TABLE 3

Enzyme inhibition interactions, in vitro to in vivo translation

PMR indicates the study was requested as a PMR. The inhibition studies were performed using human liver microsomes except cholic acid and ivabradine, for which the inhibition studies were performed using recombinant enzymes. If the in vitro substrate was not provided, then it is not listed; either CYP3A or CYP3A4 was used depending on how the enzyme was presented in the NDA reviews.

Perpetrator	IC₅₀	R₁ or R₂	AUC Ratio	C_max Ratio	In Vivo Victim	Reference
	µM
Alectinib	2.0 (K_i, competitive) (CYP2C8)	1.6^{^a}	1.08^{^b}	1.06^{^b}	Repaglinide	FDA (2015b)
	K_I ≥ 60, K_inact = 0.0624/minute (CYP3A4)	N/A	0.97	0.92	Midazolam
Alectinib metabolite M4	K_I = 369, K_inact = 0.0620/minute (CYP3A4)	N/A
Brexpiprazole	8.19 (CYP2B6, bupropion), 5.01 (K_i, inhibition type N/P), no TDI observed	1.092	1.02	0.96	Bupropion	FDA (2015v)
	22.23 (CYP2C9, diclofenac), no TDI observed	1.041	N/T
	39.82 [CYP2C19, (S)-mephenytoin], no TDI observed	1.023	N/T
	13.44 (CYP2D6, bufuralol), no TDI observed	1.068^{^c}	0.96		Dextromethorphan
	29.88, K_I = 32.1, K_inact = 0.02/minute, K_obs = 0.00024/minute (CYP3A, midazolam)	R₂ = 4.0^{^a}^,^{^d} with k_deg = 0.00008/minute	1.10	0.96	Lovastatin
	40.78, K_I = 4.7, K_inact = 0.022/minute, K_obs = 0.00169/minute (CYP3A, testosterone)	R₂ = 22.1^{^a}^,^{^e} with k_deg = 0.00008/minute
Cangrelor metabolite AR-C69712	58–59 (CYP2C19)	<1.1	N/T			FDA (2015o)
Cangrelor metabolite AR-C90439	58–59 (CYP2C19)	<1.1	N/T
Cariprazine^{^f}	Weak (value N/P, CYP1A2)	N/A				FDA (2015zd)
	weak (value N/P, CYP2A6)	N/A
	weak (value N/P, CYP2C9)	N/A
	weak (value N/P, CYP2C19)	N/A
	weak (value N/P, CYP2D6)	N/A
	weak (value N/P, CYP2E1)	N/A
	weak (value N/P, CYP3A4)	N/A
Cariprazine metabolites DCAR	Weak (value N/P, CYP1A2)	N/A
	weak (value N/P, CYP2C9)	N/A
	weak (value N/P, CYP2D6)	N/A
	weak (value N/P, CYP3A4)	N/A
Cariprazine metabolites DDCAR	Weak (value N/P, CYP1A2)	N/A
	Weak (value N/P, CYP2C9)	N/A
	weak (value N/P, CYP2D6)	N/A
	weak (value N/P, CYP3A4)	N/A
Cholic acid	38.1% (P < 0.01) at 100 µM (UGT1A1, 4-methylumbelliferone)	N/A				Fang et al. (2013); FDA (2015f)
	13.9% (P < 0.05) at 100 µM (UGT1A8, 4-methylumbelliferone)	N/A
	25.65% (P < 0.01) at 100 µM (UGT1A10, 4-methylumbelliferone)	N/A
	27.9% (P < 0.01) at 100 µM (UGT2B15, 4-methylumbelliferone)	N/A
Cobimetinib	1.8, 1.1 (unbound K_i) (CYP2D6, bufuralol)	1.5^{^a}	0.65	0.92	Dextromethorphan	FDA (2015h)
	5.9 (CYP3A, testosterone); 17, 7.6 (unbound K_i) (CYP3A, midazolam), TDI (value N/P)	1.2^{^a} (testosterone), 1.1^{^a} (midazolam)	1.02	1.05	Midazolam
Daclatasvir	11.0 (CYP3A4, testosterone), 31.8 (CYP3A4, midazolam), no TDI observed	1.42^{^a}^,^{^g} (testosterone), 1.15^a^,^{^g} (midazolam)	0.85	0.94	Midazolam	FDA (2015j)
Eluxadoline	20 (CYP2E1, chlorzoxazone)	1.00^{^g}	N/T			FDA (2015zc)
	−5% (coincubation) and 42% (preincubation) at 50 µM (CYP3A4/5, midazolam)	N/A	1.05	0.98	Ethinyl estradiol
	1% (coincubation) and 30%–40% (preincubation) at 50 µM (CYP3A4/5, testosterone)	N/A	1.06	1.05	Norethindrone
Flibanserin	6.4 (K_i) (CYP2B6)	1.17^{^a}^,^{^g}	1.03	1.03	Bupropion	FDA (2015a)
	7.5 (K_i) (CYP3A4)	1.14^a^,^{^g}	1.31, simvastatin acid 1.47	1.15, simvastatin acid 1.36	Simvastatin
Isavuconazonium sulfate metabolite isavuconazole	2.86 (K_i) (CYP2C8)	6.98^{^a}^,^{^g}	No effect^{^h} (value N/P)	No effect^{^h} (value N/P)	Repaglinide	FDA (2015i)
	4.78 (K_i) (CYP2C9)	4.58^{^a}^,^{^g}	No effect^{^h} (value N/P)	No effect^{^h} (value N/P)	(S)-warfarin
	5.40 (K_i) (CYP2C19)	4.17^{^a}^,^{^g}	No effect^{^h} (value N/P)	No effect^{^h} (value N/P)	Omeprazole
	4.82 (K_i) (CYP2D6)	4.55^{^a}^,^{^g}	No effect^{^h} (value N/P)	No effect^{^h} (value N/P)	Dextromethorphan
	0.622–1.93 (K_i) (CYP3A4)	9.86–28.49^{^a}^,^{^g}	2.03	1.72	Midazolam
Ivabradine	46 (CYP3A4, midazolam)	1.00^{^g}	N/T			FDA (2015g)
	17 (CYP3A5, midazolam)	1.01^{^g}	N/T
	140 (K_i) (CYP3A4, midazolam)	1.00^{^g}	N/T
Ivabradine metabolite S18982	Weak inhibition (value N/P, CYP3A4/5, testosterone)	N/A	N/T
Lenvatinib	10.1 (CYP2C8, paclitaxel)	1.20–1.31^{^a}^,^{^g}	1.01^{^b}	1.00^{^b}	Repaglinide	FDA (2015q)
	K_I = 72.266, K_inact = 5.01/hour (CYP3A, midazolam)	N/P	1.24^{^b}	1.21^{^b}	Midazolam
	10.6 (UGT1A1, estradiol)	1.19–1.29^{^g}	N/T
	14.0 (UGT1A4, trifluoperazine)	1.14–1.22^{^g}	N/T
Lesinurad	16.2 (CYP2C8)	1.00^{^g}	1.31	1.27	Repaglinide	FDA (2015zg)
	40.7 (CYP2C9)	1.00^{^g}	1.04	1.03	(S)-warfarin
		1.00^{^g}	1.11	1.06	Tolbutamide
	148 (UGT1A1)	1.00^{^g}	N/T
	384 (UGT2B7)	1.00^{^g}	N/T
Lumacaftor	Value N/P (CYP2C8)	N/A				FDA (2015u)
	Value N/P (CYP2C9)	N/A
Osimertinib	22.8 (CYP2C8)	<1.1				FDA (2015x)
	5.1 (CYP3A)	>1.1^{^a}	PMR
Palbociclib	K_I = 10, K_inact = 0.036/minute (CYP3A, midazolam)	R₂ = 1.05 with k_deg = 0.18/minute	1.58	1.38	Midazolam	FDA (2015n)
	K_I = 19, K_inact = 0.087/minute (CYP3A, testosterone)	R₂ = 1.06 with k_deg = 0.18/minute
Palbociclib metabolite M17	16 (CYP3A, felodipine)	<1.1	N/T
	K_I = 7.0, K_inact = 0.094/minute (CYP3A, midazolam)	1.01	N/T
	K_I = 6.4, K_inact = 0.15/minute (CYP3A, testosterone)	1.03	N/T
Panobinostat	15–75 (CYP2C19), no TDI observed	<1.1	N/T			FDA (2015l)
	2, 0.167 (K_i) (CYP2D6), no TDI observed	1.37^{^a}	1.20–2.30	1.20–3.00	Dextromethorphan
	15–75, K_I = 12, K_inact = 0.137/hour (CYP3A4/5)	R₂ = 1.4^{^a} with k_deg = 0.000321/minute, K_obs = 0.000117/minute	1.04^{^b}	1.04^{^b}	Midazolam
Rolapitant	39% at 100 µM (coincubation), 90 (preincubation) (CYP1A2, phenacetin)	N/A	N/T			FDA (2015za)
	22 (coincubation), 10 (preincubation) (CYP2A6, coumarin)	N/A	N/T
	13 (CYP2B6, bupropion), no TDI observed	1.13^{^a}	1.32	1.09	Efavirenz
	23 (CYP2C8, amodiaquine), no TDI observed	<1.1	1.27	1.26	Repaglinide
	9.6 (CYP2C9, diclofenac), no TDI observed	1.18^{^a}	1.05	0.96	Tolbutamide
	8.7 [CYP2C19, (S)-mephenytoin], no TDI observed	1.20^{^a}	1.34	1.48	Omeprazole
	7.1, 3.4 (K_i, competitive) (CYP2D6, dextromethorphan), no TDI observed	1.50^{^a}	3.33	2.77	Dextromethorphan
	49 (coincubation), 35 (preincubation) (CYP3A4/5, testosterone)	<1.1	0.97	0.87	Midazolam
	41 (coincubation), 28 (preincubation) (CYP3A4/5, midazolam)	<1.1
Rolapitant metabolite M19	8.65 (CYP2B6, bupropion)	N/A
	21.1% at 10 µM (CYP2C9, diclofenac)	N/A
	44.8% at 10 µM [CYP2C19, (S)-mephenytoin]	N/A
	31.4% at 10 µM (CYP2D6, dextromethorphan)	N/A
Sacubitril^ⁱ	15 (CYP2C8)	N/A	N/T			FDA (2015k)
	20 (CYP2C19)	N/A	No effect (value N/P)	No effect (value N/P)	Omeprazole
Sacubitril metabolite LBQ657	40 (CYP2C9)	N/A	No effect (value N/P)	No effect (value N/P)	(S)-warfarin
			No effect (value N/P)	No effect (value N/P)	Carvedilol
Selexipag	3.6 (CYP2C8), no TDI observed	1.02^{^g}	N/T			FDA (2015z)
	8.3 (CYP2C9), no TDI observed	1.00^{^g}	1.00	1.00	(S)-warfarin
Selexipag metabolite ACT-333679	15 (CYP2C8), no TDI observed	N/A
	32 (CYP2C9), no TDI observed	N/A
Sonidegib	0.045 (K_i, inhibition type N/P) (CYP2B6),	34^{^a}	N/T^{^j}			FDA (2015t)
	1.7 (K_i, inhibition type N/P) (CYP2C9), no TDI observed	1.8^{^a}	N/T^{^j}
Tenofovir alafenamide fumarate	7.4 (CYP3A, testosterone), 7.6 (CYP3A, midazolam), no TDI observed	1.00^{^g}	N/T			FDA (2015m)
Uridine triacetate	6600 (CYP2C19)	1.00^{^g}	N/T			FDA (2015ze)
	8300 (CYP3A)	1.00^{^g}	N/T
Uridine triacetate metabolite uridine	5100 (CYP2C19)	N/A
	2000 (CYP3A)	N/A

N/A, not applicable; N/P, not provided; N/T, not tested; TDI, time-dependent inhibition.
↵^a Values exceed the FDA cut-off value of 1.1.
↵^b Results are obtained from PBPK modeling and simulations.
↵^c The ratio is the dextromethorphan/dextrorphan urinary ratio with or without brexpiprazole.
↵^d R₂ = 1.5 assuming k_deg of 0.0005/minute.
↵^e R₂ = 4.4 assuming k_deg of 0.0005/minute.
↵^f The in vitro evaluation of inhibition potential of cariprazine toward CYP2C8 as well as DCAR and DDCAR toward CYP2B6, 2C8, and 2C19 has been requested as a PMR.
↵^g The R₁ value was calculated by the University of Washington Drug Interaction Database editorial team using K_i or assuming K_i = IC₅₀/2.
↵^h Prodrug isavuconazonium sulfate was administered in the clinical studies.
↵ⁱ Perpetrator was administered as the combination drug.
↵^j Clinical studies are undergoing.