Tacrolimus is metabolized by
CYP3A4 and
CYP3A5 enzymes. Patients expressing
CYP3A5 (in Caucasian patients about 15% of the population but more frequent in African Americans and Asians) have a dose requirement that is around 50% higher than non-expressers to reach the target concentration.
CYP3A5 expressers can be considered fast metabolizers. The trough concentration/dose (C0/D) ratio of
tacrolimus has recently been proposed as a prognostic marker for poor outcome after
kidney transplantation. Patients with a low C0/D ratio (also referred to as fast metabolizers) seem to have more
tacrolimus-related nephrotoxicity, more BK-
viremia, and a lower graft survival. At first sight, the expression of
CYP3A5 and a low C0/D ratio seem to be overlapping factors, both pointing towards patients in whom a higher
tacrolimus dose is needed to reach the
tacrolimus target concentration. However, there are important differences, and these differences may explain why the impact of the C0/D ratio on long term outcome is stronger than for
CYP3A5 genotype status. Patients with a low C0/D ratio require a high
tacrolimus dose and are exposed to high
tacrolimus peak concentrations. The higher peak exposure to
tacrolimus (and/or its metabolites) may explain the higher incidence of nephrotoxicity, BK-
viremia and graft loss. A potential confounder is the concurrent maintenance treatment of
corticosteroids, as
steroids are sometimes continued in patients at high immunological risk.
Steroids induce the metabolism of
tacrolimus via
pregnane X receptor mediated increased
CYP3A4 expression, resulting in lower
tacrolimus C0/D ratio in high risk patients. Also non-adherence may result in lower C0/D ratio which is also associated with poor outcome. The C0/D ratio of
tacrolimus does seem to identify a group of patients with increased risk of poor outcome after
kidney transplantation. Our recommendation is to monitor
tacrolimus peak concentrations in these patients, and if these are high then target slightly lower pre-dose concentrations. Another possibility would be to switch to a prolonged release formulation or to dose the drug more frequently, in smaller doses, to avoid high peak concentrations.