SUN-342 UNUSUAL HIGH DOSE OF TACROLIMUS IN RENAL TRANSPLANT PATIENTS: A CASE SERIES

Abstract

Tacrolimus, is an immunosuppressant, characterized by highly variable pharmacokinetics (PK) and a small therapeutic window, which make therapeutic drug monitoring (TDM) mandatory for maintaining adequate exposure. TDM allows dose adjustment in order to avoid graft rejection and tac-induced adverse effects, which are the most challenging after transplantation. Tacrolimus is metabolized specifically by the CYP3A isoenzyme: CYP3A4 and CYP3A5. Many single nucleotide polymorphisms (SNPs) such as CYP3A4*1B -392A>G, CYP34*22 15389C>T, and CYP3A5*3 6986A>G related to the expression levels of CYP enzymes may explain a part of the variability in tacrolimus PK. It is admitted that patients harboring the predominant CYP3A5*3, associated with enzymatic function loss, require roughly 50% lower tacrolimus doses than those with CYP3A5*1. CYP3A4*1B. Recently, it has been shown that CYP3A4*22 carriers had a lower clearance of tacrolimus (-16%). We describe herein two cases of renal transplant patients who have great difficulty in reaching the desired trough blood levels despite the use of high dose tacrolimus. It is a retrospective study reporting the case of 2 patients with difficulty in reaching the desired trough blood levels of tacrolimus. Our first patient is a 34-year-old man who received a living donor kidney transplant (his mother) on March 15, 2017. He was prescribed Tacrolimus at an initial dose of 14 mg/day divided every 12 hours (0.12-0.15 mg/kg/day) in association with a corticosteroid and mycophenolate mofetil. The trough blood concentration C0 was 5ng/ml. The dose was progressively increased reaching a daily dose of 22 mg divided every 12 hours with the trough blood concentration C0 = 6.4 ng/ml.CYP3A4 and CYP3A5 genotyping were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP). The patient was heterozygous for the CYP3A5*3 allele (*1/*3) and homozygous for the CYP3A4*1B (*1B/*1B) and CYP3A4*22 alleles (*1/*1). So the patient was considered a high metabolizer, the reason behind the need for elevated doses of tacrolimus to achieve a therapeutic trough concentration. Our second patient is a 42-year-old man who received a living donor kidney transplant (his sister) on September 28, 2016. He was initially prescribed Tacrolimus at 12mg/day in two divided doses (0.12-0.15 mg/kg/day) in association with a corticosteroid and mycophenolate mofetil. The trough blood concentration (C0) was 3 ng/ml. The dose was then progressively increased reaching a daily dose of 20 mg/day. C0 was 4.1 ng/ml. The patient was homozygous for the three alleles (CYP3A5*1/*3, CYP3A4*1B/*1B, and CYP3A4*1/*1). Our patient is a CYP3A5 expressor and a CYP3A4*1B and CYP3A4*22 carrier, thereby making him a high metabolizer and requiring high doses of tacrolimus in order to achieve a therapeutic trough concentration. The present case series appears to confirm the main responsibility of the CYA3A4 and CYP3A5 genetic polymorphisms in determining the dose requirements of tacrolimus in renal transplant patients. Although pharmacogenetic analysis cannot substitute TDM, the availability of genotyping renders possible to better define the initial tacrolimus dosage.