The Clinical and Economic Potential of Cyclosporin Drug Interactions

Abstract

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.

Drug-Metabolizing Enzyme Inhibition by Ketoconazole Does Not Reduce Interindividual Variability of CYP3A Activity as Measured by Oral Midazolam

“…Martin et al (1999) evaluated the use of ketoconazole as an inhibitor of cyclosporine to reduce the dose and thus the cost of therapy. Tham et al (2006) investigated the use of ketoconazole to reduce variability in clearance of midazolam and docetaxel.…”

“…Some studies have explored the use of potent CYP3A inhibitors such as the imidazole antifungal agent ketoconazole to increase exposure of drugs such as in cyclosporine at reduced doses. Usually, the intention of P450 inhibition in these studies has been to allow use of smaller doses and thereby decrease cost (Martin et al, 1999). However, investigation of the effect of inhibition on interindividual variability has not been well established.…”

Legemiddelinteraksjoner og immunsuppresjon hos organtransplanterte

“…Kalsiumantagonistene diltiazem og verapamil hemmer også CYP3A4 og P-gp og kan forårsake betydelig forhøyede konsentrasjoner av CNI og mTORi (9,(15)(16)(17). På en annen side kan enkelte kalsiumantagonister (f.eks.…”

“…Rifampicin induserer uttrykket av glukuronosyltransferaser slik at glukuronideringen av mykofenolat øker (36,46). Fenobarbital, fenytoin, karbamazepin (7) Rifampicin (6,7,10) Erytromycin, klaritromycin (6-10, 13, 14) Johannesurt (Hypericum perforatum) 1 (6) Diltiazem, verapamil (6)(7)(8)(9)(10)(15)(16)(17)(18) Indinavir, ritonavir (6,8) Grapefruktjuice 2 (8,9) Ciklosporin ⇒ økt systemisk nivå av sirolimus og everolimus (10,19) Orlistat ⇒ redusert absorpsjon og systemisk nivå av ciklosporin 3 (20) Sirolimus, everolimus ⇒ økt lokalt nivå av ciklosporin og takrolimus i nyrevev kan gi økt nefrotoksisitet (21) 1 Naturlegemiddel 2 Naeringsmiddel 3 Ikke relatert til induksjon av CYP3A4 eller P-gp…”

Long-term follow-up of co-administration of diltiazem and cyclosporine in Chinese kidney transplant recipients

“…Randomized trials of co-administration of cyclosporine and diltiazem in transplant patients show the significant reduction of daily dose of cyclosporine but this reduction has not resulted in any observed side effect including patient survival, graft rejection, or other complications. 8,9 However, these studies are designed generally with small sample size, short-term follow-up, and most in developed countries. Longterm outcome of this combination with a large sample size has rarely been observed in developing countries.…”