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

BackgroundTacrolimus 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 methodsTwenty-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.ResultsThirteen 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.ConclusionsCYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3060-4) contains supplementary material, which is available to authorized users.

Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation

“…Khaled et al [20] reported that eight recipients with CYP3A5*1/*1 exhibited a significantly higher cumulative rate of grade 2–4 acute GVHD than recipients with CYP3A5*1/*3 ( n = 40) and CYP3A5*3/*3 ( n = 122) within 100 days after HSCT. Yamashita et al [21] reported that recipients with the CYP3A5*1 allele ( n = 11) exhibited a significantly higher cumulative rate of grade 3–4 acute GVHD than those with CYP3A5*3/*3 ( n = 13) within 100 days after HSCT. In this study, although there were three CYP3A5*1/*1 recipients (data not shown), grade 3–4 acute GVHD occurred in only two recipients (data not shown).…”

“…The majority of previous reports on organ transplant recipients show a significant effect of CYP3A5*3 on the pharmacokinetics of tacrolimus [17]. In HSCT recipients, several studies have shown that the concentration/dose (C/D) ratio or trough-blood concentration of tacrolimus is higher in recipients with the CYP3A5*3/*3 genotype than in those with the CYP3A5*1 allele ( *1/*1 and *1/*3 genotypes) and that the required daily dosage of tacrolimus is, thus, significantly reduced [18,19,20,21]. However, reports discussing the utility of information related to CYP3A5 polymorphism at the time of continuous intravenous infusion [18,19,20] and oral administration [21] are limited.…”

Prolonged‐Release Tacrolimus Is Less Susceptible to Interaction With the Strong CYP3A Inhibitor Voriconazole in Healthy Volunteers

“…Tacrolimus is metabolized by CYP3A4 and CYP3A5 and is a substrate of the drug transporter P‐glycoprotein . Patients carrying at least one functional CYP3A5 allele (CYP3A5*1) require approximately twofold higher oral tacrolimus doses than patients homozygous for CYP3A5*3 and appear to be less susceptible to drug–drug interactions with azole antimycotics, which may be explained by stronger inhibition of CYP3A4 than CYP3A5 by azoles . High expression of intestinal ABCB1 messengerRNA (mRNA) (which is translated into P‐glycoprotein) was related to higher dose requirements, but several common ABCB1 polymorphisms were not related to tacrolimus pharmacokinetics, suggesting that P‐glycoprotein is of lesser importance in oral tacrolimus pharmacokinetics.…”

Influence of azole antifungal drugs on blood tacrolimus levels after switching from intravenous tacrolimus to once‐daily modified release tacrolimus in patients receiving allogeneic hematopoietic stem cell transplantation

“…In fact, it has been reported that the blood concentration of tacrolimus (Tac-MR) after co-administration of FLCZ is significantly higher in CYP3A5 non-expressing patients than in those expressing CYP3A5. 19 These findings suggest that the variation in (C iv /D iv )/(C po3-5 /D po3-5 ) ratio in the FLCZ group may be attributable to the isoform selectivity of FLCZ-mediated CYP3A inhibition and interindividual differences in CYP3A5 expression. No such variation was observed in the (C iv /D iv )/ (C po1-2 /D po1-2 ) ratio.…”

“…When these patients take FLCZ together with tacrolimus, the potent inhibition of tacrolimus metabolism by FLCZ would occur due to lack of CYP3A5‐mediated tacrolimus metabolism. In fact, it has been reported that the blood concentration of tacrolimus (Tac‐MR) after co‐administration of FLCZ is significantly higher in CYP3A5 non‐expressing patients than in those expressing CYP3A5 . These findings suggest that the variation in ( C iv / D iv )/( C po3‐5 / D po3‐5 ) ratio in the FLCZ group may be attributable to the isoform selectivity of FLCZ‐mediated CYP3A inhibition and interindividual differences in CYP3A5 expression.…”