Large within-day variation in cyclosporine absorption: circadian variation or food effect?

With the recent focus of monitoring cyclosporine (CsA) therapy using measures of CsA absorption, it is important to understand published reports of diurnal variation in CsA exposure. In 10 renal transplant patients, CsA concentrations were measured 0, 1, 2, 3, and 4 h after both the morning and the evening doses and in a repeat session at least 1 wk later. Both area under the curve for the final 4 h after cyclosporine dose and cyclosporine concentrate 2 h after the cyclosporine dose were more than two-fold higher after the morning dose in both sessions. Because the morning levels were collected in a fasted condition and the evening ones in a fed condition, the study was extended to collect evening levels after fasting. The area under the curve for the final 4 h after cyclosporine dose and cyclosporine concentrate 2 h after the cyclosporine dose values observed now were comparable to the morning fasted values. That the large diurnal variation was due to variation in food consumption, as opposed to a biologic circadian rhythm affecting CsA absorption, has significant implications for therapeutic drug monitoring.

Negative impact of new-onset diabetes mellitus on patient and graft survival after liver transplantation: Long-term follow up.

BACKGROUND: Little is known about the long-term consequences of new-onset diabetes mellitus (NODM) after liver transplantation (LTX). METHODS: In a chart review between 1996 and 2004, we evaluated its incidence and possible effect on patient and graft survival. Inclusion criteria were: adult primary LTX; deceased donor LTX without combined organs; and dual immunosuppression with tacrolimus and corticosteroid. Patients who died within six months after LTX were excluded. For analytical purposes, each patient was classified into one of four groups: 1) preLTX diabetes mellitus (DM): established DM before LTX; 2) sustained NODM: NODM sustained > or =6 months; 3) transitory NODM: NODM temporarily existed > or =1 and <6 months; and 4) normal: no DM either pre- or postLTX. Patients who had NODM <1 month due to high-dose steroid (e.g., either immediate postLTX or rejection treatment) were considered as normal. Patient and graft survival was examined using Kaplan-Meier methodology. RESULTS: In all, 778 patients met the inclusion/exclusion criteria: preLTX DM 159 (20.4%), sustained NODM 284 (36.5%), transitory NODM 108 (13.9%), and normal 227 (29.2%). Median follow-up was 57.2 months. There was a significant difference in patient (P = 0.012) and graft survival (P = 0.004) among the groups, with sustained NODM showing the poorest patient and graft survivals. Sustained NODM patients had a significantly higher rate of death due to infection, as well as graft failure due to chronic rejection and late onset hepatic artery thrombosis. CONCLUSION: NODM is a frequent complication with poor patient and graft survival after LTX.

A multicenter, prospective study of C2-monitored cyclosporine microemulsion in a U.S. population of de novo renal transplant recipients.

BACKGROUND: Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2) has been reported to optimize the efficacy and safety of CsA-ME therapy. The addition of induction therapy to a maintenance regimen including CsA-ME C2 monitoring has not been evaluated. METHODS: In all, 123 adult renal transplant recipients were recruited at 14 U.S. centers for this 6-month study. CsA-ME dose was to be titrated to attain C2 targets of 1700 and 1500 ng/ml during posttransplant months 1 and 2, respectively. After 2 months, patients were randomized to one of two groups with different, decreasing C2 targets. Basiliximab, mycophenolate mofetil, and corticosteroids completed the study immunosuppression. RESULTS: Of the 119 evaluable patients, 76% were male, 22% African American, and 66% deceased donor recipients. Biopsy-proven acute rejection occurred in 10 patients (9.3%); there were two failed grafts and one death. Serum creatinine and calculated GFR values suggest good renal function, with month 6 medians of 1.5 ng/ml and 67 ml/min/1.73 m. Safety and tolerability assessments revealed no unexpected outcomes. Observed C2 levels were generally lower than protocol targets, particularly in the first weeks posttransplantation. CONCLUSIONS: The striking efficacy and outcomes may have been achieved in this study with lower C2 levels of CsA-ME because of the addition of basiliximab induction.

Two-hour post-dose cyclosporine level is a better predictor than trough level of acute rejection of renal allografts.

Cyclosporine (CyA) trough concentrations are poor predictors for acute rejection post-transplant. Patients were part of a randomized trial of basiliximab (n=70) vs. anti-thymocyte globulin (ATGAM) (n=65), both in combination with Neoral, mycophenolate mofetil, and steroids, undergoing first or second, cadaveric or live donor renal transplants. Whole blood samples were collected just before (C0) and at 2 h after CyA dosing on day 4 and at the end of weeks 1, 2, 4, and 8. The CyA was measured by fluorescence polarization immunoassay (TDx). Mean CyA C0 and C2 concentrations were calculated. Logistic regression analysis revealed that mean C2 level was the only predictor of acute rejection (P < or = 0.001). Higher mean C2 levels predicted lower rejection probabilities. Linear regression analysis revealed that higher mean C2 levels were not related to higher serum creatinine levels at either week 4 or 24 or to incidence of headache or tremor. The CyA C2 levels predict the frequency of rejection postrenal transplant. Target C2 levels are in the range of 1500 ng/dL.