Enzyme inhibition interactions, in vitro to in vivo translation

PerpetratorIC50R1aAUC RatioReference
Alogliptin27% at 100 µM (CYP2D6)N/Ab1.30 (Dextromethorphan, CYP2D6)(FDA, 2013q)
Ado-trastuzumab emtansined0.16e (CYP3A4)N/Ab(FDA, 2013l)
Canagliflozin16 (CYP2B6)2.31cPBPK modeling negative (bupropion)(FDA, 2013k)
75 (CYP2C8)1.28c
55 (CYP2C9)1.40c1.06 (S-warfarin, CYP2C9)
1.02 (Glyburide, CYP2C9)
39 (CYP2C19)1.54cN/T
65 (CYP2D6)1.32cN/T
18 (CYP2E1)2.11cN/T
27f (CYP3A4)1.78c1.07 (Ethinyl estradiol, CYP3A)
1.06 (Levonorgestrel, CYP3A4)
1.12 (Simvastatin, CYP3A)
Dabrafenib8.2 (CYP2C8)1.69cN/T(FDA, 2013w)
7.2 (CYP2C9)1.79cN/T
22 (CYP2C19)1.26cN/T
16f (CYP3A4)1.36cN/T
Dimethyl fumarate27.6 (CYP2D6)<1.1(FDA, 2013x)
Dolutegravir12.5g (CYP1A2)N/Ab(FDA, 2013y)
33d,f (CYP3A4)N/Ab
Eslicarbazepine acetateh38% at 393 µM (Eslicarbazepine, CYP2C9)N/Ab(FDA, 2013c)
912 (Eslicarbazepine, CYP2C19)1.21.35 (Phenytoin, CYP2C19)
27%f at 393 µM (Eslicarbazepine, CYP3A4)N/Ab
38.8%i at 393 µM (Eslicarbazepine, UGT1A1)
49% at 1180 µM ((R)-licarbazepine, CYP2C19)N/Ab
666 (Oxcarbazepine, CYP2C19)<1.1k
Fluticasone (F) and vilanterol (V)4.0 (F, CYP2B6)<1.1(FDA, 2013d)
0.58 (F, CYP2C8)<1.1
2.4 (F, CYP2C9)<1.1
5.5 (F, CYP2C19)<1.1
3.2 (F), 12 (V) (CYP2D6)<1.1
0.74f (F), 3.5 (V), (CYP3A4)<1.1
Ibrutinib4.8j (CYP2B6)1.08(FDA, 2013j)
12j (CYP2C8)1.03
5.9j (CYP2C9)1.06
6.6j (CYP2C19)1.06
12.5j (CYP2D6)1.03
10.0f,j (CYP3A4)1.04
Luliconazole0.029j (CYP2C19)1.55cPostmarketing requirement(FDA, 2013n)
0.13j (CYP3A4)1.22cPostmarketing requirement
Macitentan21 (CYP2C8)1.03k(FDA, 2013s)
5.0f,j (CYP2C9)1.12k
24f (CYP3A4)1.02k
Ospemifene7.8 (CYP2B6)1.81c,k0.83 (Bupropion, CYP2B6)(FDA, 2013t)
36.4 (CYP2C8)1.17k
10 (CYP2C9)1.63c,k0.96 (S-warfarin, CYP2C9)
22.5f (CYP2C19)1.28c,k0.83 (Omeprazole, CYP2C19)
48.7 (CYP2D6)1.13k
37.9l (CYP3A4)1.17k
Riociguat0.8 (CYP1A1)1.70c,kN/T(FDA, 2013a)
44 (CYP2C19)1.01k
Simeprevir59.7 (CYP2A6)1.49c,kN/T(FDA, 2013r)
49.1 (CYP2C8)1.59c,kN/T
86.1 (CYP2C19)1.34c,k1.32 (Omeprazole, CYP2C19)
42.9 (CYP2D6)1.68c,k0.98 (Dextromethorphan, CYP2D6)
84.5f (CYP3A4)1.34c,k2.19 (Atorvastatin,m CYP3A)
1.90 (Erythromycin,n CYP3A)
1.71 (Simvastatin,m CYP3A)
1.43 (Midazolam, CYP3A)
1.32 (Ritonavir, CYP3A)
1.20 (Cyclosporine, CYP3A)
119j (UGT1A1)N/Ab
28% at 300 µM (CYP1A2)N/Ab1.26 (Caffeine, CYP1A2)
46.5% at 300 µM (CYP2C9)N/Ab1.03 (S-warfarin, CYP2C9)
Trametinib0.34 (CYP2C8)1.24cN/T(FDA, 2013p)
4.1 (CYP2C9)1.02
5 (CYP2C19)1.02
Umeclidinium (U) and vilanterol (V)0.1 (U), 11.5 (V), (CYP2D6)<1.1(FDA, 2013b)
8.0 (U), 3.5f (V), (CYP3A4)<1.1
Vortioxetine9.34 (CYP2C8)<1.1(FDA, 2013e)
15f (CYP2C9)<1.1
  • N/A, not applicable; N/T, not tested in NDA reviews.

  • a R1 cut-off value: 1.1.

  • b R values not calculated due to the lack of availability of the appropriate parameter (e.g., Ki, EC50, or Emax) used for calculation.

  • c Underlined values exceed FDA cut-off to warrant in vivo study.

  • d Antibody-drug conjugate, the active drug, mertansine, was evaluated.

  • e IC50 values obtained via pre-incubation, no inhibition observed via coincubation, however no further experiments addressing the inhibition mechanism.

  • f Multiple IC50 or percent inhibition values provided with different substrates or systems, the most potent is presented.

  • g IC50 value obtained in recombinant enzyme, IC50 estimated to be > 33 µM in HLMs.

  • h Prodrug, pharmacologic active drugs eslicarbazepine (main), (R)-licarbazepine, and oxcarbazepine were evaluated in vitro.

  • i Activation.

  • j Ki values.

  • k R value computed by the DIDB Editorial Team.

  • l IC50 obtained with omeprazole as the substrate, IC50 estimated to be >100 µM with midazolam or testosterone.

  • m Inhibition of OATP1B1 may also contribute.

  • n Inhibition of P-gp may also contribute.