Ivacaftor (VX-770) (VX-770) is a potentiator of CFTR targeting G551D-CFTR (EC50: 100 nM) and F508del-CFTR (EC50: 25 nM) in Fisher rat thyroid cells, respectively.

CFTR (G551D):100 nM(EC50, Fisher rat thyroid cells), F508del CFTR:25 nM(EC50, Fisher rat thyroid cells)

VX-770将温度修正的F508del-FRT细胞中，通过forskolin刺激的IT增加约6倍，其EC50为25 ± 5 nM。在加入VX-770之前，CFTR通道已经暴露于PKA（75 nM）和ATP（1 mM）的最大有效浓度下。在这些条件下，10 μM VX-770将G551D CFTR的Po增加了约6倍[1]。暂时表达ABCB4-wt或突变体的HEK293细胞，被10 μmol/L的ivacaftor（VX-770）处理24小时。ivacaftor处理使ABCB4-G535D的PC分泌活性增加3倍，ABCB4-G536R增加13.7倍，ABCB4-S1076C增加6.7倍，ABCB4-S1176L增加9.4倍，以及ABCB4-G1178S增加5.7倍[2]。

在大鼠剂量比例性研究中，通过口服悬浮剂型给药，Ivacaftor的剂量从1到200 mg/kg（中间剂量为3, 10, 30和100）时，其AUC和Cmax呈线性增加。在比格犬中，口服剂量从3到80 mg/kg（中间剂量为10, 30和60）增加时，观察到类似趋势，证实了高水平的口服吸收。通过从四种物种的异速生长估计，预测人类对Ivacaftor的肝脏清除率为4.7 mL min1 kg1，约占肝血流量的23% [3]。

HEK293 cells were seeded on poly-lysine precoated six-well plates at a density of 1.3 x 10^6 cells/well. Six hours after seeding, cells were transiently transfected with 1μg of ABCB4-encoding plasmids using Turbofect, following the manufacturer's instructions. Twenty-four hours post-transfection, cells were washed twice with HBSS, then the medium was replaced by phenol red-free DMEM containing 0.5 mmol/L sodium taurocholate and 0.02% fatty acid–free bovine serum albumin (BSA) in the presence or absence of 10 μmol/L of ivacaftor, 50 μM/L of UDCA, and 10 μmol/L of ivacaftor plus 50 μM/L of UDCA. Media were collected after 24 hours [2].

Male mouse,Sprague?Dawley rats,beagle dog,and cynomolgus monkeys (n = 3/group) were administered a single iv dose of compound formulated in dimethyl isosorbide/ethanol/PEG400/5% dextrose in water (D5W) (10%/15%/35%/40%) at the nominal dose indicated in a dose volume of 1 mL/kg.Blood samples (0.3 mL,sodium heparin anticoagulant) were collected from an indwelling carotid cannula at the following nominal time points: at predose,5,15,30,and 45 min and 1,2,4,6,8,12,24,36,and 48 h following iv administration and at predose,0.25,0.50,1,1.5,2,4,8,12,and 24 h following oral administration.The concentration of compound in the plasma samples was determined with a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method,which had a lowest limit of quantitation (LLOQ) of 1 ng/mL and a linearity range between 1 and 2500 ng/mL [3].