CYP3A5 Polymorphisms and Conversion to Once-Daily, Extended-Release Tacrolimus in Lung Transplant (LTx)

Abstract

Calcineurin inhibitors have a narrow therapeutic index and are associated with significant inter- and intra-patient variability. The pharmacokinetic response to immunosuppressive drugs, and their intestinal absorption, may be affected by genetic polymorphisms of CYP3A4/3A5, as well as the low bioavailability and high fluctuation of twice-daily, immediate-release tacrolimus. Patients with CYP3A5 expressor genotypes (CYP3A5*1/*1 and *1/*3) metabolize substrates, such as tacrolimus, more rapidly than CYP3A5 non-expressors and have a higher rate of tacrolimus clearance. The frequency of alleles varies widely across different race and ethnic populations. In the general population, ∼90% of Caucasian patients are non-expressors (CYP3A5*3/*3), while ∼70% of African-American patients are expressors of CYP3A5*1. Once-daily, extended-release tacrolimus (Envarsus® XR) utilizes decreased drug particle size resulting in improved absorption, and has shown increased bioavailability, reduced Cmax, and non-inferior efficacy and safety in both de-novo and stable kidney transplant recipients. Data in LTx is lacking. We performed 50 lung transplants between November 2017 and April 2019. We identified a subset of patients who had consistently subtherapeutic levels despite increases in tacrolimus dose, and who required high doses to achieve goal trough levels. Cmax levels were measured to confirm inadequate exposure if patients were admitted at the time. Cmax levels were found to be consistently low, despite ensuring compliance. We suspected CYP3A5 genotype polymorphisms in 8 patients who required >8 mg/day of oral tacrolimus (or equivalent sublingual dose, using a 1:2 conversion). 7 of 8 patients were of African-American race/ethnicity and were CYP3A5 expressors (*1/*1 or *1/*3). After conversion to once-daily, extended-release tacrolimus, patients consistently achieved tacrolimus levels in therapeutic range. This is the first observational data assessing the frequency of CYP3A5 polymorphisms in LTx, and the feasibility of using extended-release tacrolimus to achieve therapeutic levels. Further studies are needed to assess patient and graft survival, freedom from BOS, effect of drug-drug interactions, and if any renal-protective benefit exists in this population.