Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

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Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Currently tacrolimus is the mainstay of immunosuppression for most children undergoing liver transplantation (LT).• The clinical use of this agent, however, is complicated by its various adverse effects (mainly nephrotoxicity), its narrow therapeutic‐index and considerable pharmacokinetic variability.• The low and variable oral bioavailability of tacrolimus is thought to result from the action of the multidrug efflux‐pump P‐glycoprotein, encoded by the ABCB1 gene. WHAT THIS STUDY ADDS • A significant association between ABCB1 genetic polymorphisms and tacrolimus‐associated nephrotoxicity in paediatric patients following LT is reported for the first time. Genotyping such polymorphisms may have the potential to individualize better initial tacrolimus therapy and enhance drug safety.• The long‐term effect of ABCB1 polymorphisms on tacrolimus trough concentrations were investigated up to 5 years post‐transplantation. A significant effect of intestinal P‐glycoprotein genotypes on tacrolimus pharmacokinetics was found at 3 and 4 years post‐transplantation suggesting that the effect is maintained long term.AIMS: The aim of this study was to investigate the influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage‐requirements in paediatric patients following liver transplantation.METHODS: Fifty‐one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose‐adjusted tacrolimus trough concentrations and estimated glomerular filtration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes.RESULTS: The present study revealed a higher incidence of the ABCB1 variant‐alleles examined among patients with renal dysfunction (≥30% reduction in EGFR) at 6 months post‐transplantation (1236T allele: 63.3% vs 37.5% in controls, P= 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%, P= 0.057). Carriers of the G2677‐>T variant allele also had a significant reduction (%) in EGFR at 12 months post‐transplant (mean difference = 22.6%; P= 0.031). Haplotype analysis showed a significant association between T‐T‐T haplotypes and an increased incidence of nephrotoxicity at 6 months post‐transplantation (haplotype‐frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P= 0.029). Furthermore, G2677‐>T and C3435‐>T polymorphisms and T‐T‐T haplotypes were significantly correlated with higher tacrolimus dose‐adjusted pre‐dose concentrations at various time points examined long after drug initiation.CONCLUSIONS: These findings suggest that ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage‐requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the first year post‐transplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety.

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