CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients

Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Oberhänsli, Markus; Carrel, Thierry; Fiedler, Georg M; Largiadèr, Carlo Rodolfo; Mohacsi, Paul; Sistonen, Johanna (2014). CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients. Therapeutic drug monitoring, 36(6), pp. 710-715. Lippincott Williams & Wilkins 10.1097/FTD.0000000000000080

[img]
Preview
Text
00007691-201412000-00005.pdf - Published Version
Available under License Publisher holds Copyright.

Download (192kB) | Preview

BACKGROUND After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and under-immunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients. METHODS Associations between 7 functional genetic variants and blood dose-adjusted trough (C0) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively. RESULTS Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/*1 genotype) required around 2.2- to 2.6-fold higher daily TAC doses to reach the targeted C0 concentration at all studied time points (P ≤ 0.003). Additionally, the POR*28 variant carriers showed higher dose-adjusted TAC-C0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement. CONCLUSIONS The CYP3A5*3 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR*28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiovascular Surgery
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Kardiologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Kardiologie

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Carrel, Thierry; Largiadèr, Carlo Rodolfo; Mohacsi, Paul and Sistonen, Johanna

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0163-4356

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Alessandra Witsch

Date Deposited:

24 Feb 2015 10:49

Last Modified:

18 Jul 2016 13:48

Publisher DOI:

10.1097/FTD.0000000000000080

PubMed ID:

24739669

BORIS DOI:

10.7892/boris.63341

URI:

https://boris.unibe.ch/id/eprint/63341

Actions (login required)

Edit item Edit item
Provide Feedback