Pharmacology of the cystic fibrosis transmembrane conductance regulator drug ivacaftor

Cystic fibrosis is a life limiting disease caused by defective or deficient cystic fibrosis trans-membrane conductance regulator (CFTR) activity. The recent Food and Drug Administration and European Medicine Agency approval of lumacaftor combined with ivacaftor (Orkambi) targets patients with the F508del-CFTR. Although Kalydeco and Orkambi have only recently entered clinical use, various independent laboratories have reported unexpected off-target effects. The question remains is this breakthrough combination therapy the ‘magic-bullet’ cure CF patients have been waiting for? This project focuses on the understanding the pharmacology of ivacaftor and lumacaftor, their off-target effects such as CNS activity; and their synergistic antibacterial activity in combination with polymyxins which are used for CF inhalation therapy. The studies presented herein also shed light upon potential off-target effects that potentially impact the clinical efficacy of these drugs.