The clinical and economic potential of cyclosporin drug interactions

The introduction of cyclosporin significantly improved solid organ transpla ntation outcomes. However, the costs associated with immunosuppressive ther apy increased from approximately $US1000 to $US2000 per patient per year wi th 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 drugs combinations which pot entiate the therapeutic effect of cyclosporin whereby reducing the amount o f drug administered and consequently the costs of long term immunosuppressi ve therapy. To date, many drugs that interact with cyclosporin have been re cognised. Included in this list are the azole antifungal drugs, ketoconazol e, fluconazole and itraconazole; the calcium channel blockers, diltiazem, v erapamil and nicardipine; and the macrolide antibacterials, erythromycin an d related compounds. Although all of these drugs increase cyclosporin drug concentrations when used concomitantly, ketoconazole and diltiazem appear t o be the best candidates on the basis of reducing financial pressures of ch ronic 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 approxima tely 70 to 85% while maintaining therapeutic blood concentrations in renal, cardiac and liver transplant recipients. The calcium channel blocker, dilt iazem, allows a decrease in cyclosporin dosage by approximately 30 to 50% i n this same group of organ transplant patients. These reductions in cyclosp orin 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. I f all patients treated with cyclosporin are considered, these combinations could reduce medication costs by hundreds of millions of dollars per year i n the US alone. While these are promising approaches, further characterisat ion 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 potentia l of cyclosporin-sparing agents such as the azole antifungal drugs and calc ium channel blockers in an attempt to decrease the costs associated with th is expensive immunosuppressive agent.