Total and free mycophenolic acid and its 7-O-glucuronide metabolite in Chinese adult renal transplant patients: pharmacokinetics and application of limited sampling strategies

Abstract

This study aimed to investigate the pharmacokinetic characteristics of total and free mycophnolic acid (MPA) and its 7-O-glucuronide metabolite (MPAG) in Chinese renal transplant recipients. In addition, limited sampling strategies were developed to estimate the individual area under concentration curve (AUC) of total and free MPA. Total and free MPA and MPAG concentrations were determined by high performance liquid chromatography. Whole 12-h pharmacokinetic profiles were obtained on the 10th day after operation in 12 adult Chinese de novo renal transplant recipients administrated with mycophenolate mofetil (MMF, 750 mg bid), cyclosporine and corticosteroids. Limited sampling strategies with jackknife technique, a resampling method, and Bland-Altman analysis were employed to develop equations to estimate total and free MPA AUC. The pattern of total and free MPA and MPAG plasma concentration-time curves in the cohort of patients taking lower doses of MMF was consistent with previous reports of Caucasian patients taking MMF 1 g bid, except that dose-normalized exposure of total and free MPAG was much lower in the current study than in those of the Caucasians. The mean C (max) and AUC(0-12h) of total and free MPA were 9.4 +/- 3.4 mg/L, 20.2 +/- 6.5 mg x h/L and 0.4 +/- 0.4 mg/L, 0.7 +/- 0.5 mg x h/L, respectively, whereas mean C (max) and AUC(0-12h) of total and free MPAG were 97.3 +/- 32.6 mg/L, 656.0 +/- 148.0 mg.h/L and 29.9 +/- 8.5 mg/L, 222.0 +/- 58.1 mg x h/L respectively. The mean fractions of free MPA and MPAG were 3.5 +/- 2.0 and 34.6 +/- 8.0%, respectively. No determinant was identified to influence the pharmacokinetics of total and free MPA and MPAG or the free fraction of MPA and MPAG. The combinations of C (2h)-C (4h) and C (1h)-C (2h)-C (3h) were the best to estimate free and total MPA AUC(0-12h) respectively, whereas the combination of C (2h)-C (3h)-C (4h) and C (1h)-C (2h)-C (4h) was the best to estimate both simultaneously. This is the first time that the pharmacokinetics profile of total and free MPA and its main metabolite MPAG has been examined in Chinese adult renal transplant patients. The limited sampling strategies proposed to estimate individual free and total MPA AUC could be useful in optimizing patient care.