Rapid clearance of tacrolimus blood concentration triggered by variant pharmacogenes

Abstract

Tacrolimus (TAC) is a macrocyclic lactone that acts as a calcineurin inhibitor. It is indicated as prophylaxis of transplant rejection in adult kidney or liver allograft recipients and as treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients. Tacrolimus has significant interindividual pharmacokinetic variability and a narrow therapeutic index. Its administration should be based on clinical assessments of graft rejection prevention and toxicity in each individual patient, supported by whole blood TAC trough concentration (C 0 ) monitoring, that is therapeutic drug monitoring (TDM). 1 It has variable absorption after oral administration and first-pass metabolism, which are two major factors affecting its efficacy and safety. Metabolism principally occurs in the liver and small intestine through CYP3A4 and CYP3A5 enzymes. 1 Furthermore, TAC is the substrate for the transport efflux membrane protein P-glycoprotein (MDR1 and ABCB1) in the intestine, which regulates TAC absorption, and, consequently oral bioavailability. P-glycoprotein expressed in the liver and kidney effluxes TAC into bile and urine. 1 According to clinical practice, the targeted TAC C 0 in the blood is about 10 ng/ml, depending on individual patient characteristics, transplantation type and time after transplantation. 2 Over the last twenty years, clinical studies have clearly indicated the relationship between the pharmacokinetics of immunosuppressive agents and the genetic variability of their metabolic enzymes and transporters, which plays a significant role in their metabolism. 3-5 According to upto-date knowledge, TAC bioavailability is considerably impacted by hepatic and intestinal CYP3A-dependent metabolism that is altered by CYP3A genetic variants. Therefore, CYP3A4 and CYP3A5 singlenucleotide polymorphisms (SNPs) are suggested to notably cause TAC clearance interindividual variability. 6 Seven years ago, based on published evidence supporting this relationship, the CPIC published guidelines for the CYP3A5 genotype and tacrolimus dosing