Pharmacokinetics and Adverse Reactions Assessment Among Different Dosage Forms of Mycophenolate Applied to Early Kidney Transplant Recipients
- VernacularTitle: 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
- Author:
Qi-Wen ZHANG
1
Author Information
- Publication Type:Journal Article
- Keywords: Adverse reactions; Dose dependence; Early renal transplantation; Mycophenolate drug; Pharmacokinetics
- From: Chinese Pharmaceutical Journal 2020;55(17):1460-1469
- CountryChina
- Language:Chinese
- 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.
