Kimberly M Deininger1, Anh Vu1, Robert L Page2, Amrut V Ambardekar3, JoAnn Lindenfeld4, Christina L Aquilante5. 1. Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA. 2. Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA. 3. Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA. 4. Advanced Heart Failure and Cardiac Transplant Program, Vanderbilt Heart and Vascular Institute, Nashville, TN, USA. 5. Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA. christina.aquilante@ucdenver.edu.
Abstract
BACKGROUND: Cytochrome P450 (CYP) 3A polymorphisms are associated with variable CYP3A metabolizing enzyme activity and tacrolimus pharmacokinetics. We sought to determine the singular and combined impact of CYP3A4*22 and CYP3A5*3 variants on tacrolimus drug disposition in adult heart transplant recipients. METHODS: The retrospective study included 76 patients greater than one year post-heart transplant and receiving tacrolimus. Patients were genotyped for CYP3A4*22 and CYP3A5*3, and combined genotypes were classified as follows: extensive metabolizers (EM, CYP3A4*1/*1+CYP3A5*1 carriers), intermediate metabolizers (IM, CYP3A4*1/*1+CYP3A5*3/*3, or CYP3A4*22 carriers+CYP3A5*1 carriers), and poor metabolizers (PM, CYP3A4*22 carriers+CYP3A5*3/*3). The primary outcome was tacrolimus dose-adjusted trough concentration (C0 /D, ng/mL per mg/d). RESULTS: In singular analysis, tacrolimus C0 /D did not differ significantly between CYP3A4*22 genotype groups. However, tacrolimus C0 /D was 1.8-fold lower (P<.001) in CYP3A5 expressers vs non-expressers. When combined CYP3A genotypes were evaluated, tacrolimus C0 /D was 1.8-fold lower in EMs vs IMs (P<.001) and EMs vs PMs (P=.001). Tacrolimus C0 /D did not differ significantly between CYP3A IMs vs PMs. CONCLUSION: Combined CYP3A genotype was associated with tacrolimus drug disposition in adult heart transplant recipients, but the effect was largely driven by CYP3A5*3. These data suggest that CYP3A4*22 and combined CYP3A genotypes are unlikely to provide additional information beyond CYP3A5 genotype.
BACKGROUND: Cytochrome P450 (CYP) 3A polymorphisms are associated with variable CYP3A metabolizing enzyme activity and tacrolimus pharmacokinetics. We sought to determine the singular and combined impact of CYP3A4*22 and CYP3A5*3 variants on tacrolimus drug disposition in adult heart transplant recipients. METHODS: The retrospective study included 76 patients greater than one year post-heart transplant and receiving tacrolimus. Patients were genotyped for CYP3A4*22 and CYP3A5*3, and combined genotypes were classified as follows: extensive metabolizers (EM, CYP3A4*1/*1+CYP3A5*1 carriers), intermediate metabolizers (IM, CYP3A4*1/*1+CYP3A5*3/*3, or CYP3A4*22 carriers+CYP3A5*1 carriers), and poor metabolizers (PM, CYP3A4*22 carriers+CYP3A5*3/*3). The primary outcome was tacrolimus dose-adjusted trough concentration (C0 /D, ng/mL per mg/d). RESULTS: In singular analysis, tacrolimus C0 /D did not differ significantly between CYP3A4*22 genotype groups. However, tacrolimus C0 /D was 1.8-fold lower (P<.001) in CYP3A5 expressers vs non-expressers. When combined CYP3A genotypes were evaluated, tacrolimus C0 /D was 1.8-fold lower in EMs vs IMs (P<.001) and EMs vs PMs (P=.001). Tacrolimus C0 /D did not differ significantly between CYP3A IMs vs PMs. CONCLUSION: Combined CYP3A genotype was associated with tacrolimus drug disposition in adult heart transplant recipients, but the effect was largely driven by CYP3A5*3. These data suggest that CYP3A4*22 and combined CYP3A genotypes are unlikely to provide additional information beyond CYP3A5 genotype.
Authors: A B Sanchez Spitman; D J A R Moes; H Gelderblom; V O Dezentje; J J Swen; H J Guchelaar Journal: Eur J Clin Pharmacol Date: 2017-08-28 Impact factor: 2.953
Authors: Jessica van Setten; Evangeline G Warmerdam; Olivier Q Groot; Nicolaas de Jonge; Brendan Keating; Folkert W Asselbergs Journal: Transplant Direct Date: 2019-01-21