PURPOSE: The pharmacokinetics of orally administered immediate-release, twice-daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients. METHODS: Ninety-seven Japanese renal transplant patients (47 patients on tacrolimus BID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration-time curve from 0 to 24 h (AUC0-24) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient. RESULTS: The median (quartile 1-quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3-10.7 %) and 15.4 % (11.5-18.7 %), respectively] than for the tacrolimus BID group [12.6 % (9.9-14.2 %) and 19.3 % (16.5-24.8 %), respectively] (P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC0-24 of tacrolimus in patients on continuous intravenous infusion (P = 0.906). CONCLUSION: The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing.
PURPOSE: The pharmacokinetics of orally administered immediate-release, twice-daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients. METHODS: Ninety-seven Japanese renal transplant patients (47 patients on tacrolimusBID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration-time curve from 0 to 24 h (AUC0-24) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient. RESULTS: The median (quartile 1-quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3-10.7 %) and 15.4 % (11.5-18.7 %), respectively] than for the tacrolimusBID group [12.6 % (9.9-14.2 %) and 19.3 % (16.5-24.8 %), respectively] (P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC0-24 of tacrolimus in patients on continuous intravenous infusion (P = 0.906). CONCLUSION: The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing.
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