May 9, 2022

Gene variants and transplant drug dose

Genotyping multiple enzymes that metabolize the immunosuppressive drug tacrolimus — common used for lung transplant recipients — is important for correct dosing of the drug, Vanderbilt researchers found.

by Leigh MacMillan

Tacrolimus — a commonly used immunosuppressive drug for lung transplant recipients — requires strict monitoring of concentrations because of variability in metabolism and adverse effects at high levels. 

Genetic variation in enzymes that metabolize tacrolimus (CYP3A4 and CYP3A5) contributes to inter-individual variability, and though guidelines have been published for CYP3A5 testing, variants in CYP3A4 have not been considered. 

Michelle Liu, PharmD, and colleagues investigated the impact of both increased and decreased CYP3A variants on tacrolimus concentrations (C0/D). Using BioVU, they conducted a retrospective analysis of lung transplant recipients during initial hospitalization. Based on CYP3A4 and CYP3A5 variants, they grouped patients into four groups from least to most CYP3A activity. 

They report in Pharmacogenetics and Genomics that 58 of 92 patients were in Group 2 and that median tacrolimus C0/D differed significantly between the groups. The findings support incorporating CYP3A4 and CYP3A5 variants into a composite CYP3A phenotype to guide dosing of tacrolimus during the early postoperative period.

Joining Liu on the study were Ciara Shaver, MD, PhD, Kelly Birdwell, MD, MSCI, Stephanie Heeney, PharmD, Christian Shaffer, and Sara Van Driest, MD, PhD. The research was supported by grants from the National Institutes of Health (TR000445, HG004798, NS032830, GM092618, GM115305, HG006378, HL065962, HD074711, HL136888, GM100183, GM132204).