TABLE 3

Predictions of clinical DDIs from in vitro inhibition parameters of CYP3A, CYP2C9, and CYP2D6 inhibitors (63 clinical DDIs)

Inhibitor	Victim Drug	[I]_{ave, total}	K_{i, app}		Predicted Fold Increase in AUC by		Observed Fold-Increase in AUC	Reference
Inhibitor	Victim Drug	[I]_{ave, total}	HMM	Plasma	Free [I] with HMM K_{i, app}	Total [I] with Plasma K_{i, app}	Observed Fold-Increase in AUC	Reference
		μM
Ketoconazole	Midazolam	2.82	0.26	0.75	1.93	6.60	15.90	Olkkola et al., 1994
Ketoconazole	Midazolam	3.46	0.26	0.75	1.96	7.41	16.00	Tsunoda et al., 1999
Ketoconazole	Midazolam	4.76	0.26	0.75	2.04	8.89	6.47	Eap et al., 2004
Ketoconazole	Midazolam	1.88	0.26	0.75	1.86	5.21	7.72	Lam et al., 2003
Ketoconazole	Midazolam	2.82	0.26	0.75	1.65	5.66	9.51	Chung et al., 2006
Ketoconazole	Midazolam i.v.	3.46	0.26	0.75	1.12	4.24	5.10	Tsunoda et al., 1999
Ketoconazole	Midazolam	1.87	0.26	0.75	1.47	4.09	6.45	McCrea et al., 1999
Fluconazole	Midazolam	21.55	25.23	4.56	2.66	6.84	3.51	Olkkola et al., 1996
Fluconazole	Midazolam	29.99	25.23	4.56	2.84	7.70	3.60	Olkkola et al., 1996
Fluconazole	Midazolam	5.6	25.23	4.56	1.60	2.78	2.16	Kharasch et al., 2005
Aprepitant	Midazolam	1.72		14.43		1.92	2.27	Majumdar et al., 2003
Aprepitant	Midazolam	2.22		14.43		1.97	3.30	Majumdar et al., 2003
Aprepitant	Midazolam	0.41		14.43		1.72	1.28	Majumdar et al., 2003
Aprepitant	Midazolam i.v.	3.11		14.43		1.26	1.47	Majumdar et al., 2007
Voriconazole	Midazolam i.v.	1.64	20.93	1.80	1.03	1.79	3.64	Saari et al., 2006
Voriconazole	Midazolam	1.46	20.93	1.80	1.64	2.74	9.85	Saari et al., 2006
Nefazodone	Midazolam	1.73	0.46	1.02	1.79	4.17	4.44	Lam et al., 2003
Conivaptan	Midazolam	1.57	1.78	1.02	1.57	3.58	3	NDA 021697^{^a}
Conivaptan	Midazolam i.v.	1.57	1.78	1.02	1.00	2.29	2	NDA 021697^{^a}
Sulfaphenazole	Tolbutamide	160	0.25	8.55	4.90	4.16	5.28	Veronese et al., 1990
Sulfaphenazole	Tolbutamide	320	0.25	8.55	4.95	4.53	3.09	Back et al., 1988
Sulfaphenazole	Phenytoin	640	0.25	8.55	3.99	3.85	3.05	Hansen et al., 1979
Fluconazole	S-Warfarin	46.5	47.33	12.92	1.68	3.13	2.84	Black et al., 1996
Fluconazole	Tolbutamide	11.68	47.33	12.92	1.17	1.61	2.09	Lazar and Wilner, 1990
Fluconazole	Phenytoin	24	47.33	12.92	1.30	1.95	1.75	Blum et al., 1991
Fluconazole	Phenytoin	46.5	47.33	12.92	1.54	2.42	1.33	Touchette et al., 1992
Fluconazole	Losartan	23.4	47.33	12.92	1.33	2.01	1.69	Kazierad et al., 1997
Fluconazole	Losartan	23.4	47.33	12.92	1.33	2.01	1.27	Kaukonen et al., 1998
Fluconazole	Fluvastatin	23.4	47.33	12.92	1.22	1.63	1.84	Kantola et al., 2000
Fluconazole	Glimepiride	23.4	47.33	12.92	1.41	2.58	2.38	Niemi et al., 2001
Miconazole	S-Warfarin	0.27	1.86	1.82	1.01	1.13	4.72	O'Reilly et al., 1992
Fluvastatin	Diclofenac	1	3.57	6.11	1.00	1.12	1.07	Andersson et al., 2004
Ibuprofen	Diclofenac	114	132.72	1081	1.00	1.08	0.99	Andersson et al., 2004
Tolbutamide	Diclofenac	165	88.67	1081	1.05	1.11	0.93	Andersson et al., 2004
Diphenhydramine	Metoprolol	0.26	1.46	21.21	1.03	1.01	1.61	Hamelin et al., 2000
Diphenhydramine	Metoprolol	0.26	1.46	21.21	1.03	1.01	1.10	Hamelin et al., 2000
Diphenhydramine	Metoprolol	0.26	1.46	21.21	1.03	1.01	1.92	Sharma et al., 2005
Diphenhydramine	Metoprolol	0.26	1.46	21.21	1.03	1.01	0.82	Sharma et al., 2005
Sertraline	Desipramine	0.071	2.65	9.70	1.00	1.01	1.24	Preskorn et al., 1994
Sertraline	Desipramine	0.065	2.65	9.70	1.00	1.01	1.37	Alderman et al., 1997
Sertraline	Desipramine	0.2	2.65	9.70	1.00	1.02	1.74	Zussman et al., 1995
Sertraline	Desipramine	0.2	2.65	9.70	1.00	1.02	1.54	Kurtz et al., 1997
Sertraline	Imipramine	0.2	2.65	9.70	1.00	1.01	1.68	Kurtz et al., 1997
Sertraline	Desipramine	0.2	2.65	9.70	1.00	1.02	2.29	Kurtz et al., 1997
Paroxetine	Desipramine	0.14	0.03	0.05	1.23	2.87	4.64	Brøsen et al., 1993
Paroxetine	Imipramine	0.14	0.03	0.05	1.11	1.52	1.74	Albers et al., 1996
Paroxetine	Desipramine	0.14	0.03	0.05	1.23	2.87	4.28	Albers et al., 1996
Paroxetine	Metoprolol	0.14	0.03	0.05	1.21	2.60	7.93	Hemeryck et al., 2000
Paroxetine	Metoprolol	0.14	0.03	0.05	1.21	2.60	5.08	Hemeryck et al., 2000
Paroxetine	Desipramine	0.14	0.03	0.05	1.23	2.87	5.21	Alderman et al., 1997
Paroxetine	Desipramine	0.017	0.03	0.05	1.03	1.29	1.36	Alderman et al., 1997
Paroxetine	Desipramine	0.14	0.03	0.05	1.23	2.87	4.8	Laine et al., 2004
Quinidine	Desipramine	0.451	0.03	0.01	2.56	6.83	7.5	Brøsen and Gram, 1989
Quinidine	Imipramine	0.451	0.03	0.01	1.47	1.81	1.54	Brøsen and Gram, 1989
Quinidine	Encainide	0.451	0.03	0.01	2.47	6.03	3.18	Funck-Brentano et al., 1989b
Quinidine	Encainide	0.41	0.03	0.01	2.37	5.94	11.4	Turgeon et al., 1990
Quinidine	Metoprolol	0.23	0.03	0.01	1.80	4.59	3.24	Johnson and Burlew, 1996
Quinidine	Mexiletine	0.45	0.03	0.01	1.51	1.91	1.32	Turgeon et al., 1991
Quinidine	Propafenone	0.34	0.03	0.01	1.91	3.70	2.7	Funck-Brentano et al., 1989a
Quinidine	Desipramine	4.6	0.03	0.01	6.38	8.15	3.14	Ayesh et al., 1991
Fluoxetine	Desipramine	0.57	0.03	0.24	1.88	2.63	2.25	Bergstrom et al., 1992
Fluoxetine	Desipramine	1.54	0.03	0.24	2.98	4.19	7.43	Bergstrom et al., 1992
Duloxetine	Desipramine	0.3	0.19	0.47	1.07	1.53	2.9	Skinner et al., 2003

↵a New Drug Application (NDA) 021697 (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021697s000_VaprisolTOC.cfm).