TABLE 4

Enzyme induction interactions, in vitro to in vivo translation

The R3 values were not provided for any of the compounds listed. Induction experiments were conducted using human hepatocytes; either CYP3A or CYP3A4 was used depending on how the enzyme was presented in the NDA reviews.

PerpetratorInduction EffectCmaxAUC RatioCmax RatioIn Vivo VictimReference
µM
Alectiniba2.1-fold in mRNA at 1 µM (CYP2B6)1.38FDA (2015b)
2.1-fold in mRNA at 1 µM (CYP3A4b)0.970.92Midazolam
CangrelorInduction observed at 100 µM, value N/P (significantly lower than positive control) (CYP2C9)0.77N/TFDA (2015o)
Induction observed at 100 µM, value N/P (significantly lower than positive control) (CYP3A4/5)
Cangrelor metabolite AR-C69712Induction observed at 100 µM, value N/P (significantly lower than positive control) (CYP2C9)
Induction observed at 100 µM, value N/P (significantly lower than positive control) (CYP3A4)
Cholic acid0.4-fold (P < 0.001) in mRNA at 50 µM (CYP3A4)1.88N/TFDA (2015f); Zhang et al. (2015)
Cobimetinib9.1-fold at 10 µM in mRNA (but not activity, also no PXR activation up to 25 µM) at 10 µM (CYP3A4b)0.511.021.06MidazolamFDA (2015h)
Daclatasvir0.458- to 1.36-fold with 0.5-fold observed in two lots at 9.6 µg/ml (CYP1A2)2.34N/TFDA (2015j)
1.66- to 3.95-fold in mRNA at 9.6 µg/ml (CYP2B6)N/T
8.76- to 27.3-fold in mRNA at 9.6 µg/ml (CYP3A4b)0.850.94Midazolam
Deoxycholic acid43% of positive control in activity at 10 µM in one out three lots (CYP1A2)2.61N/TFDA (2015p)
Isavuconazonium sulfate metabolite isavuconazole2.77-fold (≤10% of positive control) in activity (concentrations N/P) (CYP1A2)17.14No effect (value N/P)No effect (value N/P)CaffeineFDA (2015i)
13.4-fold (84.3% of positive control) in activity (concentrations N/P) (CYP2B6)0.580.69Bupropion
2.63-fold (37.4% of positive control) in activity (concentrations N/P) (CYP2C8b)No effect (value N/P)No effect (value N/P)Repaglinide
3.43-fold (42.2% of positive control) in activity (concentrations N/P) (CYP3A4/5b)0.69N/PRitonavir
0.73N/PLopinavir
No effect (value N/P)No effect (value N/P)Ethinyl estradiol
No effect (value N/P)No effect (value N/P)Norethindrone
No effect (value N/P)No effect (value N/P)Prednisone
Lenvatinib1.65-fold in mRNA and 1.54-fold in activity up to 3 µM (CYP3A4b)1.01–1.551.24 (NS, PBPK)1.21 (NS, PBPK)MidazolamFDA (2015q)
Lesinurad3.04-fold in mRNA and 3.15-fold in activity at 30 µM (CYP2B6)0.000015N/TFDA (2015zg)
4.18-fold in mRNA at 30 µM and 2.38-fold in activity at 10 µM (CYP2C8b)1.100.99Repaglinide
3.46-fold in mRNA at 30 µM and 1.04-fold in activity at 10 µM (CYP2C9b)1.041.03(S)-warfarin
1.061.11Tolbutamide
1.36-fold in mRNA at 100 µM and 3.25-fold in activity at 30 µM (CYP2C19)N/T
3-fold and 67% of positive control rifampin in activity (mRNA not evaluated) at 10 µM (CYP3A4/5)0.580.61Amlodipine
0.660.66Sildenafil
0.730.99Atorvastatin
0.750.82Colchicine
LumacaftorInduction observed, value N/P (CYP2B6)55.26N/TFDA (2015u)
Induction observed, value N/P (CYP2C8b)N/T
Induction observed, value N/P (CYP2C9b)N/T
Induction observed, value N/P (CYP2C19)N/T
Induction observed, value N/P (CYP3A4/5)0.20N/PIvacaftor
Osimertinib16% of positive control in activity at 3.3 µM (CYP1A2)0.13N/TFDA (2015x)
45% of positive control in activity at 3.3 µM (CYP3A4/5b)N/T
Activation of PXR (value N/P)
Rolapitant18.1-fold and 80% of positive control in activity at 10 µM (CYP1A2b)1.93N/TFDA (2015za)
2.10-fold (P < 0.05) in activity at 10 µM (CYP2C8b)1.271.26Repaglinide
1.16-fold (P < 0.05) in activity at 10 µM (CYP2C9b)1.021.00Tolbutamide
2.42-fold (P < 0.05) in activity at 10 µM (CYP2C19b)1.341.48Omeprazole
3.03-fold (P < 0.05) and 68% of positive control in activity at 10 µM (CYP3A4/5b)0.970.87Midazolam
Selexipag38% of positive control rifampin in mRNA at 10 µM (CYP3A4)0.032N/TFDA (2015z)
Selexipag metabolite ACT-33367926% of positive control rifampin in mRNA at 10 µM (CYP3A4)
Tenofovir alafenamide fumarate3.89-fold activation of PXR and 31% of positive control at 50 µM (although no induction of CYP3A)0.00033FDA (2015m)
  • N/P, not provided; NS, not significant; N/T, not tested.

  • a Metabolite M4 was formed in human hepatocytes; therefore, it may also be responsible for the observed induction effect.

  • b Inhibition of the same enzyme was also observed.