| Objective Mycophenolate mofetil (MMF) is nowadays widely used inorgan transplantation. Just as other immunosurpressive drugs, MMF can cause toxicity as well as prevent acute rejection. It is a crucial step in organ transplantation clinic to use immunosuppressants rationally in order to minimize the risk of organ rejection with acceptable tolerability. The primary goal of clinical pharmacokinetic monitoring (CPM) is to search and select appropriate pharmacokinetic / pharmacodynamic parameters correlated with clinical events and to maintain a proper blood level of the immunosuppressants by tailoring individual dosage leading to the best combination of efficacy and tolerability. This study was designed toinvestigate the relationship between the clinical events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplantation patients.METHODS Twenty- two adult kidney recipients were included in thestudy. From twelve of them, MPA pharmacokinetic profiles (blood sampling at 0, 0.5, 1, 1.5,2, 4, 6,8,10 and 12 h after MMF oral dose) were obtained 1 or 2 days before and 12 days after grafting. Predose blood samples were gathered from all the recipients at 4th, 12th , 21st days and lst,1.5th, 2nd, 2.5th, 3rd, 6th month after grafting. Plasma concentration of MPA was measured by reverse-phase HPLC. Data about clinical events (e.g., side effects or acute rejection)were carefully collected and recorded. All patients received a triple therapy of cyclosporine, MMF and steroids. The initial dosage of MMF was either 1 g twice daily for weight>60kg or 0.75 g twice daily for weight<60kg ,reducing dosage as time progress.RESULTS (1/Thirteen single-dose and thirteen multi-dose MPA pharmacokinetic profiles were obtained. Mean MPA-AUCo-i2 for single-dose study was 31.3524 mg.h/L 1-2 days before grafting and 32.2468mg/L.h for multi-dose study 12 days after grafting. Mean Tpeak for single-dose study was 1.615 h and 1.000 h for multi-dose study. (2) 151 predose blood samples were obtained from the 22 patients in total, MPA-Co value obtained accordingly. A MPA- Co value together with its corresponding clinical events at the same time point were looked as a study unit. The 151 units were divided into three groups (groups 1, 2 and 3)according to the clinic events. One hundred and two units (67.55%;group1) had uneventful outcomes, 43 units (28.48%; group 2) presented with MPA-related toxicity or side effects, and 6 units (3.97%; group 3) experienced acute allograft rejection. (3) For groups 1 and 2, mean MPA-C0 were 0.8866 + 0. 1063 and 1.5114 + 0. 2784mg/L, respectively (P <0.001). By ROC analysis, C0 of 1.0800mg/L had a diagnostic sensitivity of 62.8 % and a diagnostic specificity of 78.7% for discrimination of units with adverse reaction. (4) For groups 1 and 3, mean MPA-Co were 0.8866±0. 1063 and 0.5305± 0.2883mg/L, respectively (P = 0.022). By ROC analysis, Co of 0.5900 mg/L had a diagnostic sensitivity of 83.3%and a diagnostic specificity of 74.5% for discrimination of units with acute rejection.(5) We also divided the 151 units into initial phase(<1 month, 78 units) and stable phase(>l month, 73 units), and subsequently devided again the units of each phase into three subgroups (groups 1 ,2 and 3)according to the clinic events in order to minimize the bias due to the deferent post-operative time. For subgroups 1 and 2 in initial phase, mean MPA-Co were 0.9710± 0. 1366 and 1.5877 ± 0. 4224 mg/L, respectively (P<0.001). The discrimination threshold of adverse reaction for Co in initial phase was 1.095mg/L with a sensitivity of 63.6%and a specificity of 73.2%. For subgroups 1 and 3 in stable phase, mean MPA-Co were 0.9710 ±0.1366 and 0.5586?.3692 mg/L, respectively (P = 0.022).The discrimination threshold of acute rejection for Co in initial phase was 0.5950mg/L with a sensitivity of 80%and a specificity of 83.60%. For subgroups 1 and 2 in stable phase, the mean MPA-C0 were 1.5709± 0.4744 and 0.7294 ± 0. 1115mg/L, respectively (P <0.001). The discrimination threshold of adverse reaction...
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