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


Autoria(s): Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Englberger, Lars; Fiedler, Georg M.; Largiadèr, Carlo R.; Mohacsi, Paul; Sistonen, Johanna
Data(s)

01/12/2015

Resumo

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.

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application/pdf

Identificador

http://boris.unibe.ch/74061/1/ctr12653.pdf

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 <http://dx.doi.org/10.1111/ctr.12653>

doi:10.7892/boris.74061

info:doi:10.1111/ctr.12653

info:pmid:26458301

urn:issn:0902-0063

Idioma(s)

eng

Publicador

Wiley-Blackwell

Relação

http://boris.unibe.ch/74061/

Direitos

info:eu-repo/semantics/restrictedAccess

Fonte

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 <http://dx.doi.org/10.1111/ctr.12653>

Palavras-Chave #610 Medicine & health
Tipo

info:eu-repo/semantics/article

info:eu-repo/semantics/publishedVersion

PeerReviewed