title: Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients.
abstract: Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose methotrexate and a macrolide antibiotic (pristinamycin) leading to prolonged methotrexate exposure has been described. Because a randomized prospective trial comparing tacrolimus with cyclosporine (both in combination 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 participants of this trial to evaluate the possibility that an interaction of 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 patients. 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 attributable to pharmacologic interactions with methotrexate.
authors.affiliation: University of Florida College of Medicine, Department of Medicine, Gainesville 32610-0277, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Wingard
authors.forename: R A
authors.initials: RA
authors.lastname: Nash
authors.forename: V
authors.initials: V
authors.lastname: Ratanatharathorn
authors.forename: J W
authors.initials: JW
authors.lastname: Fay
authors.forename: J L
authors.initials: JL
authors.lastname: Klein
authors.forename: D
authors.initials: D
authors.lastname: Przepiorka
authors.forename: R M
authors.initials: RM
authors.lastname: Maher
authors.forename: S M
authors.initials: SM
authors.lastname: Devine
authors.forename: G
authors.initials: G
authors.lastname: Boswell
authors.forename: I
authors.initials: I
authors.lastname: Bekersky
authors.forename: W
authors.initials: W
authors.lastname: Fitzsimmons
mesh_terms: D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D002648:Child; D004347:Drug Interactions; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008727:Methotrexate / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage*; D014184:Transplantation, Homologous
chemical_list: D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D016559:Tacrolimus; D008727:Methotrexate