CYP3A pharmacogenetics and tacrolimus disposition in adult heart transplant recipients

• Published in: Clinical transplantation Vol. 30; no. 9; pp. 1074 - 1081
• Main Authors: Deininger, Kimberly M., Vu, Anh, Page II, Robert L., Ambardekar, Amrut V., Lindenfeld, JoAnn, Aquilante, Christina L.
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.09.2016
• Subjects: Cross-Sectional Studies; CYP3A4; CYP3A5; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; cytochrome P450; DNA - genetics; Female; Genotype; Graft Rejection - genetics; Graft Rejection - metabolism; Graft Rejection - prevention & control; heart transplant; Heart Transplantation; Humans; Immunosuppressive Agents - pharmacokinetics; Male; pharmacogenetics; pharmacogenomics; Polymorphism, Single Nucleotide; Retrospective Studies; Tacrolimus - pharmacokinetics; Transplant Recipients; heart transplant; pharmacogenomics; cytochrome P450; CYP3A4; CYP3A5; pharmacogenetics
• ISSN: 0902-0063; 1399-0012
• DOI: 10.1111/ctr.12790

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.