The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites

Abstract

Ivacaftor-lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators. The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand binding assays. Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT_2C receptor (p<i>K</i>_i=6.06±0.03), β₃-adrenergic receptor (p<i>K</i>_i=5.71±0.07), δ-opioid receptor (p<i>K</i>_i=5.59±0.06) and the dopamine transporter (p<i>K</i>_i=5.50±0.20); iva-M1 displayed significant affinity to the 5-HT_2C receptor (p<i>K</i>_i=5.81±0.04) and the muscarinic M3 receptor (p<i>K</i>_i=5.70±0.10); iva-M6 displayed significant affinity to the 5-HT_2A receptor (p<i>K</i>_i=7.33±0.05). The <i>in vivo</i> central nervous system activity of ivacaftor (40 mg·kg^-1 intraperitoneally for 21 days) was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s), similarly to fluoxetine (33.8±11.0 s), and increased climbing/swimming activity (181.5±9.2 s). In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6 <i>versus</i> fluoxetine 57.9±9.5) and total distance travelled (ivacaftor 120.6±16.8 cm <i>versus</i> fluoxetine 84.5±16.0 cm) in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor-lumacaftor resulted in significant improvements in quality of life (including anxiety) in all five domains of the AweScoreCF questionnaire (p=0.092-0.096). Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood.