TABLE 1

Overview of the clinical trial design for the 19 drug interaction studies

Interactions of AZ4 and AZ5 with metoprolol are mediated by CYP2D6; all other interactions are CYP3A4-mediated.

Category of AZ Compounds	Interacting Drug	Perpetrator Oral Dose	Perpetrator Dosing Regimen	Victim Oral Dose	Victim Dosing Regimen	Fed/Fasted	n	Age Range	Proportion of Females
		mg		mg				yr
Perpetrators of P450 inhibition
AZ1	Midazolam	400	5 days, q.d.	7.5	Single, day 5	Fasted	28	18–65	0
AZ1	Simvastatin	400	5 days, q.d.	40	Single, day 5	Fasted	10	20–50	0
AZ2	Midazolam	400	4 days, q.d.	7.5	Single, day 4	Fasted	30	18–65	0.34
AZ3	Midazolam	125	11 days, q.d.	7.5	Single, day 11	Fasted	12	20–49	0
AZ4	Metoprolol	750	6 days, bid	100	Single, day 6	Fasted	14	18–65	0.34
AZ5	Metoprolol	500	28 days, q.d.	50	Single, day 15	Fasted	18	44–55	0.44
Victims of P450 inhibition
AZ6	Ketoconazole	400	5 days, q.d.	125	Single, day 3	Fasted	22	18–65	0.34
AZ6	Verapamil	240	7 days, q.d.	125	Single, day 5	Fasted	23	18–65	0.34
AZ7	Ketoconazole	200	10 days, bid	90	Single, day 4	Fasted	14	20–45	0.22
AZ7	Diltiazem	240	14 days, q.d.	90	Single, day 8	Fasted	17	20–45	0.22
AZ8	Ketoconazole	200	4 days, q.d.	3	Single, day 4	Fed	4	22–40	0
AZ8	Ketoconazole	100	4 days, bid	3	Single, day 4	Fed	8	20–40	0
AZ9	Itraconazole	200	7 days, q.d.	10	Single, day 4	Fasted	6	30–49	0
AZ10	Ketoconazole	200	4 days, q.d.	25	Single, day 4	Fed	12	24–42	0
Perpetrators or victims of P450 induction
AZ5	Rifampicin	600	16 days, q.d.	500	Single, day 10	Fasted	18	27–56	0
AZ7	Rifampicin	600	12 days, q.d.	180	Single, day 12	Fasted	16	22–49	0.375
AZ9	Rifampicin	600	13 days, q.d.	15	Single, day 10	Fasted	12	20–61	0
AZ10	Carbamazepine	600	25 days, q.d.	300	35 days b.i.d.	Fed	18	29–63	0.2
AZ11	Midazolam	10	12 days, q.d.	5	Single, day 12	Fed	24	20–49	0