Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

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.

KEYWORDS:

• Calcineurin inhibitor
• cytochrome P450
• ethnicity
• kidney
• pharmacodynamics
• pharmacogenetics
• pharmacokinetics
• tacrolimus
• transplanation

Article highlights

• The CYP3A5 and CYP3A4 genotypes of the transplant recipient have an impact on Tac dose requirement in SOT recipients. Other variants, such as CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirement.

• The evidence that implementing genotype-based Tac dosing will improve clinical outcome is missing.

• Dosing algorithms which incorporate genetics with demographic and clinical factors may allow for more precise Tac dosing.

• ABCB1 and CYP3A5 expression within the kidney transplant is associated with Tac-induced nephrotoxicity. The results about the relationship between other toxic effects of Tac (hypertension, neurotoxicity and PTDM) and pharmacogenetics are conflicting and seem to be of little value for the clinician.

• Ethnicity plays an important role in interindividual variability in Tac metabolism. Preemptive genotyping for CYP3A5 or other relevant Tac metabolizing enzymes may be more promising in ethnic populations containing higher proportions of expressers.

This box summarizes key points contained in the article.

Declaration of interest

DA Hesselink has received lecture fees from Chiesi Pharmaceuticals and research grants and consulting fees from Astellas. LL Wang received a research fund grant (81571561) from the National Natural Science Foundation of China. T van Gelder has received honoraria for presentations/advirsory committees from Astellas, Novartis and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.