来氟米特治疗类风湿关节炎血浆浓度与疗效关系的初步报告

The relationship between leflunomide plasma concentration and therapeutic efficacy in rheumatoid arthritis patients

目的探讨类风湿关节炎（RA）患者来氟米特（LEF）活性代谢产物A771726的浓度与剂量、疗效及不良反应的关系，从而根据药代动力学的差异指导RA患者合理化个性化用药。方法多中心、前瞻性、分组对照研究。将RA患者分为50mg／d与30mg/d冲击组及20mg/d与10mg／d、10mg隔日1次3组。各组患者于用药前，冲击3d后及用药1个月后分别检测A771726血浆谷浓度，同时记录压痛、肿胀关节数、关节痛程度、晨僵时间及C反应蛋白（CRP），并检查血尿常规、肝肾功能。结果50mg／d组，30mg／d组3d后的血药浓度分别为（19±14）、（18±15）μg／ml，两组间P〉0．05；20mg／d组、10mg／d组及10mg隔日1次组1个月后血药浓度分别为（46±30）、（26±10）、（13±7）μg／ml，20mg／d与10mg／d两组比较、10mg隔日1次组与20mg／d及10mg／d组比较差异均有统计学意义（P〈0．01）。20mg／d与10mg／d组间RF改善率差异有统计学意义（P〈0．01）。除了10mg／d组晨僵改善不明显外，各组在治疗后RF、关节疼痛、压痛、肿胀、晨僵改善方面差异均有统计学意义（P〈0．01）。由于观察时间较短，例数尚少，各组间不良反应差异不明显。结论在一定范围内LEF血药浓度与剂量有关。50mg／d与30mg／d冲击治疗3d，部分患者达到治疗RA的有效血浓度，缩短起效时间。为了持续维持有效治疗血药浓度，口服剂量至少10mg／d，20mg／d组RF改善率优于10mg／d组。

Objective To investigate the relationship between plasma concentration of A771726, the active metabolic product of leflunomide （LEF）, and therapeutic efficacy and adverse reactions in rheumatoid arthritis （RA） patients treated with LEF. Methods This was a muhicentre prospective and compared trial. 113 patients with RA were divided into 5 groups： 50 mg/d×3 d, 30 mg/d×3 d, 20 mg/d×1 month, 10 mg/d×1 month and 10 mg/2 d×1 month. Plasma concentration of A771726 were detected before and after treatment respectively. Tender joint count, swollen joint count, joint pain VAS score,duration of morning stiffness and CRP were recorded simultaneously. Results Plasma concentration of A771726 of 50 mg/d×3 d group and 30 mg/d× 3 d groups after treatment were （19±14） and （18±15） μg/ml respectively （P〉0.05）. Plasma concentration of 20 mg/d×1 month, 10 mg/d×1 month and 10 mg/2 d×1 month groups after treatment were （46±30）, （26±10）, （13±7） μg/ml respectively. There was statistical significant difference in the plasma concentration between 20 mg/dxl month group and 10 mg/d×1 month group （P〈0.01）. Plasma concentration of 10 mg/2 d×1month group was lower than that of 20 mg/d×1 month and 10 mg/d×1 month groups （P〈0.01）. Patients of each group improved in the titer of RF, tender joint count, swollen joint count,joint pain VAS score and duration of morn- ing stiffness at the end of treatment （P〈O.O1）, except duration of morning stiffness in 10 mg/d^l month group. There was no significant difference among the 5 groups in adverse reactions, because the follow up time was short and the sample size was small. Condusions LEF plasma concentration is correlated positively with dose within certain limits. Some of the patients in 50 mg/d×3 d group and 30 mg/d×3 d group reached the effective plasma concentration for RA. The least effective dose of LEF is 10 mg/d based on the plasm effective concentration. The impovement rate of RF in group 20 mg/d was higher than that in group 10 mg/d.