Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation

Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Englberger, Lars; Fiedler, Georg M.; Largiadèr, Carlo R.; Mohacsi, Paul; Sistonen, Johanna (2015). Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation. Clinical transplantation, 29(12), pp. 1213-1220. Wiley-Blackwell 10.1111/ctr.12653

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BACKGROUND

Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high inter-individual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients.

METHODS

Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped and clinical data were retrieved from patient charts.

RESULTS

While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (P = 0.031). ERL dose requirement was 0.02 mg/kg/day higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (P = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 ml/min/1.73m(2) ) in patients with baseline kidney dysfunction.

CONCLUSION

ERL pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability. This article is protected by copyright. All rights reserved.

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 Cardiology
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiovascular Surgery
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; Englberger, Lars; Largiadèr, Carlo Rodolfo; Mohacsi, Paul and Sistonen, Johanna

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0902-0063

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Sara Baumberger

Date Deposited:

14 Dec 2015 10:52

Last Modified:

18 Jul 2016 13:47

Publisher DOI:

10.1111/ctr.12653

PubMed ID:

26458301

Uncontrolled Keywords:

CYP3A5*3 Everolimus heart transplantation pharmacogenomics

BORIS DOI:

10.7892/boris.74061

URI:

https://boris.unibe.ch/id/eprint/74061

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