Pharmacokinetic Study of the Combination of Tacrolimus and Fluconazole in Renal Transplant Patients
Dusit Lumlertgul MD*, Khajornsakdi Noppakun MD*, Noppamas Rojanasthien MD**, Kittika Kanchanarattanakorn MD***, Suparoek Jittikanont MD*, Amara Manoyot MD*, Derek Bunnachak MD*, Vuddhidej Ophascharoensuk MD*
Affiliation : * Renal Division, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai ** Division of Clinical Pharmacology, Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai *** Medical Education Section, Faculty of Medicine, Chiang Mai University, Chiang Mai
Background : It was hypothesized that fluconazole in combination with tacrolimus can be used safely with an
imitated area under curve (AUC) compared to tacrolimus. At every time point, this combination was presumed
to correlate well with pre-intervention AUC, thus the dosage could be significantly reduced.
Materials and Methods : There were two groups of patients. Group I (n = 15) included patients who received
tacrolimus at 0.1-0.3 mg/kg/day within one week after transplantation. These patients were studied for
tacrolimus whole blood concentrations. The tacrolimus dosage was then reduced by 40% and given in
combination with fluconazole at 100-200 mg/day for one week, tacrolimus whole blood concentrations were
studied again. Group II (n = 8) included patients who had been transplanted for more than 3 months and had
received a stable dosage of tacrolimus in combination with fluconazole for at least one month.
Results : In group I, before fluconazole combination, trough levels correlated well with AUC0-12. After
fluconazole combination, trough levels still correlated well with AUC0-12. The after/before fluconazole-
combination ratio of AUC0-12 and maximum tacrolimus concentration (Cmax) was 1.08 (90%CI; 0.98-1.19)
and 1.17 (90%CI; 1.00-1.36), respectively. Correspondingly, the oral bioavailability, which was the after/
before fluconazole combination ratio of AUC0-12/dose and absorption rate (Cmax/dose/body weight), was
significantly increased [2.08 (90%CI; 1.80-2.40) and 2.24 (90%CI; 1.99-2.51), respectively]. Tacrolimus
clearance after the fluconazole combination was significantly reduced, compared with before the combina-
tion (14.74 vs 38.79 L/h, p = 0.001). Mean tacrolimus dosage in this group could be reduced from 10.7 mg/day
before fluconazole combination to 5.7 mg/day after it and to 3.7 mg/day at 3 months after transplantation
(p = 0.001). In group II, trough levels correlated well with AUC0-12 and the mean tacrolimus dosage in this
group was only 2.9 mg/day.
Conclusion : This present study showed a good correlation between tacrolimus trough levels and AUC, which
occurred in monotherapy or in patients who received fluconazole. The tacrolimus trough levels could be
trusted in monitoring patients who received a tacrolimus-based immunosuppressive regimen. The combina-
tion to fluconazole was ascertained and it was safe to reduce the dose of tacrolimus.
Keywords : Tacrolimus, Fluconazole, Renal transplant
