BTS Report 2014: Impact of cytochrome P450 genetic polymorphisms on tacrolimus pharmacokinetics, oral presentations

by Maria Dalby – Genetic polymorphisms are known to influence the pharmacokinetics of tacrolimus and may thus have a significant impact on the clinical outcome. Studies of these genetic polymorphisms have been carried out predominantly in renal transplant patients; however, the cytochrome P450 isoenzyme CYP3A5 which has been shown to have the greatest effect on tacrolimus pharmacokinetics is primarily expressed in the liver. Stuart Falconer and colleagues at the University of Edinburgh Transplant Unit hypothesised that it may be the case that the donor, rather than recipient genotype is playing the most important role in this respect. A total of 121 patients undergoing liver transplantation between 2007 and 2012 were included in the study. Donors and recipients were genotyped for single nucleotide polymorphisms of ABCB1 exon 26 (3435C>T), CYP3A5 (6986A>G) and CYP3A4 intron 6 (CYP3A4*22). The tacrolimus dose and trough levels were evaluated during the first month and at 3, 6 and 12 months post-transplant and correlated with clinical outcomes including acute rejection, survival, and side effects. The results of the analysis showed that patients receiving a liver from a heterozygote CYP3A5*3/*1 (GA) donor required significantly higher tacrolimus doses and had a significantly lower concentration/dose ratio (0.771 vs 2.10; p<0.01) throughout the first year of follow-up. Donor CYP3A5*3/*1 expression also increased the time to reaching therapeutic drug levels (p=0.02), and recipients of livers from donors with CYP3A5 *3/*1 genotype had a significantly higher incidence of biopsy proven acute rejection (p=0.0001) compared with the *3/*3 genotype.  Neither donor ABCB1 or CYP3A4*22 nor any recipient polymorphisms affected either tacrolimus pharmacokinetics or the clinical outcome. The investigators concluded that it is indeed donor rather than recipient expression of the *1 (A) allele of CYP3A5 that reduces tacrolimus exposure, which affects tacrolimus dose requirements and initial tacrolimus levels and increases the incidence of acute rejection.

The impact of genetic polymorphisms on tacrolimus dose requirements post-transplantation was the subject of a study carried out at St George’s Hospital Medical School in London by Jennifer Jardine and co-workers. The background for this study was findings that a dosing regimen based on predicted CYP3A5 expression did not improve the number of patients achieving target tacrolimus levels within three days of starting treatment, and the aim of the study was to determine the role of single nucleotide polymorphisms  CYP3A4*22 and POR*28 for post-transplant tacrolimus dose requirements. Out of a total of 174 patients analysed, 10 (5.6%) carried CYP3A4*22 (mutant CT genotype which predicts reduced CYP3A4 activity) and were found to have significantly higher tacrolimus concentrations at day 7 post-transplant compared with patients with the wild-type genotype (mean 13.4 vs 9.2ng/ml; p<0.05). A total of 82 patients (48%) were carriers for POR*28 which has been associated with increased tacrolimus dose requirement; however, POR*28 expression did not affect tacrolimus concentrations at day 7 post-transplant. The investigators concluded that CYP3A4*22 was capable of predicting initial tacrolimus dose requirements and that this assay may add value to the generation of algorithms for optimising tacrolimus dosing post-transplant.