Pharmacokinetics and Adverse Reactions Assessment Among Different Dosage Forms of Mycophenolate Applied to Early Kidney Transplant Recipients / 中国药学杂志

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 ρmax values were between 4 and 12 μg•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 30 μg•h•mL-1, while AUC0-12 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 AUC0-12 h was nonlinear, and the correlation of AUC0-12 h and ρ0, 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 500-1 000 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 AUC0-12 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 AUC0-12 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 AUC0-12 h values are similar for different groups. There is inconclusively linear correlation between AUC0-12 h and ρ0, ρmax. There are few cases of adverse reactions in therapeutic window of MPA.