Many patients who receive a kidney transplant are treated with the drug tacrolimus (Tac), a medication that decreases the activity of the immune system to prevent the body from rejecting the transplanted organ. Until recently, the initial dose of this drug was decided based only on the person’s body weight. Once steady state is reached, subsequent doses are adjusted according to the physician’s empirical experience, by trial and error, and based on blood Tac values. Administering the correct dose of Tac is crucial: if patients treated with this drug are exposed too much or too little during the first days after a kidney transplant, the risk of complications, such as toxicity or rejection, increases. Furthermore, Tac is a drug with a very narrow therapeutic range, which is why good monitoring of its blood levels is necessary.

Now, researchers from the nephrology and kidney transplant group of the Bellvitge Biomedical Research Institute and the Bellvitge University Hospital, led by Dr. Núria Lloberas, have faced the challenge of finding the therapeutic dose of Tac that adapts to the characteristics individual patients in order to achieve a good balance between efficacy and toxicity. To do this, they have studied in detail the metabolism of the drug, which the body carries out through the enzymatic action of cytochrome P450 3A (CYP3A for short). CYP3A4 and CYP3A5 are enzymes located mainly in the liver and intestine, which oxidize small foreign molecules, such as toxins or drugs, so that they can be eliminated from the body.

On the other hand, Tac is also characterized by showing great variability, both within and between patients, which is a risk factor for a greater probability of rejection and side effects. The study, recently published in the journal Nefrologia, has analyzed a total of 425 kidney transplant patients, in whom, on the one hand, the genetic polymorphisms of CYP3A (CYP3A4 and CYP3A5) that affect the metabolism of Tac have been determined, and on the other, the concentration/dose (C/D) relationship of the drug (that is, its pharmacokinetics). The participants were classified into three phenotypes, extensive, intermediate and slow metabolizers, and it was analyzed whether the stratification of patients according to the C/D ratio coincided with the classification according to CYP3A4/5 polymorphisms.

According to Dr. Anna Vidal-Alabro, first author of the article and researcher in the nephrology and kidney transplant research group at IDIBELL and Bellvitge Hospital, “both strategies are proposed as an additional tool to individualize the dose of Tac in transplant patients”. This study has shown that being able to know what type of metabolizer the patient is, both according to the CYP polymorphisms (important for the starting dose) and by determining the C/D ratio (important in the follow-up doses), allows us to differentiate the exposure to Tac and, consequently, individualize their doses. Probably, the combination of both classification criteria would be a good tool to personalize Tac doses in transplant patients.

In summary, maintaining a good immunosuppressive regimen, especially in the early stages after kidney transplantation, is essential to ensure a good long-term transplant prognosis. The high intra- and inter-individual variability in response to Tac makes correct dose adjustment a challenge, so knowing the metabolizing phenotype of the transplant patient can be very useful.

The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).