Table 2:
Clinical DDIs likely involving intestinal P-gp induction and modulation of other transporters and drug metabolizing enzymes.
| Inducer (Dose and Pre-treatment Duration) | Substrate (Dose) | Dosing interval between substrate and inducer | No. of subjects | AUC (% ↓) | Cmax (% ↓) | t1/2 (% ↓) | Other transporters/enzymes potentially involved in substrate disposition |
|---|---|---|---|---|---|---|---|
| Rifampin (600 mg/d) | Tenofovir alafenamide (Emtricitabine 200 mg and tenofovir alafenamide 25 mg/d x 28 d alone or with rifampin) | Concomitant | 21 | 55a,b | 50b | NR | BCRP, OATP1B, CES1, CatA |
| Carbamazepine (300 mg twice daily x 20d) | Tenofovir alafenamide (Emtricitabine 200 mg and tenofovir alafenamide 25 mg) | Concomitant | 26 | 54b | 57b | ↔* | |
| Rifampin (600 mg/d x 7d) | Fexofenadine (25 mg) | Staggered (~12 h) | 10 | 59b | 51b | 49 | OATP1B1, OATP1B3, OATP2B1, OAT3 |
| Rifampin (600 mg/d x 6d) | Fexofenadine (60 mg) | Staggered (<12 h) | 24 | 47 – 63c | 33-51c | ↔ | |
| Carbamazepine (100 mg three times daily x 6d) | (S)-Fexofenadine (Fexofenadine 60 mg) | Concomitant on day 7 with carbamazepine (100 mg) | 12 | 60b | 31b | 24 | |
| (R)-Fexofenadine (Fexofenadine 60 mg) | 51b | 32b | ↔ | ||||
| Carbamazepine (100 mg three times daily x 6d) | Fexofenadine (60 mg) | Concomitant on day 7 with carbamazepine (100 mg) | 12 | 39a,b | 35b | ↔ | |
| St John’s wort (300 mg three times daily x 14d) | Fexofenadine (60 mg) | Concomitant (1 hr after morning dose of St. John’s wort) | 12 | ↔ | ↔ | ↔ | |
| St John’s wort (300 mg three times daily x 9d) | Fexofenadine (60 mg) | Concomitant | 30c | 32-50 | NR | ↔ | |
| St John’s wort LI160 (300 mg Jarsin 300® three times daily x 12d) | Fexofenadine (180 mg) | Staggered (next day) | 20 | 47 | 37 | ↔ | |
| Efavirenz (600 mg/d x 14d) | Fexofenadine (60 mg) | Staggered (~12 h) | 12 | ↔f | ↔ | ↔ | |
| Apalutamide (240 mg/d x 28d) | Fexofenadine (30 mg) | NR | 21 | 30b | ↔ | NR | |
| Danshen extract (1000 mg three times daily x 10d) | Fexofenadine (60 mg) | Concomitant with Danshen (1 g) | 12 | 46b | 35b | ↔ | |
| Rifampin (600 mg/d x 10d) | Sofosbuvir (400 mg) | Concomitant | 17 | 72b | 77b | ↔* | BCRP, CatA, CES1 |
| Carbamazepine (300 mg twice daily x 10d) | Staggered (~12 h) | 24 | 48b | 48*b | ↔* | ||
| Rifabutin (300 mg/d x 11d) | Staggered (~12 h) | 20 | 24b | 36*b | ↔* | ||
| Rifampin (600 mg/d x 17d) | Glecaprevir (300 mg) | Staggered (24 h) | 12 | 88b | 86 b | NR | BCRP, OATP1B1, OATP1B3, CYP3A (minor) |
| Pibrentasvir (120 mg) | 87b | 83b | NR | BCRP | |||
| Carbamazepine (200 mg twice daily x 20d) | Glecaprevire (300 mg) | NR | 10 | 66b | 67b | NR | |
| Pibrentasvir (120 mg) | 51b | 50b | NR | ||||
| Rifampin (600 mg/d x 7d) | Ledipasvire (Ledipasvir 90 mg, Vedroprevir 200 mg and Tegobuvir 30 mg) | Staggered (next day) | 31 | 59b | 35b | 17d | BCRP |
| Rifampin (600 mg/d x 7d) | Velpatasvire (100 mg) | Staggered (next day) | 12 | 82b | 71b | NR | BCRP, CYP3A4, CYP2B6, CYP2C8 (metabolism minor) |
| Rifampin (600 mg/d x 7d) | Voxilaprevir (100 mg) | Staggered (12 hr) | 24 | 73b | ↔ | NR | BCRP, OATP1B, CYP3A4 |
| Rifampin (600 mg/d x 5d) | Celiprolol (200 mg) | Staggered (~14 h) | 10 | 56a,d | ↔g | ↔ | OATP2B1, OATP1A2, minimal metabolism |
| Rifampin (600 mg/d x 7d) | Afatinib (40 mg) | Staggered (~12 h) | 22 | 34b | 22b | ↔ | BCRP, minimal metabolism |
| Rifampin (600 mg/d x 5d) | Aliskiren (150 mg) | Staggered (12 h) | 12 | 56b | 39b | ↔ | OATP2B1, OATP1A2, CYP3A4 (minor) |
| Rifampin (600 mg/d x 6d) | Edoxaban (60 mg) | Concomitant on day 7 of rifampin | 34 | 35b | ↔ | 52 | CES1, CYP3A (minor) |
| Rifampin (600 mg/d x 7d or 9d) | Apixaban (5 mg IV) | Staggered on day 8 of rifampin | 20 | 39b | NR | 49 | BCRP, CYP3A4 (major) |
| Apixaban (10 mg) | Staggered on day 10 of rifampin | 20 | 54b | 42b | ↔ | ||
| Rifampin (150-450 mg days 1-3 and 600 mg days 4-7 once daily) | Rivaroxaban (20 mg) | NR | 20 | 49b | 22b | 47b | BCRP, CYP3A, CYP2J2 |
All data were obtained from University of Washington Drug Interaction Solutions database, product prescribing information, and Drugs@FDA Clinical Pharmacology reviews.
Notes: All inducers and substrates were administered orally. All substrates were administered as a single dose unless otherwise specified. Inducer was dosed once daily unless specified otherwise. To calculate % AUC ↓, AUC0→inf was preferred over AUC0→t wherever possible.
AUC0→t was used to calculate % ↓ in AUC. % ↓ in AUC, Cmax and t1/2 were calculated using arithmetic mean unless specified otherwise.
Geometric mean used to calculate % ↓ in AUC and Cmax.
Fexofenadine data from four study groups (n=6/group, categorized based on age and sex).
Median values used to calculate % ↓ in AUC and Cmax.
Exposure decreases following multiple-doses of efavirenz-containing antiviral therapy not summarized due to mechanistic complexity of multidrug regimen.
27% decrease observed but was not statistically significant.
34% decrease observed but was not statistically significant.
, no significant change concluded in study.
Lutz et al. data not published. NR, not reported.
Staggered represents substrate not concomitantly administered with inducer during induction phase or administered after the last dose of an inducer. Concomitant means substrate was concomitantly given with the inducer in same time frame (within minutes); either during or on the last day of the induction phase. Note: exposure ratios 0.8-1.25 are generally not considered clinically meaningful but are reported here whenever these reached statistical significance criteria defined in the study.