Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients
Authors: Satoh Shigeru , Kagaya Hideaki , Saito Mitsuru , Inoue Takamitsu , Miura Masatomo , Inoue Kazuyuki , Numakura Kazuyuki , Tsuchiya Norihiko , Tada Hitoshi , Suzuki Toshio , Habuchi Tomonori 
Published: April 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Circadian variations of tacrolimus pharmacokinetics are controversial.

• Also, the pharmacokinetics has time‐dependent variability, such as a decrease in oral clearance and increase in the dose‐adjusted AUC after transplantation.

• Although the CYP3A5 polymorphism is associated with tacrolimus pharmacokinetics, differences in the influence of this gene on the pharmacokinetics between the early and maintenance stages have not yet been clarified.

WHAT THIS STUDY ADDS

• Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage with our designated‐time administration strategy.

• Based on previous results and our own findings, the interval between food consumption and tacrolimus administration might influence the interindividual and interinstitutional variability of tacrolimus chronopharmacokinetics.

• The CYP3A5 polymorphism may be associated with the time‐dependent changes in tacrolimus oral clearance.

AIMS We investigated whether tacrolimus pharmacokinetics shows circadian variation and the influence of the CYP3A5 A6986G polymorphism on the pharmacokinetics in both the early and maintenance stages after renal transplantation.

METHODS Tacrolimus was administered twice daily at specified times (09.00 and 21.00 h) throughout the pre‐ and post‐transplant period according to the trough‐targeting strategy. Fifty recipients with stable graft function were studied on day 28 and beyond 1‐year post transplantation. Whole blood samples were collected prior to and 1, 2, 3, 4, 6, 9 and 12 h after both the morning and evening doses during hospitalization.

RESULTS Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage [AUC0–12 197.1 (95% confidence interval 182.9, 212.3) in daytime vs. 203.6 ng h ml−1 (189.8, 217.4) in the night‐time at day 28, 102.0 (92.1, 111.9) vs. 107.7 (97.9, 117.5) at 1 year, respectively]. In CYP3A5 *1 allele carriers (CYP3A5 expressers), body weight‐adjusted oral clearance was markedly decreased from the early stage to the maintenance stage [0.622 (0.534, 0.709) to 0.369 l h−1 kg−1 (0.314, 0425)] compared with a smaller decrease [0.368 (0.305, 0.430) to 0.305 (0.217, 0.393)] in CYP3A5 non‐expressers; however, the CYP3A5 genetic variation did not influence tacrolimus chronopharmacokinetics.

CONCLUSION Equivalent daytime and night‐time tacrolimus pharmacokinetics were achieved during both the early and maintenance stages with our specified‐time administration strategy. The CYP3A5 polymorphism may be associated with the time‐dependent changes in the oral clearance of tacrolimus, suggesting that genotyping of this polymorphism is useful for determining the appropriate dose of tacrolimus in both the early and maintenance stages after renal transplantation.