title: Drug interaction between voriconazole and tacrolimus and its association with the bioavailability of oral voriconazole in recipients of allogeneic hematopoietic stem cell transplantation.
abstract: In a previous study, we noted wide inter-individual variability in drug interactions between voriconazole and tacrolimus, but that analysis did not take into account the routes of administration. In the present study, we analyzed interactions between these two drugs when both agents were administered orally after allogeneic hematopoietic stem cell transplantation (HSCT); the effect of plasma voriconazole levels on the magnitude of the drug interaction was also examined. Twenty-five allogeneic HSCT recipients were evaluated. Trough concentrations of tacrolimus were measured prior to, and periodically for 7-10 days after, initiating voriconazole (400 mg/day) to determine the concentration/dose (C/D) ratio of tacrolimus. The median C/D ratio of tacrolimus increased significantly from 172.8 (range 28.6-1110.7) to 537.5 (range 127.8-1933.3) (ng/mL)/(mg/kg) (P < 0.01) following initiation of voriconazole; the median increase was 138.8 % (range -32.0 to 685.7 %). The plasma concentration of voriconazole did not correlate with the increase of the tacrolimus C/D ratio (ρ = 0.16, P = 0.44). These results indicate that oral voriconazole has a significant drug interaction with oral tacrolimus with a wide inter-individual variability, which cannot be explained by the bioavailability of voriconazole. Other possible mechanisms should be explored in future studies.
authors.affiliation: Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. tmori@a3.keio.jp
authors.forename: Takehiko
authors.initials: T
authors.lastname: Mori
authors.forename: Jun
authors.initials: J
authors.lastname: Kato
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamane
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Sakurai
authors.forename: Sumiko
authors.initials: S
authors.lastname: Kohashi
authors.forename: Taku
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ono
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001682:Biological Availability; D004347:Drug Interactions; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D065819:Voriconazole; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole; D016559:Tacrolimus