BACKGROUND: Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients. METHODS: Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers. RESULTS: CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001). CONCLUSION: Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.
BACKGROUND:Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients. METHODS: Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers. RESULTS:CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001). CONCLUSION: Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.
Authors: Laure Elens; Rachida Bouamar; Nauras Shuker; Dennis A Hesselink; Teun van Gelder; Ron H N van Schaik Journal: Br J Clin Pharmacol Date: 2014-04 Impact factor: 4.335
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Authors: Dennis A Hesselink; Rachida Bouamar; Laure Elens; Ron H N van Schaik; Teun van Gelder Journal: Clin Pharmacokinet Date: 2014-02 Impact factor: 6.447
Authors: Jean-Baptiste Woillard; Michel Mourad; Michael Neely; Arnaud Capron; Ron H van Schaik; Teun van Gelder; Nuria Lloberas; Dennis A Hesselink; Pierre Marquet; Vincent Haufroid; Laure Elens Journal: Front Pharmacol Date: 2017-06-08 Impact factor: 5.810
Authors: D J A R Moes; J J Swen; J den Hartigh; T van der Straaten; J J Homan van der Heide; J S Sanders; F J Bemelman; J W de Fijter; H J Guchelaar Journal: CPT Pharmacometrics Syst Pharmacol Date: 2014-02-12