007-2009年的抗肿瘤药市场居主导地位的是新型抗肿瘤药,用药金额最大的是奥沙利铂和多西他赛,用量最大的是卡培他滨、紫杉醇和表柔比星。社区卫生中心用量大的品种和中心医院差别较大。结论：上海市对抗肿瘤药的需求逐年增加,是一个具有巨大潜力的抗肿瘤药市场。     

抗肿瘤药物说明书的质量评价分析

目的：针对抗肿瘤药说明书常见争议问题统计分析并提出修改建议,为其修订提供依据。方法：收集整理抗肿瘤药物说明书147份,其中,西药说明书122份（国产79份、进口43份）,中药说明书25份。采用三种分类方法分析说明书中存在的常见问题,并对修改难度进行了评价。结果：国产和进口西药说明书存在的主要问题为"同一说明书对应多种规格的药品"（32.91%vs.25.58%,P>0.05）; "主要内容相互矛盾"（54.43%vs.32.56%,P>0.05）,修改难度中等。与西药说明书相比,中药说明书存在的主要问题为"说明书内容简单"（6.56%vs.36.00%,P<0.05）和"说明书内容不全"（4.00%vs.24.00%,P<0.05）,修改难度较大。结论：建议不断完善抗肿瘤药物说明书,保证患者安全用药。     

Posology adjustments of oral antineoplastic agents for special populations: patients with renal impairment,hepatic impairment and hematologic toxicities

Background: Oral antineoplastic agents (OAA) have reached 30–50% of all antineoplastic treatments. Although they seem safer than parenteral therapy, many severe problems can occur if the dose is not adequately adjusted in special situations. Our objective is to create a comprehensive guide with dosage adjustment recommendations for OAA in cases of renal and hepatic impairment and hematologic toxicities.

Research design and methods: We analyzed all OAA approved by EMA in July 2017. We assessed data related to dose adjusted from the FDA’s and EMA’s summary of product characteristics.

Results: 53 OAA were analyzed. We identified 44 (83%) OAA requiring dosage adjustments in special situations: 20 (37.7%) in renal impairment, 37 (69.8%) in hepatic impairment, and 22 (41.5%) in patients with hematologic toxicity. The dose adjustment recommendations varied in 31 (58.5%) OAA between the FDA and EMA. Detailed recommendations for each OAA were collated into comprehensive tables.

Conclusions: Most OAA have to be adjusted in special situations. Given the number of OAA available for different indications, this review can serve as an easy tool to help health professionals dose these complex treatments.     

Signalling possible drug–drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole

AIMS: In spontaneous adverse drug reaction reporting systems, there is a growing need for methods facilitating the automated detection of signals concerning possible adverse drug reactions. In addition, special attention is needed for the detection of adverse drug reactions resulting from possible drug-drug interactions. We describe a method for detecting possible drug-drug interactions using logistic regression analysis to calculate ADR reporting odds ratios. METHODS: To illustrate this method, we analysed the adverse drug reaction 'delayed withdrawal bleeding' resulting from a possible interaction between itraconazole and oral contraceptives in reports received by the Netherlands Pharmacovigilance Foundation LAREB between 1991 and 1998. RESULTS: In total 5,503 reports were included in the study. The odds ratio, adjusted for year of reporting, age and source of the reports, for a delayed withdrawal bleeding in women who used both drugs concomitantly compared with women who used neither oral contraceptives, nor itraconazole, was 85 (95% CI: 32-230). CONCLUSIONS: Since spontaneous reporting systems can only generate signals concerning possible relationships, this association needs to be analysed by other methods in more detail in order to determine the real strength of the relationship. This approach might be a promising tool for the development of procedures for automated detection of possible drug-drug interactions in spontaneous reporting systems.     

与调血脂药物相关的相互作用

通过检索Medline数据库,就目前有关调血脂药物的相互作用研究进行分类和综述,对有明显临床意义的不良药物相互作用进行重点介绍,以引起临床医师药师重视,供其在临床药物治疗中参考。     

Stereochemical considerations in pharmacokinetic processes of representative antineoplastic agents

The vast majority of chemical drugs or drug candidates contain stereocenter(s) in their molecular structures. In these molecules, stereochemical properties are vital properties that influence or even determine their drug actions. Therefore, studying the stereochemical issues of drugs (or drug candidates) is necessary for rational drug use. These stereochemical issues are usually involved with the stereoselectivity in pharmacokinetic processes, especially in the metabolism process. Thus, the investigation of the stereochemical issues in drug metabolism process deserves great attention, especially in those chiral/prochiral antineoplastic agents exhibiting pharmacodynamics and toxicologic differences between stereoisomers. Published reviews concerning this certain issue are inspiring, however they were covering all drug types and only limited antineoplastic drugs were discussed. Here in this review, the research on stereochemical issues in pharmacokinetic processes of some representative antineoplastic agents were described, especially focusing on some newly developed compounds. We highlight the chemical transformations in pharmacokinetic processes of these chiral/prochiral compounds and discuss their different behaviors with metabolic enzymes or transporter proteins, to explicate the observed stereoselectivity intrinsically.     

2013—2015年华中科技大学同济医学院附属协和医院肿瘤中心抗肿瘤药的使用情况分析

目的 分析华中科技大学同济医学院附属协和医院肿瘤中心2013—2015年抗肿瘤药的应用情况,为临床合理用药提供参考依据.方法 按照药品类型和品种对华中科技大学同济医学院附属协和医院肿瘤中心抗肿瘤药物的使用金额、用药频率(DDDs)和日均用药费用(DDC)等进行统计,分析抗肿瘤药的应用现状.结果 2013—2015年应用抗肿瘤药6亚类,用药金额、DDDs总体呈上升趋势,3年中其他抗肿瘤药在用药金额、DDDs和品种数3项指标上均位居首位,培美曲塞的用药金额3年来稳居榜首,多西他赛和他莫西芬的DDDs最高.结论 华中科技大学同济医学院附属协和医院肿瘤中心抗肿瘤药的用药现状符合当前国内该类药品消耗总趋势,使用情况基本合理.     

单克隆抗体类抗肿瘤药物的临床应用和进展

将化疗药物、放射性物质以及生物毒素等 与单克隆抗体偶联就得到单克隆类药物。由于抗原 抗体结合的特异性,这些偶联的药物被单克隆抗体 导向表达相应抗原的细胞并发挥抗肿瘤效应。单克 隆抗体类抗肿瘤药物有效地降低了传统肿瘤药物治 疗的不良反应,提高了治疗的精确性。     

Interactions between antifungal and antiretroviral agents

Importance of the field: Since the advent of combination antiretroviral therapy, the incidence of opportunistic infections has declined and the life expectancy of HIV-infected people has significantly increased. However, opportunistic infections, including fungal diseases, remain a leading cause of hospitalizations and mortality in HIV-infected people. With the availability of several new antiretroviral and antifungal agents, drug–drug interactions emerge as a potential safety concern.

Areas covered in this review: Relevant literature was identified using a Medline search of articles published up to March 2010 and a review of conference abstracts. Search terms included HIV, antifungal agents and drug interactions. Original papers and relevant citations were considered for this review.

What the reader will gain: Readers will gain an understanding of the pharmacokinetic properties of antiretroviral and antifungal agents, and insight into significant drug–drug interactions which may require dosage adjustments or a change in therapy.

Take home message: Azole antifungal drugs, with the exception of fluconazole, pose the greatest risk of two-way interactions with antiretroviral drugs through CYP450 enzymes effects. Limited studies suggest the risk of interactions between antiretroviral drugs and echinocandins is much lower. The combination of tenofovir and amphotericin B should be used with caution and close monitoring of renal function is required.     

卡培他滨治疗1例晚期胃癌的临床药学实践

口服抗肿瘤药物因服用方便，可以潜在提高生活质量等优势成为肿瘤治疗的发展趋势，然而，口服抗肿瘤药物的安全使用并未得到临床的足够重视，本文以1例晚期胃癌患者使用卡培他滨的药学监护过程为例，探讨临床药师如何在保证口服抗肿瘤药物的安全使用中发挥作用。     

Interactions between oral Yvonne contraceptives and other drugs: a review

Summary

A number of interactions have been reported between oral contraceptive steroids and other drugs. These interactions may lead to impairment of contraceptive efficacy and, in addition, the oral contraceptive steroids can modify the metabolism and pharmacological activity of several drugs.

Loss of cycle control or pregnancy have resulted from simultaneous therapy with oral contraceptives and drugs which are powerful inducers of hepatic microsomal enzymes. These include phenobarbitone, rifampicin, and phenytoin, but occasional reports have implicated other anticonvulsants and barbiturates. By stimulating the formation of enzymes that increase the rate of metabolism of the oral contraceptive, the concentration of steroids in the plasma falls to levels inadequate for the control of conception. Breakthrough bleeding and spotting are common warning signs indicating that additional drug treatment has caused accelerated steroid metabolism. In animals, steroid metabolism has also been increased by treatment with antihistamines, phenylbutazone, orphenadrine and hyoscine.

Apart from enzyme induction, an interaction may occur by competition between an oral contraceptive and another drug for a common metabolising enzyme. An example is quoted in which the dose of a tricyclic antidepressant needed to be reduced in a woman taking an oral contraceptive. In addition, the oral contraceptive might induce the opposite physiological effect from another drug, as with an oral anticoagulant whose dose may have to be increased.

There is a possibility that antibiotic-induced interference with the enterohepatic circulation of steroid metabolites might lead to a decrease in plasma oestrogen levels, and pregnancies have been reported in women treated with ampicillin whilst using oral contraceptives. The displacement of oral contraceptive steroids from their binding sites on plasma proteins and interference with the renal excretion of steroids seem, so far, to be unimportant mechanisms of interaction.

The clinical implications of drug interactions are discussed. Although the number of interaction reports is still very low, it is possible that the advent of contraceptives with a lower hormone content may reveal more interactions than were evident with those containing more than 50 μg. oestrogen.     

Potential for drug interactions involving cytochrome P450 in patients attending palliative day care centres: a multicentre audit

AIM: To determine the potential for drug interactions involving cytochrome P450 (CYP) in patients receiving palliative day care. METHODS: Drugs used by patients attending four specialist palliative day care centres were reviewed to identify combinations that could result in a pharmacokinetic interaction via any of the five main human forms of CYP. RESULTS: Of 160 patients, 145 (91%) were prescribed at least one drug that was a substrate, inhibitor or inducer of one of the five main CYP isoforms. Twenty-four drug combinations, involving 34 patients, could have given rise to a clinically important interaction. CONCLUSIONS: Prescribers should be aware that in this group of patients, one in five are at risk of a clinically important CYP-mediated drug interaction.     

支持抗肿瘤新药进入临床试验的非临床评价要点及关注问题

新药非临床评价的主要目的是决策新药能否进入临床试验。抗肿瘤新药非临床评价中的利弊权衡需考虑到肿瘤疾病及其药物应用特点。多数抗肿瘤药物常伴有严重的不良反应,其临床受试对象多为临床治疗效果较差或根本无有效治疗方法的病人。若新药具有有效性的优势或特点,潜在毒性风险小于疾病自身危险,此时是可以考虑接受新药进入临床试验。本文主要根据该思路对非临床研究中的药效学、毒性实验、药动学进行技术审评,对临床前研究结果的支持性或存在问题进行评价。此外,本文也较为详细讨论了非临床评价的考虑要点及其关注问题。     

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。