Pharmacokinetic evaluation of the drug interaction between intravenous itraconazole and intravenous tacrolimus or intravenous cyclosporin A in allogeneic hematopoietic stem cell transplant recipients

Abstract

A single-institution, open-label prospective pharmacokinetic evaluation of the interaction between intravenous itraconazole and intravenous cyclosporin A and tacrolimus was conducted in allogeneic hematopoietic stem cell transplant recipients. The study was conducted in 2 phases, with patients acting as their own controls. In phase 1, steady-state concentrations and clearance of cyclosporin A and tacrolimus administered alone were evaluated. Phase 2 evaluated serum concentrations and clearance of cyclosporin A and tacrolimus under the influence of itraconazole therapy. Among 17 patients who completed both phases of the study, the mean increase in the serum tacrolimus concentration was 83% (P<.0001), and the mean increase in the serum cyclosporin A concentration was 80% (P=.0001). There was no correlation between serum itraconazole concentrations and the serum concentrations of tacrolimus or cyclosporin A. The drug interaction between itraconazole and calcineurin inhibitors is predictable and occurs within 48 hours of concomitant drug administration. The data suggest that dose reductions of tacrolimus and cyclosporin A in the range of 50% to 100% are necessary when itraconazole therapy is initiated and that subsequent close monitoring of serum concentrations is necessary to guide further dose modifications.