LACK OF INTERACTION BETWEEN TACROLIMUS (FK506) AND METHOTREXATE IN BONE-MARROW TRANSPLANT RECIPIENTS

Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose met hotrexate and a macrolide antibiotic (pristinamycin) leading to prolon ged methotrexate exposure has been described, Because a randomized pro spective trial comparing tacrolimus with cyclosporine (both in combina tion with methotrexate) following allogeneic BMT showed the tacrolimus plus methotrexate regimen to be more effective in prevention of GVHD, we assessed methotrexate pharmacokinetics in a subgroup of the partic ipants of this trial to evaluate the possibility that an interaction o f FK506 and methotrexate was the explanation for the clinical findings . Mean and median methotrexate levels at various time-points after the day 1 and 6 methotrexate doses were comparable in the tacrolimus and cyclosporine cohorts and were elevated in only three of 70 study patie nts. Area under the curve (AUC) concentrations were also similar after the day 1 and 6 methotrexate doses, Thus, no significant interaction between tacrolimus and methotrexate is apparent and the differences in efficacy between tacrolimus and cyclosporine are unlikely to be attri butable to pharmacologic interactions with methotrexate.