Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis

AIMS: To investigate the concentration-effect relationship and pharmacokinetics of leflunomide in patients with rheumatoid arthritis (RA). METHODS: Data were collected from 23 RA patients on leflunomide therapy (as sole disease modifying antirheumatic drug (DMARD)) for at least 3 months. Main measures were A77 1726 (active metabolite of leflunomide) plasma concentrations and disease activity measures including pain, duration/intensity of morning stiffness, and SF-36 survey. A population estimate was sought for apparent clearance (CL/F) and volume of distribution was fixed (0.155 l kg(-1)). Factors screened for influence on CL/F were weight, age, gender and estimated creatinine clearance. RESULTS: Significantly higher A77 1726 concentrations were seen in patients with less swollen joints and with higher SF-36 mental summary scores than in those with measures indicating more active disease (P < 0.05); concentration-effect trends were seen with five other disease activity measures. Statistical analysis of all disease activity measures showed that mean A77 1726 concentrations in groups with greater control of disease activity were significantly higher than those in whom the measures indicated less desirable control (P < 0.05). There was large between subject variability in the dose-concentration relationship. A steady-state infusion model best described the pharmacokinetic data. Inclusion of age as a covariate decreased interindividual variability (P < 0.01), but this would not be clinically important in terms of dosage changes. Final parameter estimate (% CV interindividual variability) for CL/F was 0.0184 l h(-1) (50%) (95% CI 0.0146, 0.0222). Residual (unexplained) variability (% CV) was 8.5%. CONCLUSIONS: This study of leflunomide in patients using the drug clinically indicated a concentration-effect relationship. From our data, a plasma A77 1726 concentration of 50 mg l(-1) is more likely to indicate someone with less active disease than is a concentration around 30 mg l(-1). The marked variability in pharmacokinetics suggests a place for individualized dosing of leflunomide in RA therapy.     

来氟米特联合白芍总苷治疗老年类风湿关节炎的疗效及对ESR、CRP、RF的影响研究

目的:探索来氟米特联合白芍总苷治疗老年类风湿关节炎(RA)的临床疗效及对患者红细胞沉降率(ESR)、C反应蛋白(CRP)、类风湿因子(RF)等的影响。方法:选取2013年10月-2014年10月确诊并收治的老年RA患者84例,按照就诊顺序随机分为2组,各42例。对照组患者单用来氟米特治疗,观察组患者采用来氟米特联合白芍总苷进行治疗。观察2组临床治疗效果以及治疗前后ESR、CRP、RF等相关指标的改善情况,同时记录患者治疗期间不良反应情况。结果:观察组治疗总有效率为95.24%,显著高于对照组(P<0.05)。2组患者治疗后晨僵时间、关节压痛数、关节压痛指数、关节肿胀数、关节肿胀指数以及ESR、CRP、RF等相关指标均较治疗前明显改善,且观察组上述各项指标与对照组比较有显著差异(P<0.05)。观察组不良反应发生率为9.52%,显著低于对照组(P<0.05)。结论:来氟米特联合白芍总苷治疗老年类风湿关节炎疗效显著,可有效改善患者的临床症状及ESR、CRP、RF等相关指标,且不良反应较少,安全性高,值得临床推广应用。     

Leflunomide in active rheumatoid arthritis: a prospective study in daily practice

AIMS: We prospectively studied the efficacy, incidence of adverse drug reactions and withdrawal from leflunomide in an outpatient population with rheumatoid arthritis in a setting of care-as-usual. METHODS: In this prospective case series study, from outpatient medical records a standard dataset was collected including patient and disease characteristics, data on leflunomide use and adverse drug reactions. RESULTS: During the study period 136 rheumatoid arthritis patients started leflunomide. Median (range) follow-up duration was 317 (11-911) days. Sixty-five percent of patients experienced at least one adverse drug reaction related to leflunomide. During follow-up 76 patients (56%) withdrew from leflunomide treatment, mainly because of adverse drug reactions (29%) or lack of efficacy (13%). The overall incidence density for withdrawal from leflunomide was 56.2 per 100 patient-years. Complete data for calculating efficacy using a validated disease activity score on 28 joints (DAS(28)) was available for 48, 36, and 35% of patients at 2, 6, and 12 months follow-up, respectively. Within a 12-month period after start of leflunomide treatment 76% of the evaluable patients were classified as moderate or good responders according to the DAS(28) response criteria. CONCLUSIONS: In the setting of care-as-usual, rheumatoid arthritis patients starting leflunomide frequently experienced adverse drug reactions. More than half of the patients withdrew from leflunomide treatment within a year after start of leflunomide treatment, mainly because of adverse drug reactions.     

附桂骨痛胶囊联合来氟米特治疗类风湿关节炎的临床研究

目的 探讨附桂骨痛胶囊联合来氟米特治疗类风湿关节炎的临床疗效。方法 选取2017年8月—2019年12月上海交通大学医学院附属第九人民医院北部90例类风湿关节炎患者作为研究对象,按照治疗方法分为对照组和观察组,每组各45例。对照组口服来氟米特片,10 mg/次,1次/d。观察组在对照组治疗的基础上口服附桂骨痛胶囊,4粒/次,3次/d。两组连续治疗3个月。对比两组的临床总有效率,比较两组关节肿胀数、压痛数、晨僵时间的变化。检测患者治疗前后血清C反应蛋白（CRP）、白细胞介素-32（IL-32）、类风湿因子（RF）、血沉的水平及血液流变学指标。记录药物不良反应的发生情况。结果 治疗后,观察组患者总有效率为95.56%,对照组为82.22%,两组间比较差异有统计学意义（P<0.05）。治疗后,两组关节肿胀数、压痛数、晨僵时间显著降低（P<0.05）,以观察组降低更明显（P<0.05）。治疗后,两组的CRP、IL-32、RF、血沉水平均显著降低（P<0.05）;治疗后,观察组的CRP、IL-32、RF、血沉水平显著低于对照组,差异有统计学意义（P<0.05）。治疗后,两组的全血黏度、血浆比黏度、红细胞压积、血小板聚集率均显著降低（P<0.05）;治疗后,观察组的全血黏度、血浆比黏度、红细胞压积、血小板聚集率显著低于对照组,差异有统计学意义（P<0.05）。两组药物不良反应的发生率无明显差异。结论 附桂骨痛胶囊联合来氟米特片治疗类风湿关节炎的疗效确切,可降低炎症反应,改善血液流变学水平,显著改善临床症状。     

来氟米特与柳氮磺吡啶治疗强直性脊柱炎的临床对比研究

目的：对来氟米特（leflunomide，LEF）和柳氮磺吡啶（sulfasalazine，SASP）治疗强直性脊柱炎（ankylosing spondylitis，AS）的疗效进行为期2年的临床对比观察，以评价两种药物治疗AS的有效性及安全性。方法：将112例住院治疗的AS患者随机分为两组，每组各56例，分别采用LEF（LEF组）或SASP（SASP组）治疗，两组患者的年龄、性别、病程及病情相匹配，均选择一种非甾体类抗炎药（NSAIDs）作为基础疗法。随访2年，记录症状体征、Bath AS活动指数（BASDAI）、Bath AS功能指数（BASFI）、红细胞沉降率和C-反应蛋白浓度等实验室检查及不良反应。结果：两组患者随访第1、2年与入院时比较，腰骶痛明显减轻，腰背晨僵时间显著缩短，BASDAI和BASFI明显降低，炎性指标红细胞沉降率和C-反应蛋白浓度显著下降（均P〈0．05）；随访第1、2年两组间比较，腰骶痛、腰背晨僵时间、BASDAI、BASFI、红细胞沉降率和C-反应蛋白浓度，LEF组较SASP组改善明显，差异均有统计学意义（P〈0．05）。药物不良反应以胃肠道反应、白细胞数减少和皮疹为主，LEF组胃肠道反应明显低于SASP组（5．2％vs11．8％）（P〈0．05），白细胞数减少和皮疹两组间差异无统计学意义。结论：LEF治疗AS疗效优于SASP。LEF不良反应少，服用方便，患者易耐受，其更长期的疗效及安全性有待进一步观察。     

丹参酮ⅡA注射液联合来氟米特片、美洛昔康分散片治疗类风湿关节炎临床观察

目的通过观察丹参酮ⅡA注射液联合来氟米特片、美洛昔康分散片治疗类风湿关节炎的临床疗效,探讨中西医结合治疗类风湿关节炎的优势。方法对确诊的60例患者随机分为两组,60例活动期RA患者随机分为治疗组32例和对照组28例,对照组服用来氟米特片和美洛昔康分散片治疗,治疗组在此基础上加服丹参酮ⅡA注射液治疗。比较2组临床疗效。结果治疗后试验组关节肿胀数明显减少,ESR及CRP等明显降低,与对照组比较有显著性差异。结论丹参酮ⅡA注射液是一种治疗RA安全有效的方法。     

Population Pharmacokinetics of the Active Metabolite of Leflunomide in Pediatric Subjects with Polyarticular Course Juvenile Rheumatoid Arthritis

Leflunomide is a pyrimidine synthesis inhibitor used in the treatment of rheumatoid arthritis. Data from two clinical studies were used to establish a population pharmacokinetic (PPK) model for the active metabolite (M1) of leflunomide in patients with juvenile rheumatoid arthritis (JRA) and determine appropriate pediatric doses. Seventy-three subjects 3–17 years of age provided 674 M1 concentrations. The PPK model was derived from nonlinear mixed-effects modeling and qualified by cross-study evaluation and predictive check. A one-compartment model with first-order input described M1 PPK well. Body weight (WT) correlated weakly with oral clearance (CL/F = 0.020·[WT/40]^0.430) and strongly with volume of distribution (V/F = 5.8·[WT/40]^0.769). Steady-state concentrations (C_ss) of M1 in JRA were compared for a variety of leflunomide dose regimens using Monte–Carlo simulation. To achieve comparable C_ss values in pediatric patients with JRA to that in adult patients, doses of leflunomide should be adjusted modestly: 10 mg/d for 10–20 kg, 15 mg/d for 20–40 kg, and 20 mg/d for > 40 kg.     

来氟米特治疗类风湿关节炎随机双盲平行对照临床试验

目的 研究来氟米特（LEF）治疗类风湿关节炎（RA）的疗效和安全性。方法 用随机双盲双模拟平行对照多中心临床试验，试验组70例患者每日口服来氟米特（LEF）20mg，1天1次；对照组69例患者口服氨甲喋呤（MTX）15mg，1周1次，疗程12周，部分病例积累用药24周。结果 治疗12，24周，试验组与对照组有效率分别为44．28％（70例），79．36％（63例）；49．27％（69例），74．19％（62例），2组比较无显著性差异。2组均能改善RA患者临床症状、体征和关节功能，降低血沉、C-反应蛋白和类风湿因子水平。2组药物不良反应发生率分别为17．14％（12例）和31．88％（22例）（P〈0．05）。结论 来氟米特治疗类风湿性关节炎疗效与耐受性均较氨甲喋呤好。