Enzyme induction interactions, in vitro to in vivo translation

PerpetratorInduction EffectR3aAUC RatioReference
Alogliptin2- to 6-fold, 28% of rifampin at 100 µM (CYP3A4)1.08 (Midazolam, CYP3A)(FDA, 2013q)
Dabrafenib32-fold, 320% of phenytoin at 30 µM (CYP2B6)(FDA, 2013w)
30-fold, 150% of rifampin at 30 µM (CYP3A4)0.26 (Midazolam, CYP3A)
Dolutegravir58% of rifampin up to 10 µM (PXRb)0.95 (Midazolam, CYP3A)(FDA, 2013y)
Eslicarbazepine acetatecNo induction up to 393 µM (Eslicarbazepine, CYP1A, CYP2C19, CYP3A4, UGTs, sulfotransferases)0.77 (S-warfarin, CYP2C9)(FDA, 2013c)
No induction up to 40 µM ((R)-licarbazepine, CYP3A4)0.51 (Simvastatin, CYP3A)
No induction up to 40 µM (Oxcarbazepine, CYP3A4)0.58 (Ethinyl estradiol, CYP3A)
0.63 (Levonorgestrel, CYP3A4)
Macitentan11-fold (5-fold activity) at 10 µM (CYP3A4)1.15 (Sildenafil, CYP3A)(FDA, 2013s)
5.8-fold, 121% of rifampin, EC50 = 1.1–1.2 µM (PXR)
Ospemifene52.4-fold at 20 µM (1/4 donors, CYP1A2)(FDA, 2013t)
2.0-fold at 20 µM (2/4 donors, CYP2B6)
2.4-fold at 20 µM (1/3 donors, CYP3A4)
Trametinib76% of phenytoin up to 10 µM (CYP2B6)(FDA, 2013p)
Emax = 37.3%, 67% of rifampin up to 10 µM0.54d1.16 (Everolimus, CYP3A)
EC50 = 2.7 µM (CYP3A4)
50% of rifampin up to 10 µM (PXR)
  • N/T, not tested in NDA reviews.

  • a R3 cut-off value: 0.9.

  • b CYP3A4 mRNA levels were not increased (1.1-fold of vehicle control) with rifampin treatment.

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

  • d Underlined values are below the FDA cut-off to warrant in vivo study.