Cyclosporin C2 and C0 concentration monitoring in stable, long-term heart transplant recipients receiving metabolic inhibitors

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Background: Cyclosporin (CsA) dose selection is complicated by significant pharmacokinetic variability between patients. Although therapeutic drug monitoring (TDM) has proven to be a useful tool for dose individualization, the search for an effective and practical measure of clinical effect has uncovered a number of options. Monitoring the CsA concentration in a blood sample taken 2 hours after the dose (C2) has been utilized but has not been rigorously evaluated in all clinical situations. The aim of this study was to evaluate C2 and trough (C0) CsA concentrations as surrogate markers of area under the concentration-time curve (AUC) in stable, long-term heart transplant recipients receiving CsA alone or with diltiazem and/or ketoconazole. Methods: CsA blood concentration-time data were collected at steady state for 47 stable heart transplant recipients after the morning dose of Neoral. CsA concentration in whole blood was quantitated using the EMIT immunoassay. Patients were stratified into 4 groups, depending on the long-term concomitant administration of drugs known to inhibit CsA metabolism, as part of their routine therapy: Group A (n = 11), CsA alone; Group B (n = 10), CsA with slow-release diltiazem; Group C (n = 13), CsA with ketoconazole; and Group D (n = 12), CsA with a combination of diltiazem and ketoconazole. Results: In Group A, C2 correlated poorly with AUC0-5 (r2 = 0.197; p = 0.17), whereas C0 (trough blood sample) showed a stronger correlation (r2 = 0.710; p = 0.001). Correlations of C0 and C2 with AUC0-5 were the same, but weaker in patients receiving CsA and diltiazem (r2 = 0.650; p = 0.005); however, C2 correlated strongly with AUC0-5 in patients receiving ketoconazole (r2 = 0.870; p < 0.0001) or ketoconazole with diltiazem (r2 = 0.898; p < 0.0001). C0 was a poor predictor of AUC0-5 in the latter 2 groups. Conclusions: C2 showed a strong correlation with AUC0-5 in cardiothoracic transplant recipients receiving CsA with ketoconazole, but not with CsA alone or diltiazem. TDM using C2 as an estimate of AUC requires further evaluation before being applied in long-term, stable cardiac transplant patients, as it may lead to inappropriate dose adjustment of CsA in patients receiving concomitant metabolic inhibitors.

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Journal of Heart and Lung Transplantation