Metabolism-based clinically significant inhibitions, NMEs as substrates or perpetrators

Victim Drug (Dose)Inhibitor (Dose)Enzyme(s) Possibly InvolvedMax AUC RatioStudy Design/PopulationReference
Ibrutiniba (120 mg alone, 40 mg with ketoconazole)Ketoconazole (400 mg once daily 6 days)CYP3A23.9 (dose-normalized)One-sequence/18 healthy subjects(FDA, 2013j)
Simeprevira (150 mg once daily 7 days)Erythromycin (500 mg 3 times daily 6.5 days)CYP3Ab6.5Random Crossover/24 healthy subjects(FDA, 2013r)
Ospemifenea (60 mg SD)Fluconazole (400 mg on Day 1; 200 mg once daily 7 days)CYP3A, CYP2C9, CYP2C192.8Random Crossover/14 postmenopausal healthy women(FDA, 2013t)
Riociguata (dose not available, SD)Ketoconazole (400 mg once daily repeated doses)CYP3Ab2.5Not provided/healthy subjects(FDA, 2013a)
Vortioxetinea (10 mg once daily 28 days)Bupropion (75 mg twice daily Day 1-3; 150 mg twice daily 11 days)CYP2D62.3One-sequence/24 healthy subjects(Chen et al., 2013; FDA, 2013e)
Macitentana (10 mg SD)Ketoconazole (400 mg once daily 24 days)CYP3A2.3Random Crossover/10 healthy subjects(FDA, 2013s)
Atorvastatin (40 mg SD)Simeprevira (150 mg once daily 12 days)CYP3Ab,c2.2One-sequence/36 healthy subjects(FDA, 2013r)
  • Maximum changes in the victim AUC are presented.

  • a 2013 NMEs are underlined.

  • b Inhibition of P-gp and/or BCRP may also contribute.

  • c Inhibition of OATP1B1 may also contribute.