Original ArticlesComposite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipientsLiu, Michellea; Shaver, Ciara M.b; Birdwell, Kelly A.c; Heeney, Stephanie A.a; Shaffer, Christian M.d; Van Driest, Sara L.d,e Author Information aDepartment of Pharmacy, Vanderbilt University Medical Center bDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center cDivision of Nephrology, Department of Medicine, Vanderbilt University Medical Center dDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center eDivision of General Pediatrics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA Received 9 December 2021 Accepted 6 March 2022 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.pharmacogeneticsandgenomics.com. Correspondence to Michelle Liu, PharmD, Clinical Pharmacist Specialist – Pharmacogenomics, Department of Pharmaceutical Services, Vanderbilt University Medical Center, 1211 Medical Center Drive – VUH B-131, Nashville, Tennessee 37232, USA, Tel: +615 875 4410; e-mail: [email protected] Pharmacogenetics and Genomics: July 2022 - Volume 32 - Issue 5 - p 209-217 doi: 10.1097/FPC.0000000000000472 Buy SDC Metrics Abstract Objectives Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D). Methods We performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed. Results Of the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (P = 0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 (interquartile range: 147.6–267.5) (ng/ml)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4–116.1), P = 0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [373.5 (149.2–490.3) and 81.4 (62.6–184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes. Conclusion These data indicate that a composite CYP3A phenotype incorporating both increase and decrease variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.