Clinically significant inhibitions, NMEs as victims or perpetrators
| Dose | Enzyme/Transporter Possibly Involved | Ratio | Study Design/Populationa | Labeling Impact | Reference | ||
|---|---|---|---|---|---|---|---|
| Victim Drug | Inhibitor | AUC | Cmax | ||||
| DDIs with AUC ratio ≥ 2b | |||||||
| Ivabradinec | Josamycin | CYP3A4 | 7.70 | 3.60 | N/P | Contraindication with strong CYP3A4 inhibitors | FDA (2015g) |
| Ivabradinec | Ketoconazole (200 mg once daily) | CYP3A4, P-gp | 7.70 | 3.60 | N/P | Contraindication with strong CYP3A4 inhibitors | FDA (2015g) |
| Cobimetinib (10 mg SD)c | Itraconazole (200 mg once daily for 14 days) | CYP3A4, P-gp | 6.62 | 3.17 | One-sequence/15 healthy subjects | Avoid CYP3A strong inhibitors | FDA (2015h) |
| Flibanserin (100 mg SD)c | Fluconazole (200 mg once daily for 6 days) | CYP3A4, CYP2C19 (minor) | 6.41 | 2.11 | One-sequence/15 healthy females | Contraindication with CYP3A4 moderate inhibitors | FDA (2015a) |
| Isavuconazonium sulfate (200 mg SD)c,d | Ketoconazole (200 mg twice daily for 24 days) | CYP3A | 5.22 | 1.09 | N/P | Contraindication with strong CYP3A4 inhibitors | FDA (2015i) |
| Flibanserin (50 mg SD)c | Ketoconazole (400 mg once daily for 5 days) | CYP3A4, CYP2C8/9 (minimal) | 4.61 | 1.84 | Random crossover/20 healthy females | Contraindication with CYP3A4 strong inhibitors | FDA (2015a) |
| Cobimetinib (60 mg once daily for 35 days)c | Erythromycin (500 mg three times daily for 35 days) | CYP3A4, P-gp | 4.27 (PBPK) | 3.76 (PBPK) | PBPK modeling/simulations of healthy subjects | Avoid CYP3A moderate inhibitors | FDA (2015h) |
| Eluxadoline (100 mg SD)c | Cyclosporine (600 mg SD) | OATP1B1, MRP2 (minimal) | 4.20 | 6.81 | Random crossover/30 healthy subjects | Reduce dose with OATP1B1 inhibitors; monitor for adverse reactions | FDA (2015zc) |
| Cariprazine (0.5 mg once daily for 14 days)c | Ketoconazole (400 mg) | CYP3A4 | 3.78 | 3.27 | N/P/16 patients | Reduce dose with CYP3A strong inhibitors | FDA (2015zd) |
| Dextromethorphan (30 mg SD) | Rolapitant (200 mg SD)c | CYP2D6 | 3.33 | 2.77 | One-sequence/26 subjects (CYP2D6 EMs and IMs) | Monitor for adverse reactions if concomitant use with other CYP2D6 substrates with a NTI cannot be avoided | FDA (2015za) |
| Cobimetinib (60 mg SD)c | Diltiazem (1200 mg twice daily) | CYP3A4, P-gp | 3.26 (PBPK) | 1.85 (PBPK) | PBPK modeling/simulations of healthy subjects | Avoid CYP3A moderate inhibitors | FDA (2015h) |
| Daclatasvir (10 mg SD)c | Ketoconazole (400 mg once daily for 9 days) | CYP3A, CYP2C8 (minor), P-gp | 3.01 | 1.57 | One-sequence/13 healthy subjects | Reduce dose with CYP3A strong inhibitors | FDA (2015j) |
| Ivabradinec | Diltiazem (120 mg twice daily) | CYP3A4, P-gp | 3.00 | 2.50 | N/P | Contraindication with strong CYP3A4 inhibitors | FDA (2015g) |
| Dextromethorphan (60 mg SD) | Panobinostat (20 mg once daily for 3 days)c | CYP2D6 | 2.30e | 3.00e | One-sequence/14 patients (CYP2D6 EMs) | Avoid CYP2D6 sensitive substrates or CYP2D6 substrates with a NTI | FDA (2015l) |
| Sonidegib (200 mg once daily at steady state)c | Erythromycin (500 mg once daily for 120 days) | CYP3A | 2.80 (PBPK) | 2.40 (PBPK) | PBPK modeling/simulations of patients | Avoid long-term use of CYP3A moderate inhibitors | FDA (2015t) |
| Rocuroniumf | Sugammadex (4 mg/kg SD)c,f | Not by P450s | 2.70 | N/P | Parallel/2 | Adjust dose | FDA (2015e) |
| Tenofovir alafenamide fumarate (8 mg once daily for 22 days)c | Cobicistat (150 mg once daily for 10 days) | P-gp, BCRP, OATP1B1, OATP1B3 | 2.65 | 2.83 | One-sequence/12 healthy subjects | Combination drug | FDA (2015m) |
| Flibanserin (50 mg SD)c | Itraconazole (200 mg once daily for 7 days) | CYP3A4, CYP2C8/9 (minimal) | 2.58 | 1.70 | Random crossover/12 healthy subjects | Contraindication with CYP3A4 strong inhibitors | FDA (2015a) |
| Sonidegib (800 mg SD)c | Ketoconazole (200 mg twice daily for 14 days) | CYP3A | 2.26 | 1.50 | Parallel/15 healthy subjects | Avoid CYP3A strong inhibitors | FDA (2015t) |
| Tacrolimus (5 mg SD) | Isavuconazonium sulfatec | CYP3A4 | 2.25 | 1.42 | N/P | Caution; adjust immunosuppressant’s dose as needed | FDA (2015i) |
| Daclatasvir (60 mg once daily for 7 days)c | Simepravir (150 mg once daily for 7 days) | CYP3A, P-gp | 2.20 | 1.60 | Random crossover/15 healthy nonsmokers | Reduce dose when it is coadministered with simeprevirg | FDA (2015j) |
| Ivabradinec | Grapefruit juice | CYP3A4 | 2.20 | 1.60 | N/P | Avoid concomitant use of moderate CYP3A4 inhibitors | FDA (2015g) |
| Sulfasalazine (500 mg SD) | Rolapitant (200 mg SD)c | BCRP | 2.18 | 2.38 | One-sequence/20 | Monitor for adverse events | FDA (2015za) |
| Brexpiprazole (2 mg SD)c | Ketoconazole (200 mg twice daily for 7 days) | CYP3A4, CYP2D6 | 2.17 | 1.18 | One-sequence/12 healthy subjects (CYP2D6 EMs and IMs) | Reduce dose with CYP3A strong inhibitors | FDA (2015v) |
| Daclatasvir (60 mg once daily for 4 days + 20 mg once daily for 10 days)c | Atazanavir/ritonavir (300/100 mg once daily for 10 days) | CYP3A | 2.10 | 1.35 | One-sequence/14 healthy subjects | Reduce dose with CYP3A strong inhibitors | FDA (2015j) |
| Midazolam (3 mg SD) | Isavuconazonium sulfatec | CYP3A4 | 2.03 | 1.72 | N/P | Caution; reduce dose | FDA (2015i) |
| Brexpiprazole (2 mg SD)c | Quinidine (324 mg once daily for 7 days) | CYP3A4, CYP2D6 | 2.03 (EMs) | 1.12 (EMs) | One-sequence/11 healthy subjects (CYP2D6 EMs and IMs) | Reduce dose with CYP2D6 strong inhibitors | FDA (2015v) |
| Ivabradinec | Verapamil (120 mg twice daily) | CYP3A4, P-gp | 2.00 | 1.90 | N/P | Avoid concomitant use with moderate CYP3A4 inhibitors | FDA (2015g) |
| Selexipagc | Lopinavir and ritonavir | P-gp, OATP1B1, OATP1B3 | 2.00 | 2.00 | N/P | None | FDA (2015z) |
| DDIs with 1.25 ≤ AUC ratio < 2h | |||||||
| Isavuconazonium sulfatec,d | lopinavir and ritonavir (400 mg/100 mg twice daily) | CYP3A | 1.96 | 1.74 | N/P | Caution with lopinavir/ritonavir, monitor for toxicity by isavuconazole | FDA (2015i) |
| Digoxin (0.5 mg SD) | Flibanserin (100 mg once daily for 8 days)c | P-gp | 1.93 | 1.46 | Random crossover/23 healthy subjects | Increase monitoring of digoxin concentrations | FDA (2015a) |
| Edoxaban (60 mg SD)c | Ketoconazole (400 mg once daily for 7 days) | P-gp | 1.87 | 1.89 | N/P/healthy subjects | Reduce dose with P-gp inhibitors | FDA (2015w) |
| Edoxaban (60 mg SD)c | Erythromycin (500 mg four times daily for 8 days) | P-gp | 1.85 | 1.68 | N/P/healthy subjects | Reduce dose with P-gp inhibitors | FDA (2015w) |
| Palbociclib (125 mg SD)c | Itraconazole (200 mg once daily for 11 days) | CYP3A | 1.85 | 1.35 | One-sequence/11 healthy subjects | Avoid CYP3A strong inhibitors | FDA (2015n) |
| Edoxaban (60 mg SD)c | Dronedarone (400 mg twice daily) | P-gp | 1.84 | 1.45 | N/P/healthy subjects | Reduce dose with P-gp inhibitors | FDA (2015w) |
| Sirolimus (2 mg SD) | Isavuconazonium sulfatec | CYP3A4 | 1.84 | 1.65 | N/P | Caution; adjust immunosuppressant’s dose as needed | FDA (2015i) |
| Edoxaban (60 mg SD)c | Quinidine (300 mg three times daily) | P-gp | 1.75 | 1.75 | N/P / healthy subjects | Reduce dose with P-gp inhibitors | FDA (2015w) |
| Edoxaban (60 mg SD)c | Cyclosporine (500 mg SD) | P-gp, OATP1B1 (metabolite M4) | 1.73 (metabolite M4: 6.87) | 1.74 (metabolite M4: 8.71) | N/P/healthy subjects | Reduce dose with P-gp inhibitors | FDA (2015w) |
| Trabectedin (1.3 mg/m2 SD (alone); 0.58 mg/m2 (coadministration))c,f | Ketoconazole (200 mg twice daily × 15 doses) | CYP3A4, P-gp | 1.69 | 1.21 | Random crossover/8 patients | Avoid strong CYP3A inhibitors | FDA (2015zf) |
| Midazolam (2 mg SD) | Palbociclib (125 mg once daily for 8 days)c | CYP3A | 1.58 | 1.38 | Random crossover/26 healthy females | Reduce dose with sensitive CYP3A substrates with a NTI | FDA (2015n) |
| Lesinurad (400 mg SD)c | Fluconazole (400 mg loading dose + 200 mg once daily for 2 days) | CYP2C9 | 1.54 | 1.34 | One-sequence/12 healthy males | Caution with moderate CYP2C9 inhibitors | FDA (2015zg) |
| Simepravir (150 mg once daily for 7 days) | Daclatasvir (60 mg once daily for 7 days)c | CYP3A, OATP1B1, OATP1B3 | 1.51 | 1.43 | Random crossover/24 healthy nonsmokers | Reduce dose when coadministered with simeprevirg | FDA (2015j) |
| Rosuvastatin (10 mg SD) | Daclatasvir (60 mg once daily for 9 days)c | CYP3A, BCRP, OTATP1B1, OATP1B3 | 1.47 | 1.84 | One-sequence/21 healthy subjects | Monitor for adverse events | FDA (2015j) |
| Flibanserin (25–100 mg SD)c | Oral contraceptives | CYP3A4, CYP2C19 (minor) | 1.42 | 1.12 | N/P/39 healthy female subjects and patients | Oral contraceptives and other weak CYP3A4 inhibitors may increases flibanserin exposures and incidence of adverse reactions | FDA (2015a) |
| Panobinostat (20 mg SD)c | Ketoconazole (400 mg once daily for 5 days) | CYP3A, P-gp | 1.66 | 1.62 | One-sequence/14 patients | Reduce dose with strong CYP3A inhibitors | FDA (2015l) |
| Panobinostat (25 mg 3 times a week for 3 weeks)c | Bortezomib (1.3 mg/m2 twice a week for 2 weeks)f | CYP3A | 1.42 | 1.50 | One-sequence/7 patients | Reduce dose with strong CYP3A inhibitors | FDA (2015l) |
| Rosuvastatin (20 mg SD) | Eluxadoline (100 mg SD)c | OATP1B1 | 1.41 | 1.18 | Random crossover/27 healthy subjects | Reduce dose of rosuvastatin; caution for an increased risk of myopathy/rhabdomyolysis | FDA (2015zc) |
| Atorvastatin (20 mg SD) | Isavuconazonium sulfatec | CYP3A4 | 1.40 | 1.05 | N/P | Caution; monitor for adverse reactions | FDA (2015i) |
| Edoxaban (60 mg SD)c | Amiodarone (400 mg once daily for 4 days) | P-gp | 1.40 | 1.60 | N/P | Reduce dose with P-gp inhibitors | FDA (2015w) |
| Mycophenylate mofetil (1 g SD) | Isavuconazonium sulfate (200 mg once daily)c | UGTs | 1.35 | 0.89 | N/P | Caution; monitor for toxicity | FDA (2015i) |
| Flibanserin (100 mg SD)c | Grapefruit juice (240 ml regular strength SD) | CYP3A4 | 1.34 | 1.07 | One-sequence/26 healthy females | Contraindication with CYP3A4 moderate inhibitors | FDA (2015a) |
| Cyclosporine (300 mg SD) | Isavuconazonium sulfatec | CYP3A4 | 1.30 | 1.10 | N/P | Caution; monitor cyclosporine concentrations and adjust dose as needed | FDA (2015i) |
| Edoxaban (60 mg once daily for 5 days)c | Acetylsalicylic acid (325 mg once daily for 5 days) | N/P | 1.30 | 1.30 | N/P/healthy volunteers | Monitor for bleeding | FDA (2015w) |
| Digoxin (0.125 mg once daily for 20 days) | Daclatasvir (60 mg once daily for 10 days)c | P-gp | 1.27 | 1.65 | One-sequence/15 healthy subjects | Monitor digoxin concentrations; adjust digoxin doses if necessary | FDA (2015j) |
| Digoxin (0.5 mg SD) | Rolapitant (180 mg SD)c | P-gp | 1.27 | 1.67 | One-sequence/16 | Monitor for adverse reactions for concomitant use of P-gp substrates with a NTI | FDA (2015za) |
| Digoxin (0.5 mg SD) | Isavuconazonium sulfate (200 mg once daily)c | P-gp | 1.25 | 1.33 | N/P | Adjust dose for P-gp substrates with a NTI; monitor serum digoxin concentrations | FDA (2015i) |
IM, intermediate metabolizer; N/P, not provided; SD, single dose.
↵a The number of subjects listed represents the number of subjects who completed both treatments, as described in the University of Washington Drug Interaction Database.
↵b For victim exposure.
↵c NMEs in 2015.
↵d Isavuconazonazole was measured.
↵e Large variabilities were observed; maximum values were obtained from the product label.
↵f Drug was given intravenously.
↵g Labeling recommendations were extracted from clinical pharmacology and biopharmaceutics reviews.
↵h For victim exposure with dose recommendation.