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

Pharmacokinetics and Adverse Reactions Assessment Among Different Dosage Forms of Mycophenolate Applied to Early Kidney Transplant Recipients

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500,750,1000 mg)、吗替麦考酚酯分散片(赛可平,MMF-T)(给药剂量分别为500,750,1000 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AUC0-12 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1.0~3.0μg·mL^-1;平均ρmax在4~12μg·mL^-1之间,相应的tmax基本维持在1~3 h;各组别半衰期t1/2基本在4~9 h以内;除MMF-T组的AUC0-12 h小于30μg·h·mL^-1,其余3组的AUC0-12 h基本维持在治疗窗30~60μg·h·mL^-1内。MMF和MMF-T均在500~1000 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AUC0-12 h呈非线性关系,而AUC0-12 h与ρ0,ρmax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AUC0-12 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(500~1000 mg,bid),MMF-T组(500~1000 mg,bid),MMF-DT组(500~750 mg,bid)和EC-MPS组(360~900 mg,bid)的药物剂量与AUC0-12 h呈非线性关系,AUC0-12 h值基本一致;AUC0-12 h与ρ0,ρmax之间相关性一般;治疗窗范围内不良反应出现例数较少。

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 1000 mg,respectively),mycophenolate mofetil dispersible tablets(Saikeping,MMF-T)(500,750 and 1000 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 meanρ0 values(1 to 3μg·mL^-1)among four dose groups.Theρmax values were between 4 and 12μg·mL^-1,and their respective tmax values ranged from 1.0 to 3.0 h.Their t1/2 values were between 4 and 9 h.In addition,the AUC0-12 h values for MMF-T group were less than 30μg·h·mL^-1,while AUC0-12 h values for other three groups fall in the therapeutic window of MPA(30 to 60μg·h·mL^-1).Furthermore,power regression results indicated that dose proportionality of AUC0-12 h was nonlinear,and the correlation of AUC0-12 h andρ0,ρmax were not conclusively linear(r=0.591 to 0.817,P<0.01)for MMF,MMF-T,MMF-DT and EC-MPS groups within 500-1000 mg(bid),500-1000 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 AUC0-12 h values of MPA were less than 30μg·h·mL^-1 or over 60μg·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 AUC0-12 h for MMF group(500-1000 mg,bid),MMF-T(500-1000 mg,bid),MMF-DT(500-750 mg,bid)and EC-MPS group(360-900 mg,bid),and their AUC0-12 h values are similar for different groups.There is inconclusively linear correlation between AUC0-12 h andρ0,ρmax.There are few cases of adverse reactions in therapeutic window of MPA.