Influences of Donor and Recipient Gene Polymorphisms on Tacrolimus Dosing and Pharmacokinetics in Asian Liver Transplant Patients

Abstract

Background: Tacrolimus pharmacokinetics has large inter-individual variability. Objectives: This study aimed to investigate the impact of donor and recipient gene polymorphisms on tacrolimus dosing and pharmacokinetics in Asian liver transplant patients. Methods: Steady-statetacrolimus concentrations at 0, 1, 2, 4 and 6 h were measured. Pharmacokinetic parameters were estimated with a one-compartment linear model using WinNonlin 6.1 program. DNA from donor liver and recipient blood samples were genotyped for CYP3A and ABCB1 polymorphisms. 3) (64.48 versus 129.21 (mcg/L)/(mg/kg/day), P = 0.040). Hence, the dose required to achieve target concentration in patients with donor genotype CYP3A5 expressors was higher than non-expressors (0.12 versus 0.08 mg/kg, P = 0.045). Recipient with ABCB1-C3435T genotype TT demonstrated higher apparent oral clearance of tacrolimus as compared to genotype CC (17.7 versus 7.9 L/h, P = 0.033). Conclusions: Donor liver CYP3A polymorphism could potentially affect tacrolimus C0/D ratio as early as the first week post liver transplant. Genotyping of liver donors may be useful to achieve the optimal drug concentration during this critical period.

Meta-analysis and systematic review of the effect of the donor and recipient CYP3A5 6986A>G genotype on tacrolimus dose requirements in liver transplantation

“…Six studies analyzed the tacrolimus C/D ratio versus the donor genotype [21][22][23][24][25][26], whereas four studies analyzed the parameter versus the recipient genotype [21,22,25,27]. The studies globally included 254 and 180 patients, respectively.…”

“…Patients were followed up for 1 week in five studies [21,[23][24][25][26], 2 weeks in five studies [21,23,[25][26][27], one month in five studies [21-23,25,26], 3 and 6 months in two studies [21,22], and 9 and 12 months in one study [21]. Six studies were published in English and one in Chinese.…”

“…Two other studies omitted information on outcomes and methods, but these data were obtained by contacting the author in one case [27]. The author of the other incomplete study did not provide these data, thus the missing information (setting range of tacrolimus) was imputed [24].…”

“…Only in one study [24] were we unable to determine whether the cohorts were representative and selected from the same community. Methodological details were obtained or deduced from most studies.…”

Long-term outcome of ketoconazole and tacrolimus co-administration in kidney transplant patients

“…However, this correlation varies considerably and the best sampling time for a spot tacrolimus level to predict its total body exposure remains controversial [2,3,[12][13][14] . The advance in pharmacogenetics has led the discovery of several gene polymorphisms in P450 family, which explains the inter-individual variability of tacrolimus metabolism [13,15,16] . Transplant patients Table 4 Multivariable analysis of risk factors for acute rejection expressing P450-3A5 (expressers) were shown to need higher doses of tacrolimus than non-expressers to reach similar trough levels [13,16] .…”