The clinical and economic potential of cyclosporin drug interactions.

The introduction of cyclosporin significantly improved solid organ transplantation outcomes. However, the costs associated with immunosuppressive therapy increased from approximately $US1000 to $US2000 per patient per year with azathioprine (AZA) and prednisone to $US5000 to $US8000 per patient per year with the addition of cyclosporin (1997 values). Because of the financial demands placed on medical care in the current era, research has been directed towards developing drug combinations which potentiate the therapeutic effect of cyclosporin whereby reducing the amount of drug administered and consequently the costs of long term immunosuppressive therapy. To date, many drugs that interact with cyclosporin have been recognised. Included in this list are the azole antifungal drugs, ketoconazole, fluconazole and itraconazole; the calcium channel blockers, diltiazem, verapamil and nicardipine; and the macrolide antibacterials, erythromycin and related compounds. Although all of these drugs increase cyclosporin drug concentrations when used concomitantly, ketoconazole and diltiazem appear to be the best candidates on the basis of reducing financial pressures of chronic immunosuppressive therapy without sacrificing patients' well-being. Studies of various regimens involving the combined use of ketoconazole and cyclosporin have shown that cyclosporin dosages can be reduced by approximately 70 to 85% while maintaining therapeutic blood concentrations in renal, cardiac and liver transplant recipients. The calcium channel blocker, diltiazem, allows a decrease in cyclosporin dosage by approximately 30 to 50% in this same group of organ transplant patients. These reductions in cyclosporin dosage have been achieved with no reported severe adverse effects that would discourage the use of these agents concurrently in practice. The combined use of cyclosporin and ketoconazole or diltiazem could reduce medication costs by approximately $US915 to $US3000 per year per patient. If all patients treated with cyclosporin are considered, these combinations could reduce medication costs by hundreds of millions of dollars per year in the US alone. While these are promising approaches, further characterisation of these drug interactions is necessary before this practice is adopted as standard protocol worldwide. The objective of this paper is to review the clinical and economic potential of cyclosporin-sparing agents such as the azole antifungal drugs and calcium channel blockers in an attempt to decrease the costs associated with this expensive immunosuppressive agent.

Are surveillance endomyocardial biopsies necessary during OKT3 induction therapy?

BACKGROUND: To determine the utility of surveillance endomyocardial biopsies (EMBs) during a 14-day OKT3 induction course after cardiac transplantation, histologic results of the first two EMBs were retrospectively reviewed. METHODS: Seventy-three consecutive cardiac transplant recipients who received an OKT3-based quadruple sequential immunosuppressive protocol were analyzed. Patients were predominantly white (85%) and male (72%), with ischemic cardiomyopathy (54%) and a pretransplant panel-reactive antibody level of <10% (93%). RESULTS: The first EMB in 73 patients demonstrated no rejection in 70 patients (96%) and grade 1A rejection in 3 patients (4%). The second EMB showed no rejection in 64 patients (88%), grade 1A or 1B rejection in 8 patients (11%), and grade 3A rejection without hemodynamic compromise in only 1 patient (1%). Absolute CD3+ cells remained below 25 lymphocytes/mm3, and mean trough OKT3 serum levels exceeded 500 ng/ml throughout the 14 days of therapy, demonstrating the immunosuppressive efficacy of OKT3. Posttransplant echocardiograms showed normal left ventricular systolic function. CONCLUSIONS: Since 145 of 146 EMBs (99%) demonstrated no or minimal allograft rejection, a large cost savings could be realized if EMBs were performed only when clinically indicated during the 14-day OKT3 induction course in cardiac transplant recipients. Appropriate immunologic monitoring and echocardiographic testing may obviate the need for performing costly EMBs during OKT3 induction without an adverse clinical outcome.