Comparison of pharmacokinetics and pharmacogenetics of once- and twice-daily tacrolimus in the early stage after renal transplantation.
BACKGROUND
This study investigated pharmacokinetic and pharmacogenetic differences between a modified-release once-daily formulation of tacrolimus (Tac-QD) and the original formulation requiring twice-daily intake (Tac-BID) in de novo renal transplant recipients.


METHODS
Forty-seven and 25 patients who received Tac-BID and Tac-QD, respectively, were enrolled. The pharmacokinetics and CYP3A5 6986A>G and ABCB1 3435C>T pharmacogenetics of each formulation were analyzed on day 28 posttransplantation.


RESULTS
The dose-adjusted trough level (C0) and area under the concentration-time curve (AUC0-24) of tacrolimus were approximately 25% lower for Tac-QD than Tac-BID. However, there was a good correlation between the AUC0-24 and C0 in the Tac-BID and Tac-QD groups (r=0.575, P<0.001; and r=0.638, P<0.001, respectively) and a similar coefficient in each regression equation. The dose-adjusted AUC0-24 was approximately 25% lower in carriers of the CYP3A*1 allele (CYP3A5 expressers), but not individuals with the CYP3A*3/*3 genotype (nonexpressers), for TAC-QD than Tac-BID. In the Tac-QD group, the interpatient variability for dose-adjusted parameters was small, and the interquatile ranges of dose-adjusted parameters differed between CYP3A5 expressers and nonexpressers and did not overlap. The ABCB1 polymorphism was not associated with any pharmacokinetic parameters of Tac-QD.


CONCLUSIONS
C0-guided monitoring may lead to similar AUC0-24 values for both formulations. However, to maintain the same AUC0-24 value, a higher dose of Tac-QD than Tac-BID may be needed, especially for CYP3A5 expressers, in the early stage posttransplantation. The narrow interindividual variability of Tac-QD pharmacokinetics and its difference between CYP3A5 expressers and nonexpressers might contribute to a dosing strategy based on CYP3A5 genotype.
Department of Pharmacy, Akita University School of Medicine, Akita, Japan.
Takenori
T
Niioka
Shigeru
S
Satoh
Hideaki
H
Kagaya
Kazuyuki
K
Numakura
Takamitsu
T
Inoue
Mitsuru
M
Saito
Shintaro
S
Narita
Norihiko
N
Tsuchiya
Tomonori
T
Habuchi
Masatomo
M
Miura
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D012044:Regression Analysis; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus