Relationship between gastrointestinal adverse event and plasma concentrations of mycophenolate mofetil in Thai renal transplanted patients

Abstract

To determine the relationship between GAE and MPA plasma concentrations at different sampling time points including MPA AUC. And also to find the minimum optimum sampling time points which could be used for prediction of both. MMF efficacy and GAE toxicity. This study was designed as a prospective unicenter trial. All patients received a triple immunosuppressive regimen (MMF, cyclosporine, and prednisolone) with MMF dosage ranging from 1,000 mg to 2,000 mg daily. Blood samples to create complete plasma concentration-time profiles (9 points) were collected at steady state after the patients who enrolled in the study has been administered with their current dosage regimens. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 3, 4, 6 and 12 hours after MMF dosing Then, the dosage regimen were either increased or decreased 500 mg daily a time per week depended on his/her conditions whether GAE had occurred, MPA AUC reference range and/or 200 mg daily dose had been reached. Each time, after one week, 4-6 blood samples were again collected at 0, 1, 3 and 6 hours or 0, 0.5, 1, 3, 4 and 6 hours after MMF dosing. The MPA concentrations in plasma samples were analyzed using HPLC method. Among the 23 post renal transplanted Thai patients participated in this study, 12 were female. The mean ± SD of age and weight were 43.70 ± 10.02 years and 58.42 ± 9.73 kg, respectively. Mean duration time after renal transplantation was 21.31 ± 14.51 months while mean duration of taking MMF was 20.56 ± 13.66 months. Four patients showed sign of serious GAE while three patients experienced mild GAE. There were relationship between C trough (C0, C12), C peak (C0.25, C0.5, C1) and MPA AUC with GAE. However, C0 might be the most optimum point for routine MMF monitoring to predict the incidence of GAE as compared to C12 (inconvenience to obtained) or C peak (peak time were highly varied among patient) or 12-hours MPA AUC (laborious and expensive to obtain). C0 which were higher than 3 mcg/mL or 5 mcg/mL could result in a high risk of experiencing mild GAE or serious GAE, respectively. In addition, MPA AUC which were higher than 79 or 99 mcg/mL could cause a high risk of experiencing mild GAE or serious GAE, respectively. When prediction of both efficacy and GAE toxicity of MMF were required, 3 or 4 STP models, which could accurately predicted MPA AUC; C0, C0.5 and C1 hours (R 2 = 0.866 and absolute prediction error = 12.060 ± 2.189%) or C0, C0.5 and C1 and C2 hours (R 2 = 0.940 and absolute prediction error = 9.308 ± 1.495%) after MMF dosing, respectively were recommended.