Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation

Abstract

Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.

Influence of POR*28 Polymorphisms on CYP3A5*3-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation

“…These results suggested that the POR*28 polymorphism decreased the TAC C/D ratio through an increase in the CYP3A5 activity. Similar results have been reported in studies targeting kidney transplant patients [21,22,24,41,42], heart transplant patients [43], and hematopoietic stem cell transplant patients [44]. However, this is the first report on liver transplant patients.…”

“…On the other hand, in experiments using recombinant systems, with testosterone or midazolam used as a substrate for CYP3A4, the CYP3A4 activity was reduced by approximately 20%-40%, owing to the POR*28 polymorphism [48]. In vivo studies indicated that CYP3A4 activity was not affected by the POR*28 polymorphism [21,24,44]. However, there are reports showing that the activity was increased [22,49] and others suggesting that it was decreased [25].…”

CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients

“…Tacrolimus is effective in UC at a target trough blood concentration of 10–15 ng/mL [ 4 , 8 ]. However, the side effects of tacrolimus including nephropathy, headache, and tremors related to the trough blood levels deter its use [ 9 , 10 , 11 ].…”

Donor CYP3A5 Gene Polymorphism Alone Cannot Predict Tacrolimus Intrarenal Concentration in Renal Transplant Recipients

“…Especially, the drug efflux transporter ABCB1 is also closely related to the metabolism of tacrolimus. The activity and expression levels of ABCB1 could contribute to the variability in tacrolimus absorption and excretion [23,27,28]. Even though ABCB1 polymorphisms' impact on tacrolimus pharmacokinetics is still unclear [10,[29][30][31], the ABCB1 polymorphism has been identified as a critical factor in intracellular tacrolimus exposure [32,33].…”