University of Maryland, Baltimore Baltimore, Maryland, United States
Background: Tacrolimus is an immunosuppressant used to prevent rejection in patients with solid organ transplants. Tacrolimus has a narrow therapeutic index drug, and small differences in dose or blood concentration may lead to serious therapeutic failures (i.e., organ rejection) and/or adverse drug reactions (such as nephrotoxicity). Although genetic factors influencing immunosuppressive response have been studied in kidney, heart and liver transplant patients, data regarding lung transplant recipients (LTRs) are limited. The aim of our study was to find the clinical relevance of the factors such as race, age, gender, and genetic factors in a cohort of LTRs initiated on a fixed tacrolimus dose. This will allow doctors and other medical professionals to improve clinical care by individualizing the dosage and optimizing monitoring of transplantation outcome. Methods: Twenty-five LTRs (72% Caucasians and 28% African Americans) with various underlying lung diseases, transplanted from 1/2015-10/2019, initiated on an equivalent tacrolimus dose posttransplant per institutional protocol were included in the analysis. The majority of the patients were on a systemic azole (i.e., a competitive CYP3A4 inhibitor) at 1 and 3 months posttransplant. Ordinal logistic regression models were developed using Tacrolimus dose requirement (TDRs), CYP enzyme genotype (CYP3A4, CYP3A5, CYP2C9 and CYP2C19), tacrolimus concentrations, systemic azole use, biopsy proven acute rejection (BPAR), patient survival, and graft survival data for the first year. To assess the factors associated with TDRs and transplantation outcome, stepwise multivariable regression procedure was used, and results are presented as odds-ratio and corresponding 95% confidence interval (CI). Results: Under multivariable proportional odds model, CYP3A4 genotype, CYP2C9 genotype and Race were found to be significantly associated factors with TDRs at 0.05 significance level. In addition, no factors significantly affect transplantation outcome based on the clinical dataset. Conclusion: While CYP polymorphisms and race are significantly associated with TDRs to maintain similar trough levels, they did not influence transplantation outcomes. Further research on bigger datasets is needed to determine the optimal dosing strategy in LTRs immediately posttransplant.
