Objective To provide reference for clinical rational drug use via signal mining of the side effects of sofosbuvir. Methods The warning signals of sofosbuvir-induced neuropsychic adverse drug reaction (ADR) were mined by proportional reporting ratio(ROR)method from Adverse Event Reporting System in the United States from 2014 to the second quarter of 2015 were mined by proportional repoting ratio (ROR) method. The distribution characteristic of signals, such as gender, age and dosage, were analyzed. Results A total of 52 relevant ADR signals were detected, and 49 were not recorded in the drug label. The ROR of ADR signals which were higher than others were mental disorders (13.49), hangover (11.36), irritability (12.40), homicidal ideation (13.93), violence-related symptom (13.37). The strengths of signals were all weak. There was no significant difference in the distribution of gender (P = 0.227), however, there were significant differences in the in the distribution of patient age (P<0.001) and sofosbuvir dosage (P=0.001). Conclusion Mining and analysis of ADR signals induced by sofosbuvir can provide preliminary references to evaluate the safety.
Key words:
Sofosbuvir
;
Adverse drug reactions
;
neuropsychic
;
Signals mining and analysis
目前全球有1.30亿~1.70亿人感染丙型肝炎病毒(hepatitis C virus,HCV),约占总人口的3%,而我国约有4000万人感染HCV,占总人口的3.2%[1,2]。因此,HCV感染逐渐成为了关注焦点之一。既往对慢性HCV感染的治疗手段主要为利巴韦林及聚乙二醇干扰素。但上述疗法存在诸多不足[3],限制了其广泛使用。抗HCV新药索非布韦(sofobuvir)为HCVNS5B RNA聚合酶抑制药,在细胞内代谢形成具有药理学活性三磷酸尿苷的类似物,从而起到抑制HCV病毒增殖的作用[4]。相对于既往治疗手段,索非布韦更为有效、方便、安全。有系统评价显示,其联合利巴韦林治疗HCV较利巴韦林联合干扰素制剂SVR12及24的有效性更高,若采用索非布韦联合利巴韦林+干扰素方案,可使SVR4,12及24较两药联合治疗的有效性大幅度提高,同时大大降低慢性丙型肝炎复发的概率[5]。目前认为,索非布韦对HCV基因2和3型引起的慢性丙型肝炎可全口服治疗,对基因1和4型慢性丙型肝炎需与聚乙二醇干扰素α和利巴韦林联用[6]。因此,索非布韦的问世,对HCV感染患者有着重要意义。该药于2017年9月进入中国。在我国上市时间虽然较短,但国内已开始临床研究[7,8]。其中,对索非布韦临床应用安全性的研究显得十分重要。
药品不良反应(adverse drug reactions,ADR)信号筛选是药物警戒和药品上市后安全性评价的重要内容之一。药物上市前研究存在样本量小、观察期短、选取对象限制等问题,很难发现迟发的、非常见的ADR。对上市后药品安全性的监测及评价,尤其是通过ADR数据库挖掘相关信号,可弥补药物上市前研究的不足[9]。本研究采用报告比值比(reporting odds ratio,ROR)法对索非布韦致神经精神ADR信号进行挖掘,拟初步探寻索非布韦在该领域新ADR表现。
1 资料与方法
1.1 数据来源
数据来源于美国不良事件报告系统收集到的2014年及2015年第一、二季度ADR报告。为保证数据分析标准的一致性,将ADR按药事管理医学用语词典(Medical Dictionary for Regulatory Activities,MedDRA)首选语(preferred terms,PT)进行编码[10,11]。
1.2 数据处理
排除ADR名称不确定和重复的报告,得到ADR 4 422 088例。通过ACCESS2007版软件检索药物通用名称sofosbuvir及商品名Sovaldi,得到索非布韦为首要怀疑药物的报告8003例。然后将上述报告按MedDRA的SOC(system organ class)标准进行统计分类,将属于“神经系统障碍”及“精神疾病”的报告进行归类。同时排除上报后因信息不全及ADR报告例数小于3例的报告,共得到最终ADR报告共1666例。
1.3 方法选择
ADR信号挖掘采用ROR法。所需四格表见表1。
表1
Tab.1
表1
表1
ROR法所需要的四格表
Tab.1
Fourfold table of ROR measurement
表3
信号影响因素的卡方检验结果
Tab.3
Result of Chi-square test for signal effect factors
影响因素与 分类
目标系统ADR 信号报告数
总报告数
检验结果
份
性别
男
508
2067
女
369
1398
χ2=1.46,P=0.227
年龄
<40岁(A)
43
133
40~65岁(B)
546
1679
>65岁(C)
70
368
χ2=26.37,P=0.000
剂量
400 mg·d-1(D)
298
942
800 mg·d-1(E)
13
98
>800 mg·d-1(F)
7
18
χ2=14.93,P=0.001
P1 comparison between A and B,P2 comparison between A and C,P3 comparison between B and C,P4 comparison between D and E,P5 comparison between D and F,P6 comparison between E and F.P1=0.964(χ2=0.00),P2=0.000(χ2=29.88), P3=0.000(χ2=26.14), P4=0.000(χ2=14.29) ,P5=0.513(χ2=0.43), P6=0.008(χ2=7.00)
WHO.Guidelines for the screening care and treatment of persons with hepatitis C infection[M].Geneva:World Health Organization,2014.
[本文引用:1]
[2]
LAVANCHYD.Evolving epidemiology of hepatitis C virus[J].Clin Microbiol Infect,2011,17(2):107-115.
More than 20 years after the discovery of the hepatitis C virus (HCV), it is now well established that HCV is of global importance affecting all countries, leading to a major global health problem that requires widespread active interventions for its prevention and control. Chronic hepatitis C was linked to the development of cirrhosis and hepatocellular carcinoma in many areas of the world. Current epidemiological assessments have identified complex patterns with highly variable local prevalence rates between countries and within countries. HCV infection patterns have not significantly changed in most parts of the world since 1997, when first analyzed, partly due to the lack of new and more accurate data. The assessment of the national HCV prevalence and transmission modes should be completed to enable national authorities to prioritize preventive measures and to make the most appropriate use of available resources. The 090004patchy090005 epidemiological situation in some areas will continue to complicate the task of the establishment of global, regional and national base line data. The present assessment finds a global prevalence of 2.35%, affecting 160 million chronically infected individuals. There is an urgent need for more accurate Information on the costs and burden of HCV to society. Twenty-one year after the discovery of HCV, the assessment is far from being complete and little progress has been made in the past 10 years in many countries. In some countries significant increases have been reported and this may also apply to countries were insufficient data exist. A safe and efficient vaccine against HCV is urgently needed.
MCHUTCHISONJ G,LAWITZE J,SHIFFMANM L,et al.Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection[J].N Engl J Med,2009,361(6):580-593.
Abstract BACKGROUND: Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. METHODS: At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 microg per kilogram of body weight per week or a low dose of 1.0 microg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 microg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. RESULTS: Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], -2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and -1.1% (95% CI, -5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. CONCLUSIONS: In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials.gov number, NCT00081770 .) 2009 Massachusetts Medical Society
HYEJ Y,JUY R,BONGK Y.Meta-analysis of the efficacy and safety of sofosbuvir for the treatment of hepatitis C virus infection[J].Int J Clin Pharm,2015,37(5):698-708
Abstract BACKGROUND: Hepatitis C virus infection is a worldwide health problem and one of the leading causes of cirrhosis and hepatocellular carcinoma. Recently, sofosbuvir was introduced to the therapeutic arsenal against this virus, thereby paving the way for all-oral regimen. Aims of the review This study aimed to systematically analyze the efficacy and safety of sofosbuvir for the treatment of hepatitis C virus infection. METHOD: PubMed and EMBASE database searches were conducted using "sofosbuvir" as the search term. Phase III clinical studies retrieved from the two databases and resources posted on the Drug@FDA and ClinicalTrials.gov websites were evaluated with regard to outcomes of the efficacy and safety analyses of the drug. RESULTS: Eight Phase III clinical studies compared the efficacy and safety of sofosbuvir. When sofosbuvir replaced peginterferon which was used in the previous standard regimen, a superior sustained virologic response, as defined by a viral RNA load less than the lower limit of quantification 12 weeks after cessation of therapy, was obtained (74.3 vs. 66.7%, p < 0.05). The response improved even more (90.8 vs. 66.7%, p < 0.0001) when sofosbuvir was used as an add-on therapy to the standard regimen. The overall odds ratio to achieve the response in the sofosbuvir-containing arm of the eight clinical studies was 3.66 times greater (95% CI 3.00-4.46) than that of the standard regimen arm. During the eight clinical studies, adverse events were observed in 83.61 and 87.22% of the patients in the sofosbuvir and non-sofosbuvir arms, respectively, with the most frequent events being mild central nervous system symptoms such as fatigue, headache, and asthenia. CONCLUSIONS: Sofosbuvir was safe and effective in the treatment of hepatitis C virus genotype 1, 2, 3, or 4 infections. However, the lack of persistence of the sustained virologic response beyond the study duration and long-term safety concerns need to be addressed in future studies.
SAKAEDAT,KADOYAMAK,OKUNOY.Statin- associa-ted muscular and renal adverse events :data mining of the public version of the FDA adverse event reporting system[J].PLoS One,2011,6(12):e28124.
Objective Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to assess the muscular and renal adverse events induced by the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and to attempt to determine the rank-order of the association. Methods After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving pravastatin, simvastatin, atorvastatin, or rosuvastatin were analyzed. Authorized pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Myalgia, rhabdomyolysis and an increase in creatine phosphokinase level were focused on as the muscular adverse events, and acute renal failure, non-acute renal failure, and an increase in blood creatinine level as the renal adverse events. Results Based on 1,644,220 AERs from 2004 to 2009, signals were detected for 4 statins with respect to myalgia, rhabdomyolysis, and an increase in creatine phosphokinase level, but these signals were stronger for rosuvastatin than pravastatin and atorvastatin. Signals were also detected for acute renal failure, though in the case of atorvastatin, the association was marginal, and furthermore, a signal was not detected for non-acute renal failure or for an increase in blood creatinine level. Conclusions Data mining of the FDA's adverse event reporting system, AERS, is useful for examining statin-associated muscular and renal adverse events. The data strongly suggest the necessity of well-organized clinical studies with respect to statin-associated adverse events.
ROTHMANK J,LANESS,SACKSS T.The reporting odds ratio and its advantages over the proportional reporting ratio[J].Pharm Drug Saf,2004,13(8):519-523.
Abstract Purpose The proportional reporting ratio (PRR) is the proportion of spontaneous reports for a given drug that are linked to a specific adverse outcome, divided by the corresponding proportion for all or several other drugs. The PRR is similar to the proportional mortality ratio (PMR), an old epidemiologic measure calculated from death registries and constructed in similar fashion to the PRR. The PMR has important deficiencies, however, which the PRR shares. Miettinen and Wang demonstrated that the PMR could be improved by reformulating it as an odds ratio and applying the principles of a case-control study to the measure. In this paper, we review the problem with the PRR and show how the corresponding odds ratio represents an improvement over the PRR. Methods The method used is discussion and illustration by way of a hypothetical example. Results The PRR does not estimate relative risk. If, however, a spontaneous report database is viewed as source data for a case-control study, the reporting odds ratio (ROR) can be used to estimate relative risk. Treating the data as source data for a case-control study allows for further reduction of bias by the judicious choice of controls. Conclusions Calculating the ROR in spontaneous report databases offers advantages over the PRR. It allows for estimation of the relative risk, and focuses attention on which people or reports should be included or excluded from the control series, permitting more deliberate elimination of biases. It also highlights the inherent weaknesses in spontaneous report data, which become more evident in light of the usual principles of control selection in case-control studies.
, 饶友义
