A mixed treatment comparison of the short-term efficacy of biologic disease modifying anti-rheumatic drugs in established rheumatoid arthritis

Abstract

Background:

The short-term efficacy of biological disease modifying anti-rheumatic drugs (bDMARDs) for the treatment of established moderate to severe rheumatoid arthritis (RA) has been demonstrated by various randomized placebo or active treatment controlled trials. However, there is a lack of direct comparison of these agents.     

风湿病治疗用生物制剂

生物制剂因具有靶向特点,近10年来在风湿病治疗领域中得到了广泛应用。本文介绍目前已获准用于临床的各生物制剂的特点以及这些生物制剂类慢作用抗风湿药在各种风湿病治疗中的应用和不良反应。     

万古霉素治疗药物监测必要性的系统评价

目的 系统评价万古霉素(三环糖肽类抗生素)治疗药物监测(TDM)的必要性.方法 通过计算机检索、手工检索及向厂家索取资料,全面收集全世界范围内万古霉素治疗药物监测的随机对照研究,共纳入3个研究,总计332名患者.比较万古霉素TDM组和非TDM组在疗效和安全性方面的差异.结果 Meta分析结果表明,抗感染所需时间、感染控制累计剂量、肌酐清除率、肌酐水平、以及其他指标,TDM组和非TDM组比较均无显著性差异;但TDM组中,Cmax＞25 μg·mL-1亚组与Cmax<25 μg·mL-1亚组比较,用药时间、累计剂量和ClIP浓度2组均有统计学意义.结论 TDM组和非TDM组在疗效和安全性上均没有显著差异;但TDM组中,Cmax＞25μg·mL-1组与Cmax<25 μg·mL-1组比较,疗效和安全性均有显著性差异.     

Cardiovascular outcomes of patients with rheumatoid arthritis prescribed disease modifying anti-rheumatic drugs: a review

Introduction: Rheumatoid arthritis (RA) is associated with a heightened risk of cardiovascular disease (CVD), with both traditional CV risk factors and inflammation contributing to this risk.

Areas covered: This review highlights the burden of CVD in RA and associated traditional CV risk factors, including the complexity of dyslipidemia in RA and the so-called ‘lipid paradox.’ Furthermore, the recognized RA-disease-specific factors associated with higher risk of CVD and the role of systemic inflammation in the pathogenesis of CVD in RA will be addressed. With the advent of biologic and targeted synthetic therapies in the treatment of RA, the effect of conventional and newer generation disease modifying anti-rheumatic therapies (DMARDs) on CV risk and associated risk factors will also be discussed.

Expert opinion: Identifying the RA phenotype at greatest risk of CVD, understanding the interplay of increased traditional risk factors, common inflammatory processes and RA-specific factors, and personalized use of DMARDs according to disease phenotype and comorbidity to reduce this risk are key areas for future research.     

A population model of early rheumatoid arthritis disease activity during treatment with methotrexate,sulfasalazine and hydroxychloroquine

Aims

To develop a population model describing the disease activity (DAS28) time course in patients with early rheumatoid arthritis (RA) treated with triple disease-modifying anti-rheumatic drug (DMARD) therapy (methotrexate, sulfasalazine and hydroxychloroquine).

Methods

DAS28 was obtained in 263 patients with early RA from initiation of therapy until 60 weeks. Using nonmem®, base models (DAS28 vs. time) and covariate influences were investigated for the population.

Results

The best model was an exponential model of DAS28 vs. time that was additive to baseline DAS28, with covariance between parameters, and a combined residual error model. Age and patient smoking history were covariates significantly affecting response to therapy. Population estimates were baseline DAS28 (5.7), extent of change in DAS28 (−2.8) and the half-life of disease activity (6.2 weeks; time to steady disease state achieved within approximately 30 weeks). Older individuals exhibited more severe baseline DAS28, described by a power function centred around 57 years (baseline DAS28 for 40- and 70-year-old patients were 5.4 vs. 5.8, respectively) and current smokers took longer to achieve a steady disease state (approximately 50 weeks). There was considerable within-patient random variability in DAS28 over time (empirical 90% CI for DAS28 in a population typical patient at 60 weeks: 1.8, 4.2 with median value of 2.8).

Conclusions

This is the first report of a disease activity model for early RA treated with triple DMARD therapy. Smoking and age were identified as covariates.     

英夫利西单抗失应答的被动治疗药物监测在炎症性肠病治疗中的药物经济学系统评价

目的:英夫利西单抗(infliximab,IFX)用于炎症性肠病(inflammatory bowel disease,IBD)治疗可能出现药物失应答,对于IFX失应答,临床采用传统经验增加药物剂量策略或根据治疗药物监测(therapeutic drug monitoring,TDM)策略.为评价其经济性,本研究系统评...     

克罗恩病治疗中英夫利西单抗药物监测的临床意义

目的：英夫利西单抗（infliximab,IFX）是首个用于克罗恩病的生物制剂,疗效显著,但30%~60%的患者会出现药物失应答。治疗药物监测（therapeutic drug monitoring,TDM）的应用,可为指导临床用药提供依据,达到安全、合理、有效、经济的用药目的。方法：通过查阅近年来在克罗恩病治疗中IFX药物监测的研究及应用情况,就IFX的药动学特点、影响因素、谷浓度及抗IFX抗体（antibodies to infliximab,ATI）与疗效相关性等作一综述。结果：研究显示,IFX免疫原性、患者病理生理状态、遗传因素、联合用药等与IFX药动学有关,监测IFX谷浓度及ATI水平能预测临床应答、内镜下表现及不良反应。结论：进行TDM可优化IFX药物治疗方案,更好地控制疾病活动度,具有重要的临床指导意义。     

Thiopurine monitoring in children with inflammatory bowel disease: a systematic review

Aims

The aim was to systematically review the evidence on the clinical usefulness of thiopurine metabolite and white blood count (WBC) monitoring in the assessment of clinical outcomes in children with inflammatory bowel disease (IBD).

Methods

Medline, Embase, Cochrane Central Register of controlled trials and http://www.clinicaltrials.gov were screened in adherence to the PRISMA statement by two independent reviewers for identification of eligible studies. Eligible studies were randomized controlled trials (RCTs), cohort studies and large case series of children with inflammatory bowel disease (IBD) (<18 years) who underwent monitoring of thiopurine metabolites and/or WBC.

Results

Fifteen papers were identified (n = 1026). None of the eligible studies were RCTs. High 6-thioguanine nucleotide (6TGN) concentrations were not consistently associated with leucopenia. Leucopenia was not associated with achievement of clinical remission. A positive but not consistent correlation between 6TGN and clinical remission was reported. Haematological toxicity could not be reliably assessed with 6TGN measurements only. A number of studies supported the use of high 6-methylmercaptopurine ribonucleotides (6MMPR) as an indicator of hepatotoxicity. Low thiopurine metabolite concentration may be indicative of non-compliance.

Conclusion

Thiopurine metabolite testing does not safely predict clinical outcome, but may facilitate toxicity surveillance and treatment optimization in poor responders. Current evidence favours the combination of thiopurine metabolite/WBC monitoring and clinic follow-up for prompt identification of haematologic/hepatic toxicity safe dose adjustment, and treatment modification in cases of suboptimal clinical outcome or non-compliance. Well designed RCTs for the identification of robust surrogate markers of thiopurine efficacy and toxicity are required.     

高效液相串联质谱法监测女性风湿病患者备孕前血浆中特立氟胺浓度

目的:运用高效液相色谱串联质谱建立测定风湿病患者血浆中特立氟胺浓度的分析方法。方法:50μL血浆加入内标工作液200μL沉淀蛋白后稀释,再采用色谱柱Welch XB-C₁₈(2.1 mm×50 mm, 5μm)进行液相分离,流动相由10 mmol·L^-1甲酸铵溶液(A)和甲醇∶乙腈∶异丙醇=7∶1.5∶1.5(0.2%甲酸)(B)组成,梯度洗脱,流速0.7 mL·min^-1,分析时间2.5 min,进样量3μL,采用多反应监测,负离子模式,电喷雾离子化,监测离子对为m/z 268.4→82.0(特立氟胺)和m/z 272.9→82.0([2H4]-特立氟胺)。结果:特立氟胺在2～1 000 ng·mL^-1线性范围良好,各质控水平准确度为97.2%～105.5%,日内和日间相对标准偏差为4.4%～9.3%,回收率为93.4%～96.4%。结论:本方法专属性强、灵敏度和准确度高、耗时短、前处理简单,可应用于监测女性风湿病患者备孕前血浆中特立氟胺浓度。     

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。     

Clinical studies on alclofenac in the treatment of rheumatic diseases: a drug in question

Summary

The potential advantage to patients with chronic rheumatic diseases of an effective, non-steroidal analgesic anti-inflammatory drug which causes insignificant gastric bleecling was a decisive factor leacling to the introduction of alclofenac. Short-term double-blind trials showed that alclofenac has analgesic / anti-inflammatory activities equivalent to phenylbutazone, indomethacin and aspirin, but superior to thefenemates and propionic acid derivatives.

Long-term controlled studies, ranging from 5 months to 3½ years and using reliable, objective measures reveal, however, that patients with rheumatoid arthritis improve in functional status and graduate to less severe classes of disease activity, a phenomenon not observed with either indomethacin or aspirin administered to matched patients over the same periods of time. So far, clinical improvement on alclofenac has been matched only by treatment with gold, D-penicillamine and the immunosuppressive antiproliferative drugs. This clinical improvement on alclofenac is reflected in haemato-logical and serological indices, and research shows that alclofenac, like these other antirheumatoid drugs, has a pronounced effect upon the acute-phase protein response and the extent to which L-tryptophan is bound to plasma protein. The clinical data reviewed suggest that alclofenac represents an advance in the therapy of the rheumatic diseases.     

2015年某院治疗药物浓度监测结果回顾性分析

目的：回顾性分析某院患者血药浓度监测数据,探讨血药浓度监测在临床合理用药的作用。方法：对某院2015年9种治疗药物监测数据进行回顾性分析,包括监测品种的构成情况,测定频率情况,监测比例情况以及各个监测品种的监测结果及科室分布情况。结果：该院监测例数和测定频率最多的是免疫抑制剂环孢霉素A,占我院所有监测品种次数的80.3%,其次是甲氨蝶呤和他克莫司。他克莫司、甲氨蝶呤、环孢素A和地高辛监测比例均达到60%以上。90.1%儿科患者的42 h甲氨蝶呤血药浓度分布在0.1~1 μmol·L^-1。抗癫痫药物中监测次数最多的是丙戊酸,但多数仅监测一次,说明医师和患者对抗癫痫药物的血药浓度的重视程度不够。万古霉素和地高辛用药人群为老年人,建议将血药浓度调整在正常范围的中下限。结论：血药浓度"正常"的构成比较高,说明该院临床医师已充分意识到治疗药物监测的重要性,此外仍需要医师与临床药师密切配合,根据血药浓度监测结果,调整给药方案,有效提高治疗成功率。     

丙戊酸钠血药浓度监测对治疗儿童癫痫的临床意义

目的:分析评价治疗药物监测(TDM)对丙戊酸钠(VPA)治疗儿童癫痫的临床意义。方法:采用高效液相色谱法检测丙戊酸钠血药浓度,统计分析血药浓度与临床疗效、剂量、合用药物等因素的相关性。统计学处理采用SPSS 11.5软件。结果:在2 002例次儿童癫痫患者的丙戊酸钠血药浓度监测结果中,血药浓度在50～100μg.mL-1范围内1 185例(59.19%),<50μg.mL-1 538例(26.87%),>100μg.mL-1 279例(13.94%);丙戊酸钠血药浓度与临床疗效、不良反应及年龄密切相关,其他抗癫痫药可能降低丙戊酸钠血药浓度而影响疗效。结论:丙戊酸血药浓度个体差异大,且受药物间相互作用等多种因素影响,临床为实现个体化用药,应常规监测血药浓度。     

Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review

Introduction: Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-based drug-drug interactions (DDIs), as well as the negative downstream effects of these DDIs, have not been fully characterized.

Areas covered: This article provides an overview of Bu PK, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs. In addition, pharmacogenomics of Bu chemotherapy and Bu-related DDIs observed in the stem cell transplant clinic (SCT) are summarized. Finally the increasing importance of Bu therapeutic drug monitoring is highlighted.

Expert opinion: Mechanistic studies of Bu metabolism have shown that in addition to GST isoenzymes, other oxidative enzymes (CYP, FMO) and ABC/MDR drug transporters likely contribute to the overall clearance of Bu. Despite many insights, results from clinical studies, especially in polypharmacy settings and between pediatric and adult patients, remain conflicting. Further basic science and clinical investigative efforts are required to fully understand the key factors determining Bu PK characteristics and its effects on complications after SCT. Improved TDM strategies are promising components to further investigate, for instance DDI mechanisms and patient outcomes, in the highly complex SCT treatment setting.     

4例精神药物治疗药物监测典型病例回顾分析

目的:总结治疗药物监测在精神科应用的临床经验。方法:回顾国内外治疗药物监测在精神科发展的历史,结合临床经验对4例个案进行分析:患者氯丙嗪中毒后出现浓度反弹,通过监测药物清除过程辅助判断救治效果;通过利培酮与9-羟利培酮浓度比例判断患者CYP2D6酶活性及其代谢型,为患者个体化用药提供参考;对同时使用9种精神药物的患者进行浓度测定,结果表明该用药方案不合理,患者经单药治疗后已康复;少部分服用氯氮平患者,血药浓度长期维持在高浓度,需严密监视此类患者药物浓度波动。结果:治疗药物监测可应用于如下领域:监测药物中毒后的药物清除过程;结合代谢酶活性数据指导患者个体化用药;以浓度测定结果辅助判断合并用药是否合理;重视异常结果,结合患者症状判断浓度是否合理。结论:治疗药物监测结果需结合患者病情与临床疗效综合判断,方能实现个体化给药这一目的。     

Current use of daptomycin and systematic therapeutic drug monitoring: Clinical experience in a tertiary care institution

Therapeutic drug monitoring (TDM) could optimise daptomycin use. However, no validated serum target levels have been established. This prospective study at a tertiary centre including hospitalised patients receiving daptomycin aimed to evaluate the adequacy of daptomycin doses in a real-life study, assess interpatient variability in serum levels, identify predictive factors for non-adequate serum levels and assess their clinical impact. Blood samples [trough (C_min) and peak (C_max) levels] were drawn ≥3 days post-treatment initiation. Serum daptomycin concentrations were determined by HPLC. Outcome was classified as: (i) favourable, if clinical improvement or cure occurred with no adverse events; or (ii) poor, in the case of no clinical response, recurrence, related mortality or if adverse events were detected. Sixty-three patients (63.5% male; median age 63.0 years) were included. The most common indications for daptomycin use were bacteraemia (46.0%), complicated skin and soft-tissue infection (30.2%) and endovascular infection (15.9%). The initial dosage was adequate in 43 patients (68.3%), low in 14 (22.2%) and high in 6 (9.5%). Large interindividual variability in serum levels was observed, with a median C_min of 10.6 mg/L (range 1.3–44.7 mg/L) and median C_max of 44.0 mg/L (range 3.0–93.7 mg/L). Multivariate analysis showed that C_min < 3.18 mg/L was independently related to poor outcome (OR?=?6.465, 95% CI 1.032–40.087; P?=?0.046). High variability in daptomycin use and serum levels was detected. Specific serum targets were identified as risk factors for poor outcome. TDM might be useful to optimise daptomycin doses and to avoid therapeutic failure.     

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.