TABLE 4

Summary of clinical studies and pharmacokinetic parameters

Perpetrator Drug						Midazolam Oral Dose	Reference
Drug	Oral Dose	C_max	f_u	k_a	F_a	Midazolam Oral Dose	Reference
	mg	µg/ml		min⁻¹		mg
ASV (twice a day)	200	0.351	0.002	0.0063^{^a}	1^{^b}	5	Eley et al. (2011)
ASV (twice a day)	600	0.632	0.002	0.0053^{^a}	1^{^b}	5	Unpublished data^{^c}
DCV (every day)	60	1.288	0.006	0.013^a	0.71	5	Bifano et al. (2013)
BCV (twice a day)	150	1.835^{^d}/0.434^{^e}	0.012^{^d}^,^{^e}	0.0067^{^a}^,^{^d}	0.72^{^d}	5	AbuTarif et al. (2014)
BCV (twice a day)	300	3.875^{^d}/0.944^{^e}	0.012^{^d}^,^{^e}	0.0067^{^a}^,^{^d}	0.72^{^d}	5	AbuTarif et al. (2014)
Triple I
ASV (twice a day)	200	0.492	0.002	0.0063^{^f}	1	5	Tao et al. (2016)^{^g}
DCV (twice a day)	30	0.975	0.006	0.013^{^f}	0.71
BCV (twice a day)	75	1.675^{^d}/0.350^{^e}	0.012^{^d}^,^{^e}	0.0067^{^d}^,^{^f}	0.72^{^d}
Triple II
ASV (twice a day)	200	0.473	0.002	0.0063^{^f}	1	5	Tao et al. (2016)^{^g}
DCV (twice a day)	30	0.974	0.006	0.013^{^f}	0.71
BCV (twice a day)	150	3.141^{^d}/0.664^{^e}	0.012^{^d}^,^{^e}	0.0067^{^d}^,^{^f}	0.72^{^d}

↵^a Determined based on plasma concentration profile from the same study.
↵^b The F_h value of ASV is calculated to be 7%, which is lower than the oral bioavailability of ASV (9.3%), suggesting ASV oral absorption is high in humans. Thus, the F_a value of ASV is set as 1.
↵^c Data from an open-label, single-sequence study (AI447007), in which 18 healthy subjects (17 male and one female) received: 1) a single oral dose of 5 mg midazolam on day 1; 2) an oral dose of 600 mg ASV twice daily from day 2 to day 8; and 3) a single dose of 5 mg midazolam on day 8 (morning). The study protocol was approved by the Institutional Review Board at the investigational site (MDS Pharma Services (US) Inc., Lincoln, NE). All subjects were closely monitored for adverse events throughout the study.
↵^d Values for BCV.
↵^e Values for BCV-M1.
↵^f Determined based on plasma concentration profile from the single agent studies.
↵^g Data from an open-label, single-sequence study (AI443021), in which 20 healthy subjects (19 male and one female) received the following: 1) a cocktail of P450 and transporter probe substrates (including 5 mg midazolam) administered orally as a single dose on day 1; 2) a combination of 200 mg ASV, 20 mg DCV, and 75 mg BCV administered orally twice daily from day 6 to 20 and a cocktail of P450 and P-glycoprotein substrates (including 5 mg midazolam) administered orally as a single dose on day 16; and 3) a combination of 200 mg ASV, 20 mg DCV, and 150 mg BCV administered orally twice daily from day 21 to 35 and a cocktail of P450 and transporter probe substrates (including 5 mg midazolam) administered orally as a single dose on day 31. The study protocol was approved by the Institutional Review Board at the investigational site (IntegReview, LTD, Austin, TX). All subjects were closely monitored for adverse events throughout the study.