不同剂型霉酚酸类药物在早期肾移植患者体内的药动学研究及不良反应分析

doi:10.11669/cpj.2020.17.011

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摘要目的研究不同剂型霉酚酸类药物在早期肾移植患者体内的药动学特征与不良反应的相关性。方法肾移植患者121例,术后分别服用吗替麦考酚酯胶囊(骁悉, MMF) (给药剂量分别为500,750,1 000 mg)、吗替麦考酚酯分散片(赛可平,MMF-T)(给药剂量分别为500,750,1 000 mg)、吗替麦考酚酯分散片(国药川抗, MMF-DT) (给药剂量分别为500,750 mg)和麦考酚钠肠溶片(米芙,EC-MPS)(给药剂量分别为360,540,720,900 mg),每12 h给药1次;分别于术后第7天服药前和服药后0.5,1,1.5,2,3,4,6,8,10和12 h采集静脉血样2 mL;采用超高效液相色谱法(UHPLC-DAD)测定MPA的血药浓度;以WinNoLin6.3软件,采用非房室模型计算药动学参数,并分析AUC_{0-12 h}与不良反应的相关性。结果不同剂型给药组的平均ρ₀变化不大,基本维持在1.0~3.0 μg·mL^-1;平均ρ_max在4~12 μg·mL^-1之间,相应的t_max基本维持在1~3 h;各组别半衰期t_1/2基本在4~9 h以内;除MMF-T组的AUC_{0-12 h}小于30 μg·h·mL^-1,其余3组的AUC_{0-12 h}基本维持在治疗窗30~60 μg·h·mL^-1内。MMF和MMF-T均在500~1 000 mg (bid)、MMF-DT在500~750 mg (bid)和EC-MPS在360~900 mg (bid)剂量范围内,各组别药物剂量与AUC_{0-12 h}呈非线性关系,而AUC_{0-12 h}与ρ₀, ρ_max呈不确定地线性关系(r=0.591~0.817,P<0.01)。肾移植术后早期患者主要出现中度贫血,血压异常,腹泻等不良反应,超出MPA的AUC_{0-12 h}治疗窗范围,更容易出现各种不良反应。结论患者个体间MPA的药动学差异较大;MMF组(500~1 000 mg, bid),MMF-T组(500~1 000 mg, bid),MMF-DT组(500~750 mg, bid)和EC-MPS组(360~900 mg, bid)的药物剂量与AUC_{0-12 h}呈非线性关系,AUC_{0-12 h}值基本一致;AUC_{0-12 h}与ρ₀, ρ_max之间相关性一般;治疗窗范围内不良反应出现例数较少。

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	姚新生

关键词 ：霉酚酸类药物, 早期肾移植, 药动学, 剂量依赖性, 不良反应

Abstract：OBJECTIVE To evaluate the pharmacokinetic characteristics and adverse reactions among different dosage forms of mycophenolate applied to early kidney transplant recipients. METHODS One hundred and twenty-one early kidney transplant recipients were divided into four groups, and received oral administration of mycophenolate mofetil capsules (Xiaoxi, MMF) (500, 750 and 1 000 mg, respectively), mycophenolate mofetil dispersible tablets (Saikeping, MMF-T) (500, 750 and 1 000 mg, respectively), mycophenolate mofetil dispersible tablets (Guoyaochuankang, MMF-DT) (500 and 750 mg, respectively), and mycophenolate sodium enteric-coated tablets (Mifu, EC-MPS) (360, 540, 720 and 900 mg, respectively) twice per day, respectively. The blood samples were collected on postoperative day 7 before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h after oral administration of different dosage forms of mycophenolate, respectively. Ultra high-performance liquid chromatography equipped diode array detector (UHPLC-DAD) was employed to determine the plasma concentration of MPA. Pharmacokinetic (PK) parameters of MPA were estimated by non-compartmental method using WinNoLin 6.3 software. RESULTS There were no significant differences of mean ρ₀ values (1 to 3 μg·mL^-1) among four dose groups. The ρ_max values were between 4 and 12 μg·mL^-1, and their respective t_max values ranged from 1.0 to 3.0 h. Their t_1/2 values were between 4 and 9 h. In addition, the AUC_{0-12 h} values for MMF-T group were less than 30 μg·h·mL^-1, while AUC_{0-12 h} values for other three groups fall in the therapeutic window of MPA (30 to 60 μg·h·mL^-1). Furthermore, power regression results indicated that dose proportionality of AUC_{0-12 h} was nonlinear, and the correlation of AUC_{0-12 h} and ρ₀, ρ_max were not conclusively linear (r=0.591 to 0.817, P<0.01) for MMF, MMF-T, MMF-DT and EC-MPS groups within 500-1 000 mg (bid), 500-1 000 mg (bid), 500-750 mg (bid) and 360-900 mg (bid), respectively. Moreover, moderate anemia, abnormal blood pressure and diarrhea mainly occurred in early kidney transplant recipients. When AUC_{0-12 h} values of MPA were less than 30 μg·h·mL^-1 or over 60 μg·h·mL^-1, the patients were more likely to have various adverse reactions. CONCLUSION PK parameters of MPA show marked individual difference among Chinese early kidney transplant recipients. There is a nonlinear relationship between drug dose and AUC_{0-12 h} for MMF group (500-1 000 mg, bid), MMF-T (500-1 000 mg, bid), MMF-DT (500-750 mg, bid) and EC-MPS group (360-900 mg, bid), and their AUC_{0-12 h} values are similar for different groups. There is inconclusively linear correlation between AUC_{0-12 h} and ρ₀, ρ_max. There are few cases of adverse reactions in therapeutic window of MPA.

Key words： mycophenolate drug early renal transplantation pharmacokinetics dose dependence adverse reactions

收稿日期: 2020-02-28

PACS:

R969.1

基金资助:国家自然科学基金青年科学基金项目资助(81703799,81803638);河南省高等学校重点科研项目资助(20A350012)

通讯作者: 秦子飞, 男, 主管药师研究方向:药动学 Tel:(0371) 66913423 E-mail:qzf1989@163.com; 杨晶, 女, 副主任药师研究方向:临床药学与药物基因组学 Tel:(0371) 66913425 E-mail:jingyang_0101@163.com

作者简介: 张绮雯,女,药师研究方向:临床药学

引用本文:

张绮雯, 贾萌萌, 杨晶, 姚志红, 秦子飞, 张晓坚, 姚新生. 不同剂型霉酚酸类药物在早期肾移植患者体内的药动学研究及不良反应分析[J]. 中国药学杂志, 2020, 55(17): 1460-1469. ZHANG Qi-wen, JIA Meng-meng, YANG Jing, YAO Zhi-hong, QIN Zi-fei, ZHANG Xiao-jian, YAO Xin-sheng. Pharmacokinetics and Adverse Reactions Assessment Among Different Dosage Forms of Mycophenolate Applied to Early Kidney Transplant Recipients. Chinese Pharmaceutical Journal, 2020, 55(17): 1460-1469.

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