TY - JOUR
T1 - Pharmacogenetic approach to losartan in Marfan patients
T2 - A starting point to improve dosing regimen?
AU - Falvella, Felicia Stefania
AU - Marelli, Susan
AU - Cheli, Stefania
AU - Montanelli, Stefano
AU - Viecca, Federico
AU - Salvi, Lucia
AU - Ferrara, Alfio
AU - Clementi, Emilio
AU - Trifirò, Giuliana
AU - Pini, Alessandro
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Losartan is under evaluation for managing Marfan patients with aortic root dilatation. Cytochrome P450 (CYP) enzymes convert losartan to E3174 active metabolite. The aim of this study is to describe the distribution of CYP2C9∗2, CYP2C9∗3, CYP3A4∗22 and CYP3A5∗3 defective alleles, according to losartan tolerance in paediatric Marfan patients. We genotyped 53 paediatric Marfan patients treated with losartan. The rate of aortic root dilatation was evaluated using the delta z-score variation. Differences in tolerated losartan daily doses with respect to CYP metabolic classes were assessed through the Kruskal-Wallis test. The losartan daily dose spans from 0.16 to 2.50 mg/kg (median 1.10 mg/kg). As we expect from the pharmacokinetics pathway, we observe highest tolerated dose in CYP2C9 poor metabolisers (median 1.50 mg/kg, interquartile range 1.08-1.67 mg/kg); however, this difference is not statistically significant. The optimal dose of angiotensin receptor blocker is not known, and no data are available about losartan pharmacogenetic profile in Marfan syndrome; we have proposed a strategy to tackle this issue based on evaluating the major genetic polymorphisms involved in the losartan conversion into active carboxylic acid metabolite. Further studies are needed to support the use of genetic polymorphisms as predictors of the right dose of losartan.
AB - Losartan is under evaluation for managing Marfan patients with aortic root dilatation. Cytochrome P450 (CYP) enzymes convert losartan to E3174 active metabolite. The aim of this study is to describe the distribution of CYP2C9∗2, CYP2C9∗3, CYP3A4∗22 and CYP3A5∗3 defective alleles, according to losartan tolerance in paediatric Marfan patients. We genotyped 53 paediatric Marfan patients treated with losartan. The rate of aortic root dilatation was evaluated using the delta z-score variation. Differences in tolerated losartan daily doses with respect to CYP metabolic classes were assessed through the Kruskal-Wallis test. The losartan daily dose spans from 0.16 to 2.50 mg/kg (median 1.10 mg/kg). As we expect from the pharmacokinetics pathway, we observe highest tolerated dose in CYP2C9 poor metabolisers (median 1.50 mg/kg, interquartile range 1.08-1.67 mg/kg); however, this difference is not statistically significant. The optimal dose of angiotensin receptor blocker is not known, and no data are available about losartan pharmacogenetic profile in Marfan syndrome; we have proposed a strategy to tackle this issue based on evaluating the major genetic polymorphisms involved in the losartan conversion into active carboxylic acid metabolite. Further studies are needed to support the use of genetic polymorphisms as predictors of the right dose of losartan.
KW - losartan
KW - Marfan syndrome
KW - metabolism
KW - pharmacogenetics
KW - polymorphism
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U2 - 10.1515/dmpt-2016-0006
DO - 10.1515/dmpt-2016-0006
M3 - Article
AN - SCOPUS:84989173806
SN - 2363-8907
VL - 31
SP - 157
EP - 163
JO - Drug Metabolism and Personalized Therapy
JF - Drug Metabolism and Personalized Therapy
IS - 3
ER -