Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations. (3rd May 2016)

• Record Type: Journal Article
• Authors: Tang, J.T.; Andrews, L.M.; van Gelder, T.; Shi, Y.Y.; van Schaik, R.H.N.; Wang, L.L.; Hesselink, D.A.
• Is Part Of: Expert opinion on drug metabolism and toxicology. Volume 12:Number 5(2016:May)
• Page Start: 555
• Page End: 565
• Publication Date: 2016-05-03
• Subjects: Calcineurin inhibitor -- cytochrome P450 -- ethnicity -- kidney -- pharmacodynamics -- pharmacogenetics -- pharmacokinetics -- tacrolimus -- transplanation; Drugs -- Toxicology -- Periodicals; Drugs -- Metabolism -- Periodicals; 615.7
• DOI: 10.1517/17425255.2016.1170808
• Languages: English
• ISSNs: 1742-5255

Abstract

ABSTRACT: Introduction : Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered : The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion : The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a ~ 40–50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.