TABLE 8

Clinically significant inhibitions, NMEs as victims or perpetrators

DoseEnzyme/Transporter Possibly InvolvedRatioStudy Design/PopulationaLabeling ImpactReference
Victim DrugInhibitorAUCCmax
DDIs with AUC ratio ≥ 2b
 IvabradinecJosamycinCYP3A47.703.60N/PContraindication with strong CYP3A4 inhibitorsFDA (2015g)
 IvabradinecKetoconazole (200 mg once daily)CYP3A4, P-gp7.703.60N/PContraindication with strong CYP3A4 inhibitorsFDA (2015g)
 Cobimetinib (10 mg SD)cItraconazole (200 mg once daily for 14 days)CYP3A4, P-gp6.623.17One-sequence/15 healthy subjectsAvoid CYP3A strong inhibitorsFDA (2015h)
 Flibanserin (100 mg SD)cFluconazole (200 mg once daily for 6 days)CYP3A4, CYP2C19 (minor)6.412.11One-sequence/15 healthy femalesContraindication with CYP3A4 moderate inhibitorsFDA (2015a)
 Isavuconazonium sulfate (200 mg SD)c,dKetoconazole (200 mg twice daily for 24 days)CYP3A5.221.09N/PContraindication with strong CYP3A4 inhibitorsFDA (2015i)
 Flibanserin (50 mg SD)cKetoconazole (400 mg once daily for 5 days)CYP3A4, CYP2C8/9 (minimal)4.611.84Random crossover/20 healthy femalesContraindication with CYP3A4 strong inhibitorsFDA (2015a)
 Cobimetinib (60 mg once daily for 35 days)cErythromycin (500 mg three times daily for 35 days)CYP3A4, P-gp4.27 (PBPK)3.76 (PBPK)PBPK modeling/simulations of healthy subjectsAvoid CYP3A moderate inhibitorsFDA (2015h)
 Eluxadoline (100 mg SD)cCyclosporine (600 mg SD)OATP1B1, MRP2 (minimal)4.206.81Random crossover/30 healthy subjectsReduce dose with OATP1B1 inhibitors; monitor for adverse reactionsFDA (2015zc)
 Cariprazine (0.5 mg once daily for 14 days)cKetoconazole (400 mg)CYP3A43.783.27N/P/16 patientsReduce dose with CYP3A strong inhibitorsFDA (2015zd)
 Dextromethorphan (30 mg SD)Rolapitant (200 mg SD)cCYP2D63.332.77One-sequence/26 subjects (CYP2D6 EMs and IMs)Monitor for adverse reactions if concomitant use with other CYP2D6 substrates with a NTI cannot be avoidedFDA (2015za)
 Cobimetinib (60 mg SD)cDiltiazem (1200 mg twice daily)CYP3A4, P-gp3.26 (PBPK)1.85 (PBPK)PBPK modeling/simulations of healthy subjectsAvoid CYP3A moderate inhibitorsFDA (2015h)
 Daclatasvir (10 mg SD)cKetoconazole (400 mg once daily for 9 days)CYP3A, CYP2C8 (minor), P-gp3.011.57One-sequence/13 healthy subjectsReduce dose with CYP3A strong inhibitorsFDA (2015j)
 IvabradinecDiltiazem (120 mg twice daily)CYP3A4, P-gp3.002.50N/PContraindication with strong CYP3A4 inhibitorsFDA (2015g)
 Dextromethorphan (60 mg SD)Panobinostat (20 mg once daily for 3 days)cCYP2D62.30e3.00eOne-sequence/14 patients (CYP2D6 EMs)Avoid CYP2D6 sensitive substrates or CYP2D6 substrates with a NTIFDA (2015l)
 Sonidegib (200 mg once daily at steady state)cErythromycin (500 mg once daily for 120 days)CYP3A2.80 (PBPK)2.40 (PBPK)PBPK modeling/simulations of patientsAvoid long-term use of CYP3A moderate inhibitorsFDA (2015t)
 RocuroniumfSugammadex (4 mg/kg SD)c,fNot by P450s2.70N/PParallel/2Adjust doseFDA (2015e)
 Tenofovir alafenamide fumarate (8 mg once daily for 22 days)cCobicistat (150 mg once daily for 10 days)P-gp, BCRP, OATP1B1, OATP1B32.652.83One-sequence/12 healthy subjectsCombination drugFDA (2015m)
 Flibanserin (50 mg SD)cItraconazole (200 mg once daily for 7 days)CYP3A4, CYP2C8/9 (minimal)2.581.70Random crossover/12 healthy subjectsContraindication with CYP3A4 strong inhibitorsFDA (2015a)
 Sonidegib (800 mg SD)cKetoconazole (200 mg twice daily for 14 days)CYP3A2.261.50Parallel/15 healthy subjectsAvoid CYP3A strong inhibitorsFDA (2015t)
 Tacrolimus (5 mg SD)Isavuconazonium sulfatecCYP3A42.251.42N/PCaution; adjust immunosuppressant’s dose as neededFDA (2015i)
 Daclatasvir (60 mg once daily for 7 days)cSimepravir (150 mg once daily for 7 days)CYP3A, P-gp2.201.60Random crossover/15 healthy nonsmokersReduce dose when it is coadministered with simeprevirgFDA (2015j)
 IvabradinecGrapefruit juiceCYP3A42.201.60N/PAvoid concomitant use of moderate CYP3A4 inhibitorsFDA (2015g)
 Sulfasalazine (500 mg SD)Rolapitant (200 mg SD)cBCRP2.182.38One-sequence/20Monitor for adverse eventsFDA (2015za)
 Brexpiprazole (2 mg SD)cKetoconazole (200 mg twice daily for 7 days)CYP3A4, CYP2D62.171.18One-sequence/12 healthy subjects (CYP2D6 EMs and IMs)Reduce dose with CYP3A strong inhibitorsFDA (2015v)
 Daclatasvir (60 mg once daily for 4 days + 20 mg once daily for 10 days)cAtazanavir/ritonavir (300/100 mg once daily for 10 days)CYP3A2.101.35One-sequence/14 healthy subjectsReduce dose with CYP3A strong inhibitorsFDA (2015j)
 Midazolam (3 mg SD)Isavuconazonium sulfatecCYP3A42.031.72N/PCaution; reduce doseFDA (2015i)
 Brexpiprazole (2 mg SD)cQuinidine (324 mg once daily for 7 days)CYP3A4, CYP2D62.03 (EMs)1.12 (EMs)One-sequence/11 healthy subjects (CYP2D6 EMs and IMs)Reduce dose with CYP2D6 strong inhibitorsFDA (2015v)
 IvabradinecVerapamil (120 mg twice daily)CYP3A4, P-gp2.001.90N/PAvoid concomitant use with moderate CYP3A4 inhibitorsFDA (2015g)
 SelexipagcLopinavir and ritonavirP-gp, OATP1B1, OATP1B32.002.00N/PNoneFDA (2015z)
DDIs with 1.25 ≤ AUC ratio < 2h
 Isavuconazonium sulfatec,dlopinavir and ritonavir (400 mg/100 mg twice daily)CYP3A1.961.74N/PCaution with lopinavir/ritonavir, monitor for toxicity by isavuconazoleFDA (2015i)
 Digoxin (0.5 mg SD)Flibanserin (100 mg once daily for 8 days)cP-gp1.931.46Random crossover/23 healthy subjectsIncrease monitoring of digoxin concentrationsFDA (2015a)
 Edoxaban (60 mg SD)cKetoconazole (400 mg once daily for 7 days)P-gp1.871.89N/P/healthy subjectsReduce dose with P-gp inhibitorsFDA (2015w)
 Edoxaban (60 mg SD)cErythromycin (500 mg four times daily for 8 days)P-gp1.851.68N/P/healthy subjectsReduce dose with P-gp inhibitorsFDA (2015w)
 Palbociclib (125 mg SD)cItraconazole (200 mg once daily for 11 days)CYP3A1.851.35One-sequence/11 healthy subjectsAvoid CYP3A strong inhibitorsFDA (2015n)
 Edoxaban (60 mg SD)cDronedarone (400 mg twice daily)P-gp1.841.45N/P/healthy subjectsReduce dose with P-gp inhibitorsFDA (2015w)
 Sirolimus (2 mg SD)Isavuconazonium sulfatecCYP3A41.841.65N/PCaution; adjust immunosuppressant’s dose as neededFDA (2015i)
 Edoxaban (60 mg SD)cQuinidine (300 mg three times daily)P-gp1.751.75N/P / healthy subjectsReduce dose with P-gp inhibitorsFDA (2015w)
 Edoxaban (60 mg SD)cCyclosporine (500 mg SD)P-gp, OATP1B1 (metabolite M4)1.73 (metabolite M4: 6.87)1.74 (metabolite M4: 8.71)N/P/healthy subjectsReduce dose with P-gp inhibitorsFDA (2015w)
 Trabectedin (1.3 mg/m2 SD (alone); 0.58 mg/m2 (coadministration))c,fKetoconazole (200 mg twice daily × 15 doses)CYP3A4, P-gp1.691.21Random crossover/8 patientsAvoid strong CYP3A inhibitorsFDA (2015zf)
 Midazolam (2 mg SD)Palbociclib (125 mg once daily for 8 days)cCYP3A1.581.38Random crossover/26 healthy femalesReduce dose with sensitive CYP3A substrates with a NTIFDA (2015n)
 Lesinurad (400 mg SD)cFluconazole (400 mg loading dose + 200 mg once daily for 2 days)CYP2C91.541.34One-sequence/12 healthy malesCaution with moderate CYP2C9 inhibitorsFDA (2015zg)
 Simepravir (150 mg once daily for 7 days)Daclatasvir (60 mg once daily for 7 days)cCYP3A, OATP1B1, OATP1B31.511.43Random crossover/24 healthy nonsmokersReduce dose when coadministered with simeprevirgFDA (2015j)
 Rosuvastatin (10 mg SD)Daclatasvir (60 mg once daily for 9 days)cCYP3A, BCRP, OTATP1B1, OATP1B31.471.84One-sequence/21 healthy subjectsMonitor for adverse eventsFDA (2015j)
 Flibanserin (25–100 mg SD)cOral contraceptivesCYP3A4, CYP2C19 (minor)1.421.12N/P/39 healthy female subjects and patientsOral contraceptives and other weak CYP3A4 inhibitors may increases flibanserin exposures and incidence of adverse reactionsFDA (2015a)
 Panobinostat (20 mg SD)cKetoconazole (400 mg once daily for 5 days)CYP3A, P-gp1.661.62One-sequence/14 patientsReduce dose with strong CYP3A inhibitorsFDA (2015l)
 Panobinostat (25 mg 3 times a week for 3 weeks)cBortezomib (1.3 mg/m2 twice a week for 2 weeks)fCYP3A1.421.50One-sequence/7 patientsReduce dose with strong CYP3A inhibitorsFDA (2015l)
 Rosuvastatin (20 mg SD)Eluxadoline (100 mg SD)cOATP1B11.411.18Random crossover/27 healthy subjectsReduce dose of rosuvastatin; caution for an increased risk of myopathy/rhabdomyolysisFDA (2015zc)
 Atorvastatin (20 mg SD)Isavuconazonium sulfatecCYP3A41.401.05N/PCaution; monitor for adverse reactionsFDA (2015i)
 Edoxaban (60 mg SD)cAmiodarone (400 mg once daily for 4 days)P-gp1.401.60N/PReduce dose with P-gp inhibitorsFDA (2015w)
 Mycophenylate mofetil (1 g SD)Isavuconazonium sulfate (200 mg once daily)cUGTs1.350.89N/PCaution; monitor for toxicityFDA (2015i)
 Flibanserin (100 mg SD)cGrapefruit juice (240 ml regular strength SD)CYP3A41.341.07One-sequence/26 healthy femalesContraindication with CYP3A4 moderate inhibitorsFDA (2015a)
 Cyclosporine (300 mg SD)Isavuconazonium sulfatecCYP3A41.301.10N/PCaution; monitor cyclosporine concentrations and adjust dose as neededFDA (2015i)
 Edoxaban (60 mg once daily for 5 days)cAcetylsalicylic acid (325 mg once daily for 5 days)N/P1.301.30N/P/healthy volunteersMonitor for bleedingFDA (2015w)
 Digoxin (0.125 mg once daily for 20 days)Daclatasvir (60 mg once daily for 10 days)cP-gp1.271.65One-sequence/15 healthy subjectsMonitor digoxin concentrations; adjust digoxin doses if necessaryFDA (2015j)
 Digoxin (0.5 mg SD)Rolapitant (180 mg SD)cP-gp1.271.67One-sequence/16Monitor for adverse reactions for concomitant use of P-gp substrates with a NTIFDA (2015za)
 Digoxin (0.5 mg SD)Isavuconazonium sulfate (200 mg once daily)cP-gp1.251.33N/PAdjust dose for P-gp substrates with a NTI; monitor serum digoxin concentrationsFDA (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.