Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation

Abstract

Background: Tacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).

Design and methods: Twenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.

Results: Thirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele.

Conclusions: CYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.

Keywords: Azole antifungal agent; CYP3A5 polymorphism; Hematopoietic stem cell transplantation; Once-daily tacrolimus formulation; Pharmacokinetics.

Fig. 1

Comparison of doses (box and whiskers plots) and the tacrolimus trough levels (open circles) between the CYP3A5*1*1 + *1/*3 group and the *3/*3 group. a Before co-administration of AZ and b after co-administration of AZ. Graphical analysis was performed using an SPSS box and whiskers plot. The box spans data between two quartiles (IQR), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. The gray circles represent the outlier of dose. AZ azole antifungal agent

Fig. 2

Comparisons of the tacrolimus trough levels according to the presence or absence of a co-administered AZ. Circles fluconazole; triangles voriconazole; boxes itraconazole; closed figures patients with AKI. AZ azole antifungal agent, AKI acute kidney injury

Fig. 3

Cumulative incidence of dose attenuation of tacrolimus from baseline (<50 %) after co-administration of AZ. Solid line, CYP3A5*1*1 + *1/*3; dotted line, CYP3A5*3/*3. Median time to reduction in tacrolimus dosage was 8.0 days in the CYP3A5*3/*3 group and not reached in the CYP3A5*1*1 + *1/*3 group. AZ azole antifungal agent