TY - JOUR
T1 - Pharmacogenetics and treatment response in narcolepsy type 1
T2 - Relevance of the polymorphisms of the drug transporter gene abcb1
AU - Moresco, Monica
AU - Riccardi, Laura Natalia
AU - Pizza, Fabio
AU - Zenesini, Corrado
AU - Caporali, Leonardo
AU - Plazzi, Giuseppe
AU - Pelotti, Susi
N1 - Ricercatori distaccati presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Fabio Pizza, Giuseppe Plazzi)
PY - 2016
Y1 - 2016
N2 - Objective: Narcolepsy type 1 (NT1) is a chronic hypersomnia clinically characterized by daytime sleepiness and cataplexy. Narcolepsy type 1 treatments target individual symptoms: wake-promoting agents (eg, modafinil) are effective for sleepiness, antidepressants (eg, venlafaxine) on cataplexy, whereas sodium oxybate on both. Narcolepsy type 1 patients variably respond to modafinil and venlafaxine independently of individual clinical features. Given the potential influence of drug transmembrane transport (glycoprotein-P) on drug response, we explored the relation between genetic polymorphisms in the ABCB1 gene and clinical response to modafinil/venlafaxine in NT1. Methods: Individual drug response and genotypes were assessed in 107 NT1 patients (males/females, 64/43; mean age, 38 ± 21 years) treated with modafinil and/or venlafaxine at stable doses for at least 3 months. Minisequencingwas performed to detect single-nucleotide polymorphisms in ABCB1. Patients with different responses to treatment were contrasted by Fisher exact test and multivariate analysis. Results: The ABCB1 diplotype was significantly associated with clinical response to modafinil, with the CGC-TTT (1236/2677/3435) being more frequent in the modafinil responder versus nonresponder group (P = 0.013). Conversely, no significant associations with clinical response to venlafaxine were found. Conclusions: The ABCB1 variants modulate therapeutic response to modafinil and may partly explain pharmacoresistance in NT1 patients.
AB - Objective: Narcolepsy type 1 (NT1) is a chronic hypersomnia clinically characterized by daytime sleepiness and cataplexy. Narcolepsy type 1 treatments target individual symptoms: wake-promoting agents (eg, modafinil) are effective for sleepiness, antidepressants (eg, venlafaxine) on cataplexy, whereas sodium oxybate on both. Narcolepsy type 1 patients variably respond to modafinil and venlafaxine independently of individual clinical features. Given the potential influence of drug transmembrane transport (glycoprotein-P) on drug response, we explored the relation between genetic polymorphisms in the ABCB1 gene and clinical response to modafinil/venlafaxine in NT1. Methods: Individual drug response and genotypes were assessed in 107 NT1 patients (males/females, 64/43; mean age, 38 ± 21 years) treated with modafinil and/or venlafaxine at stable doses for at least 3 months. Minisequencingwas performed to detect single-nucleotide polymorphisms in ABCB1. Patients with different responses to treatment were contrasted by Fisher exact test and multivariate analysis. Results: The ABCB1 diplotype was significantly associated with clinical response to modafinil, with the CGC-TTT (1236/2677/3435) being more frequent in the modafinil responder versus nonresponder group (P = 0.013). Conversely, no significant associations with clinical response to venlafaxine were found. Conclusions: The ABCB1 variants modulate therapeutic response to modafinil and may partly explain pharmacoresistance in NT1 patients.
KW - ABCB1 polymorphisms
KW - Drug efficacy
KW - Modafinil
KW - Narcolepsy type 1
KW - Pharmacogenetics
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U2 - 10.1097/WNF.0000000000000119
DO - 10.1097/WNF.0000000000000119
M3 - Article
C2 - 26757307
AN - SCOPUS:84957838210
VL - 39
SP - 18
EP - 23
JO - Clinical Neuropharmacology
JF - Clinical Neuropharmacology
SN - 0362-5664
IS - 1
ER -