TABLE 5

Predictions of human DDIs from in vitro TDI of CYP3A4 using Simcyp simulator

Inhibitor and Dose Regimen^{^a}	Simulated [I]_max,ss^{^b}	Substrate	Substrate Dose Regimen^{^c}	Predicted			Observed^{^f}	Reference
Inhibitor and Dose Regimen^{^a}	Simulated [I]_max,ss^{^b}	Substrate	Substrate Dose Regimen^{^c}	D1^{^d}	D2^{^d}	HLM^{^e}	Observed^{^f}	Reference
	μ g/ml
ERY
400 mg t.i.d., 10 days	0.96	Alprazolam	0.8 mg	1.89 (1.2–9.4)	1.52 (1.1–2.5)	1.73 (1.2–16.8)	2.47	Yasui et al., 1996
500 mg q.i.d., 3 days	2.03	Cyclosporine	350 mg	3.15 (1.5–15.5)	2.05 (1.3–3.4)	3.30 (1.6–21.4)	2.14	Gupta et al., 1988
250 mg q.i.d., 7 days	0.73	Cyclosporine	700 mg	2.44 (1.5–5.2)	1.59 (1.2–2.5)	2.69 (1.4–12.9)	2.22	Freeman et al., 1987
250 mg q.i.d., 3 days	0.73	Cyclosporine	150 mg	3.18 (1.8–7.6)	1.53 (1.2–2.1)	3.67 (1.6–17.3)	1.7	Wadhwa et al., 1987
500 mg t.i.d., 5 days	1.20	Midazolam	15 mg	6.1 (3.3–22.1)	3.02 (1.7–5.3)	14.10 (2.1–65.4)	3.81	Zimmermann et al., 1996
500 mg t.i.d., 7 days	1.20	Midazolam	15 mg	6.1 (3.3–22.1)	3.42 (1.8–5.7)	14.5 (2.2–59.3)	4.41	Olkkola et al., 1993
500 mg b.i.d., 5 days	0.97	Sildenafil	100 mg	4.65 (2.4–10.8)	2.02 (1.4–3.0)	5.81 (2.0–27.4)	2.83	Muirhead et al., 2002
500 mg t.i.d., 2 days	1.20	Simvastatin	40 mg	7.56 (5.9–18.9)	4.28 (2.7–5.3)	18.2 (5.6–45.8)	6.21	Kantola et al., 1998
333 mg t.i.d., 3 days	0.80	Triazolam	0.5 mg	4.47 (2.3–11.5)	1.52 (1.2–1.9)	5.61 (2.1–37.4)	2.06	Phillips et al., 1986
500 mg b.i.d., 2 days	0.98	Triazolam	0.125 mg	4.33 (2.3–11.2)	1.29 (1.1–1.5)	5.62 (2.1–36.8)	3.8	Greenblatt et al., 1998a
VER
80 mg q.d., 2 days	0.069	Metoprolol	50 mg	1.04 (1.0–1.2)	1.00 (1.0–1.0)	1.02 (1.0–1.7)	1.33	Bauer et al., 2000
120 mg t.i.d., 7 days	0.15	Imipramine	100 mg	1.01 (1.0–1.1)	1.01 (1.0–1.0)	1.01 ((1.0–1.1)	1.15	Hermann et al., 1992
120 mg t.i.d., 7 days	0.15	Metoprolol	100 mg	1.16 (1.0–1.8)	1.03 (1.0–1.1)	1.13 (1.0–1.9)	1.79	McLean et al., 1985
80 mg t.i.d., 2 days	0.1	Midazolam	15 mg	2.14 (1.3–4.7)	1.32 (1.1–1.7)	3.71 (1.6–12.5)	2.91	Backman et al., 1994
480 mg q.d., 3 days	0.427	Simvastatin	40 mg	4.19 (1.9–15.7)	3.58 (1.7–7.2)	6.89 (1.7–23.1)	4.21	Jacobson, 2004
80 mg t.i.d., 2 days	0.1	Simvastatin	40 mg	2.59 (1.8–4.3)	1.62 (1.2–2.2)	4.35 (2.0–15.4)	4.65	Kantola et al., 1998
120 mg t.i.d., 7 days	0.15	Theophylline	5 mg/kg	1.00 (1.0–1.0)	1.00 (1.0–1.0)	1.00 (1.0–1.1)	1.24	Sirmans et al., 1988
CLA
500 mg b.i.d., 8 days	1.07	Cyclosporine	75 mg	2.81 (1.5–8.8)	2.11 (1.3–3.5)	3.46 (1.7–11.9)	1.98	Sketris et al., 1996
250 mg b.i.d., 5 days	0.534	Midazolam	15 mg	3.94 (1.6–14.5)	2.12 (1.2–4.1)	2.69 (1.8–17.9)	3.57	Yeates et al., 1996
500 mg b.i.d., 7 days	1.07	Midazolam	8 mg	5.6 (1.9–22.5)	4.03 (1.4–8.8)	7.9 (2.1–33.3)	8.39	Gurley et al., 2006
500 mg b.i.d., 7 days	1.07	Omeprazole	20 mg	1.9 (1.1–6.7)	1.25 (1.1–1.6)	2.1 (1.2–10.7)	2.01	Calabresi et al., 2004
400 mg b.i.d., 3 days	0.86	Omeprazole	20 mg	1.93 (1.2–6.7)	1.17 (1.0–1.5)	2.19 (1.2–10.7)	2.10	Furuta et al., 1999
400 mg b.i.d., 3 days	0.86	Omeprazole	20 mg	1.93 (1.2–6.7)	1.17 (1.0–1.5)	2.19 (1.2–10.7)	2.11	Furuta et al., 1999
400 mg b.i.d., 3 days	0.86	Omeprazole	20 mg	1.93 (1.2–6.7)	1.17 (1.0–1.5)	2.19 (1.2–10.7)	2.34	Furuta et al., 1999
500 mg t.i.d., 5 days	1.29	Omeprazole	40 mg	2.23 (1.2–11.7)	1.31 (1.1–1.8)	2.47 (1.2–19.5)	1.91	Gustavson et al., 1995
500 mg Sd	0.95	Sildenafil	50 mg	1.03 (1.0–1.1)	1.07 (1.0–1.1)	1.02 (1.0–1.1)	2.28	Hedaya et al., 2006
500 mg b.i.d., 9 days	1.29	Simvastatin	40 mg	6.7 (4.1–18.1)	5.79 (1.9–11.8)	11.2 (3.7–40.4)	9.95	Jacobson, 2004
250 mg Sd	0.47	Tolbutamide	500 mg	1.00 (1.0–1.1)	1.00 (1.0–1.0)	1.00 (1.0–1.0)	1.25	Jayasagar et al., 2000
500 mg b.i.d., 2 days	1.07	Triazolam	0.125 mg	3.15 (2.0–7.2)	1.67 (1.1–2.6)	3.9 (1.8–13.1)	5.25	Greenblatt et al., 1998b
DIL
60 mg t.i.d., 2 days	0.037	Midazolam	15 mg	2.55 (1.6–4.8)	1.31 (1.2–1.6)	5.4 (2.0–21.2)	3.75	Backman et al., 1994
TAO
250 mg q.d., 2 days	0.48	Imipramine	100 mg	1.01 (1.0–1.1)	1.01 (1.0–1.0)	1.01 (1.0–1.1)	1.59	Wang et al., 1997a
500 mg, Sd	1.08	Midazolam	1 mg	5.02 (2.2–9.4)	2.51 (1.8–5.1)	13.7 (2.3–30.6)	4.39	Kharasch et al., 2004
500 mg, Sd	1.08	Midazolam	3 mg	5.02 (2.2–9.4)	2.51 (1.8–5.1)	13.7 (1.9–20.6)	4.64	Phimmasone and Kharasch, 2001
500 mg q.d., 2 days	0.96	Omeprazole	20 mg	2.18 (1.3–3.3)	1.30 (1.1–1.7)	2.57 (1.2–16.6)	1.26	He et al., 2003
500 mg q.d., 2 days	0.96	Omeprazole	20 mg	2.18 (1.3–3.3)	1.30 (1.1–1.7)	2.57 (1.2–26.6)	1.28	He et al., 2003
500 mg q.d., 2 days	0.96	Omeprazole	20 mg	2.18 (1.3–3.3)	1.30 (1.1–1.7)	2.57 (1.2–26.6)	1.81	He et al., 2003
1000 mg b.i.d., 7 days	2.15	Triazolam	0.25 mg	4.21 (2.3–12.0)	3.40 (2.1–5.8)	5.65 (2.9–15.5)	3.75	Warot et al., 1987

Sd, single dose.
↵a Inhibitor dose regimen, for example, 500 mg t.i.d., 5 days, represents the inhibitor dosed at 500 mg, three times a day for 5 consecutive days.
↵b [I]_{max, ss} = simulated maximum inhibitor plasma concentrations at steady state.
↵c Victim drug dose regimen (single dose).
↵d Predicted DDIs (median of total population) from in vitro TDI measured in hepatocytes from donors D1 and D2, respectively; values in parentheses represent the minimum (5th percentile) and maximum (95th percentile) DDI values obtained from the 10 individual trials.
↵e Predicted DDIs (median of total population) from in vitro TDI measured in HLM; values in parentheses represent minimum and maximum DDI values obtained from the 10 trials.
↵f Clinically observed DDIs calculated by AUC in the presence and absence of inhibitor.