Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral®) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption

Background: There are important differences in CsA pharmacokinetics between adult and pediatric patients, such that pharmacokinetic data can not necessarily be extrapolated from the adult to the pediatric setting. Research in adult renal transplant patients has shown that adequate cyclosporin exposure (AUC(0-4) ) in the first week post-transplant is important for successful clinical outcome, and that cyclosporin concentration at 2 h post-dose (C-2 ) provides the optimal single-time point marker for AUC(0-4) . Clinically, dose management based on C-2 level results in a low incidence of acute rejection in the adult renal transplant population. The study reported here undertook pharmacokinetic profiling in de novo renal transplant patients over a period of 6 months and retrospectively assessed alternative monitoring strategies based on pharmacokinetic findings and clinical outcomes. Methods: This open-label, observational, prospective study was carried out at four UK transplant centers over a period of 6 months in pediatric de novo renal transplant recipients receiving the microemulsion formulation of cyclosporin (Neoral((R)) ) according to local protocol. Twelve-hour pharmacokinetic profiles (8-16 blood samples each) were performed on days 5 and 14 and at weeks 4, 13 and 26 post-transplant. Results: Thirty-two patients were recruited (median age 10 yr, range 3-18 yr). At 6 months, patient survival was 100% and graft survival was 91%. The incidence of clinically determined acute rejection was 41% (13 of 32). Six patients discontinued Neoral before 6 months: three due to graft loss, one due to rejection, one due to renal toxicity and one due to hypertrichosis. At all time points studied, C-2 correlated more closely with AUC(0-4) and with AUC(0-12) than did the pre-dose cyclosporin concentration (C-0 , or trough). Patients achieving C-2 > 1.5 mu g/mL by the fifth postoperative day experienced no acute rejection in the first 6 months, compared with a 50% rejection rate among patients with C-2 < 1.5 mu g/mL (P < 0.05). Binary logistic regression analysis showed that C-2 level >1.7 mu g/mL was associated with approximately 90% probability of freedom from acute rejection. Analysis of renal function across patients grouped according to cyclosporine exposure (AUC(0-4) , C-2 ) showed no adverse effects of higher/increased exposure on creatinine or GFR. Conclusions: C-2 level provides a more reliable marker for CsA exposure than C-0 in pediatric renal transplant recipients, and is more closely predictive of acute rejection risk. A C-2 target of 1.7 mu g/mL appears appropriate in this population during the immediate post-transplant period in order to maximize clinical benefit.