Lumacaftor

Lumacaftor (VX-809; VRT 826809) is a CFTR modulator that corrects the folding and trafficking of CFTR protein. IC50 & Target: EC50: 0.1 μM (CFTR)^[1] In Vitro: In fischer rat thyroid (FRT) cells, Lumacaftor improves F508del-CFTR maturation by 7.1±0.3 fold (n=3) compared with vehicle-treated cells (EC₅₀, 0.1±0.1 μM; n=3) and enhances F508del-CFTR-mediated chloride transport by approximately fivefold (EC₅₀, 0.5±0.1 μM; n=3). At Lumacaftor concentrations greater than 10 μM, the response is reduced, resulting in a bell-shaped dose-response relationship with an IC₅₀ of approximately 100 μM. Lumacaftor is orally bioavailable in rats and achieved in vivo plasma levels significantly above concentrations required for in vitro efficacy^[1]. Lumacaftor produces a concentration-dependent increase in the HRP luminescence signal after incubation with cells at 37°C or 27°C in both cell lines, with a similar EC₅₀ value of approximately 0.3 µM. In F508-HRP CFBE41o^- cells at 37°C, Lumacaftor increases the signal maximally to approximately 250 luminescence arbitrary units (a.u.) over the DMSO control baseline of approximately 60 a.u., representing an approximately 4-fold signal increase. Similarly, with the R1070W-HRP CFBE41o^- cells, Lumacaftor increases the signal maximally to approximately 220 a.u. over the DMSO control baseline of approximately 85 a.u., representing an approximately 2.5-fold signal increase. Therefore, both cell lines produced robust signals with a good dynamic range for high-throughput screening^[2]. In Vivo: Oral dosing of 1 mg/kg Lumacaftor in male Sprague-Dawley rats results in a C_max of 2.4±1.3 μM with a t_1/2 of 7.7±0.4 h (mean±SD; n=3), indicating that that Lumacaftor is orally bioavailable and able to reach plasma levels that significantly exceeded EC₅₀s for F508del-CFTR correction^[1].