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.

PerpetratorIC50R1 or R2AUC RatioCmax RatioIn Vivo VictimReference
Alectinib2.0 (Ki, competitive) (CYP2C8)1.6a1.08b1.06bRepaglinideFDA (2015b)
KI ≥ 60, Kinact = 0.0624/minute (CYP3A4)N/A0.970.92Midazolam
Alectinib metabolite M4KI = 369, Kinact = 0.0620/minute (CYP3A4)N/A
Brexpiprazole8.19 (CYP2B6, bupropion), 5.01 (Ki, inhibition type N/P), no TDI observed1.0921.020.96BupropionFDA (2015v)
22.23 (CYP2C9, diclofenac), no TDI observed1.041N/T
39.82 [CYP2C19, (S)-mephenytoin], no TDI observed1.023N/T
13.44 (CYP2D6, bufuralol), no TDI observed1.068c0.96Dextromethorphan
29.88, KI = 32.1, Kinact = 0.02/minute, Kobs = 0.00024/minute (CYP3A, midazolam)R2 = 4.0a,d with kdeg = 0.00008/minute1.100.96Lovastatin
40.78, KI = 4.7, Kinact = 0.022/minute, Kobs = 0.00169/minute (CYP3A, testosterone)R2 = 22.1a,e with kdeg = 0.00008/minute
Cangrelor metabolite AR-C6971258–59 (CYP2C19)<1.1N/TFDA (2015o)
Cangrelor metabolite AR-C9043958–59 (CYP2C19)<1.1N/T
CariprazinefWeak (value N/P, CYP1A2)N/AFDA (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 DCARWeak (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 DDCARWeak (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 acid38.1% (P < 0.01) at 100 µM (UGT1A1, 4-methylumbelliferone)N/AFang 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
Cobimetinib1.8, 1.1 (unbound Ki) (CYP2D6, bufuralol)1.5a0.650.92DextromethorphanFDA (2015h)
5.9 (CYP3A, testosterone); 17, 7.6 (unbound Ki) (CYP3A, midazolam), TDI (value N/P)1.2a (testosterone), 1.1a (midazolam)1.021.05Midazolam
Daclatasvir11.0 (CYP3A4, testosterone), 31.8 (CYP3A4, midazolam), no TDI observed1.42a,g (testosterone), 1.15a,g (midazolam)0.850.94MidazolamFDA (2015j)
Eluxadoline20 (CYP2E1, chlorzoxazone)1.00gN/TFDA (2015zc)
−5% (coincubation) and 42% (preincubation) at 50 µM (CYP3A4/5, midazolam)N/A1.050.98Ethinyl estradiol
1% (coincubation) and 30%–40% (preincubation) at 50 µM (CYP3A4/5, testosterone)N/A1.061.05Norethindrone
Flibanserin6.4 (Ki) (CYP2B6)1.17a,g1.031.03BupropionFDA (2015a)
7.5 (Ki) (CYP3A4)1.14a,g1.31, simvastatin acid 1.471.15, simvastatin acid 1.36Simvastatin
Isavuconazonium sulfate metabolite isavuconazole2.86 (Ki) (CYP2C8)6.98a,gNo effecth (value N/P)No effecth (value N/P)RepaglinideFDA (2015i)
4.78 (Ki) (CYP2C9)4.58a,gNo effecth (value N/P)No effecth (value N/P)(S)-warfarin
5.40 (Ki) (CYP2C19)4.17a,gNo effecth (value N/P)No effecth (value N/P)Omeprazole
4.82 (Ki) (CYP2D6)4.55a,gNo effecth (value N/P)No effecth (value N/P)Dextromethorphan
0.622–1.93 (Ki) (CYP3A4)9.86–28.49a,g2.031.72Midazolam
Ivabradine46 (CYP3A4, midazolam)1.00gN/TFDA (2015g)
17 (CYP3A5, midazolam)1.01gN/T
140 (Ki) (CYP3A4, midazolam)1.00gN/T
Ivabradine metabolite S18982Weak inhibition (value N/P, CYP3A4/5, testosterone)N/AN/T
Lenvatinib10.1 (CYP2C8, paclitaxel)1.20–1.31a,g1.01b1.00bRepaglinideFDA (2015q)
KI = 72.266, Kinact = 5.01/hour (CYP3A, midazolam)N/P1.24b1.21bMidazolam
10.6 (UGT1A1, estradiol)1.19–1.29gN/T
14.0 (UGT1A4, trifluoperazine)1.14–1.22gN/T
Lesinurad16.2 (CYP2C8)1.00g1.311.27RepaglinideFDA (2015zg)
40.7 (CYP2C9)1.00g1.041.03(S)-warfarin
148 (UGT1A1)1.00gN/T
384 (UGT2B7)1.00gN/T
LumacaftorValue N/P (CYP2C8)N/AFDA (2015u)
Value N/P (CYP2C9)N/A
Osimertinib22.8 (CYP2C8)<1.1FDA (2015x)
5.1 (CYP3A)>1.1aPMR
PalbociclibKI = 10, Kinact = 0.036/minute (CYP3A, midazolam)R2 = 1.05 with kdeg = 0.18/minute1.581.38MidazolamFDA (2015n)
KI = 19, Kinact = 0.087/minute (CYP3A, testosterone)R2 = 1.06 with kdeg = 0.18/minute
Palbociclib metabolite M1716 (CYP3A, felodipine)<1.1N/T
KI = 7.0, Kinact = 0.094/minute (CYP3A, midazolam)1.01N/T
KI = 6.4, Kinact = 0.15/minute (CYP3A, testosterone)1.03N/T
Panobinostat15–75 (CYP2C19), no TDI observed<1.1N/TFDA (2015l)
2, 0.167 (Ki) (CYP2D6), no TDI observed1.37a1.20–2.301.20–3.00Dextromethorphan
15–75, KI = 12, Kinact = 0.137/hour (CYP3A4/5)R2 = 1.4a with kdeg = 0.000321/minute, Kobs = 0.000117/minute1.04b1.04bMidazolam
Rolapitant39% at 100 µM (coincubation), 90 (preincubation) (CYP1A2, phenacetin)N/AN/TFDA (2015za)
22 (coincubation), 10 (preincubation) (CYP2A6, coumarin)N/AN/T
13 (CYP2B6, bupropion), no TDI observed1.13a1.321.09Efavirenz
23 (CYP2C8, amodiaquine), no TDI observed<
9.6 (CYP2C9, diclofenac), no TDI observed1.18a1.050.96Tolbutamide
8.7 [CYP2C19, (S)-mephenytoin], no TDI observed1.20a1.341.48Omeprazole
7.1, 3.4 (Ki, competitive) (CYP2D6, dextromethorphan), no TDI observed1.50a3.332.77Dextromethorphan
49 (coincubation), 35 (preincubation) (CYP3A4/5, testosterone)<1.10.970.87Midazolam
41 (coincubation), 28 (preincubation) (CYP3A4/5, midazolam)<1.1
Rolapitant metabolite M198.65 (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
Sacubitrili15 (CYP2C8)N/AN/TFDA (2015k)
20 (CYP2C19)N/ANo effect (value N/P)No effect (value N/P)Omeprazole
Sacubitril metabolite LBQ65740 (CYP2C9)N/ANo effect (value N/P)No effect (value N/P)(S)-warfarin
No effect (value N/P)No effect (value N/P)Carvedilol
Selexipag3.6 (CYP2C8), no TDI observed1.02gN/TFDA (2015z)
8.3 (CYP2C9), no TDI observed1.00g1.001.00(S)-warfarin
Selexipag metabolite ACT-33367915 (CYP2C8), no TDI observedN/A
32 (CYP2C9), no TDI observedN/A
Sonidegib0.045 (Ki, inhibition type N/P) (CYP2B6),34aN/TjFDA (2015t)
1.7 (Ki, inhibition type N/P) (CYP2C9), no TDI observed1.8aN/Tj
Tenofovir alafenamide fumarate7.4 (CYP3A, testosterone), 7.6 (CYP3A, midazolam), no TDI observed1.00gN/TFDA (2015m)
Uridine triacetate6600 (CYP2C19)1.00gN/TFDA (2015ze)
8300 (CYP3A)1.00gN/T
Uridine triacetate metabolite uridine5100 (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 kdeg of 0.0005/minute.

  • e R2 = 4.4 assuming kdeg 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 Ki or assuming Ki = 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.