Insights into the Pharmacogenetics of Tacrolimus Pharmacokinetics and Pharmacodynamics

Abstract

The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high risk of rejection, drug-related adverse effects, or poor outcomes. In the past decade, new pharmacokinetic strategies have been developed to improve personalized tacrolimus treatment. Several studies have shown that patients with tacrolimus doses C0/D < 1 ng/mL/mg may demonstrate a greater incidence of drug-related adverse events and infections. In addition, C0 tacrolimus intrapatient variability (IPV) has been identified as a potential biomarker to predict poor outcomes related to drug over- and under-exposure. With regard to tacrolimus pharmacodynamics, inconsistent genotype-phenotype relationships have been identified. The aim of this review is to provide a concise summary of currently available data regarding the influence of pharmacogenetics on the clinical outcome of patients with high intrapatient variability and/or a fast metabolizer phenotype. Moreover, the role of membrane transporters in the interindividual variability of responses to tacrolimus is critically discussed from a transporter scientist’s perspective. Indeed, the relationship between transporter polymorphisms and intracellular tacrolimus concentrations will help to elucidate the interplay between the biological mechanisms underlying genetic variations impacting drug concentrations and clinical effects.

Keywords: fast metabolizer; intrapatient variability; membrane transporters; personalized treatment; pharmacodynamics; pharmacogenetics; pharmacokinetics; tacrolimus.

Figure 1

Tacrolimus handling by T cells. Tacrolimus accumulation in T cells determines the extent of calcineurin inhibition by tacrolimus-bound FK506 binding proteins (FKBP) and the subsequent inhibition of nuclear factor of activated T cell (NFAT) target genes, thereby contributing to immunosuppression. Tacrolimus intracellular concentrations are highly dependent upon the expression and functional activity of the ABCB1 gene product, multidrug-resistance 1 (MDR1)/P-glycoprotein. Tacrolimus influx might be mediated by a still-unknown plasma membrane transporter presumably belonging to the SLC gene superfamily. The contribution of inward tacrolimus transporters to drug accumulation in T cells is not known and opens the possibility of additional gene(s) modulating its calcineurin inhibitory activity.