TABLE 5

Prediction of VX-509 drug-drug interaction from in vitro parameters of time-dependent inhibition

Precipitant	In Vitro System	Donor	k_inact	K_I	Predicted AUC_i/AUC	Clinical AUC_i/AUC^a
VX-509	HLMs	Pool 150	^b	^b	^b	12
Metabolite (M3)	HLMs	Pool 150	0.07	0.4	13	12
VX-509	Human hepatocytes	YOW	0.08	2.4	21	12
VX-509	Human hepatocytes	HH1007	0.02	1.3	18	12
VX-509	Human hepatocytes	BPB	0.02	5.2	10	12
VX-509	Human hepatocytes	Hu8123	0.02	4.9	9	12
VX-509	Human hepatocytes	HH8004	0.02	4.9	9	12

AUC_i/AUC, fold-change in clinical plasma exposure of midazolam when coadministered with an inhibitor (AUC_i), relative to the control state (AUC).
↵^a Midazolam substrate.
↵^b No detectable TDI.