TABLE 2.
Drug–drug interactions of strong CYP3A inducers (alternatives to rifampicin) and sensitive CYP3A substrates
| Dose/dosing regimen of strong CYP3A inducer | Sensitive CYP3A substrate | Population | CYP3A substrate dose | DDI | ||
|---|---|---|---|---|---|---|
| AUC ratio | Cmax ratio | |||||
| Apalutamide | 240 mg q.d., 28 days, oral | Midazolam (as part of cocktail) 45 | Patients | 2 mg, oral, SD (day 29) | 0.08 | 0.23 |
| Avasimibe | 50 mg or 750 mg, q.d., 7 days, oral | Midazolam 25 | HVs | 2 mg, oral, SD (day 7) |
50 mg: 0.27 750 mg: 0.07 |
50 mg: 0.43 750 mg: 0.18 |
| Carbamazepine | 200 mg q.d., (days 1–3) → 200 mg b.i.d. (days 4 until day 24), oral | Paritaprevir 30 | HVs | 150 mg, oral, SD (day 22) | 0.30 | 0.34 |
| 100 mg, b.i.d. (days 1–3) → 200 mg b.i.d. (day 4 to day 31), oral | Elvitegravir 31 | HVs | 150 mg (in combination with Cobistat a ), oral, q.d. (day 22 to day 31) | 0.31 | 0.55 | |
| 400 mg b.i.d., 24 days, oral (PBPK modeling) | Abemaciclib 36 | HVs | 200 mg, oral, SD (day 7) | 0.20 | NA | |
| 400 mg b.i.d., 7 days, oral (PBPK modeling) | Acalabrutinib 37 | HVs | 100 mg, oral, b.i.d. (7 days) | 0.39 | NA | |
| 200 mg q.d. (days 1 and 2) → 300 mg, b.i.d. (12 days), oral | Simvastatin 29 | HVs | 80 mg, oral, SD (day 15) | 0.25 | 0.32 | |
| 200 mg q.d. (day 1) → 200 mg b.i.d. (day 2 to day 4) → 200 mg t.i.d. (day 5 → 25), oral | Quetiapine 97 | Patients | 25 mg b.i.d., oral, MD | 0.13 | 0.20 | |
| 400 mg q.d., 16 days, oral | Ivabradine 35 | HVs | 10 mg, oral, SD (day 15) | 0.20 | 0.23 | |
| 100 mg b.i.d. → 300 mg b.i.d. (escalated to 300 mg b.i.d. over 7 days and continued until a total of 26 days), oral | Midazolam 33 | HVs | 2 mg, oral, SD (day 18, as part of cocktail) | 0.21 | 0.31 | |
| 1600 mg q.d., 14 days, oral (population‐based simulations) | Midazolam 40 | HVs | 8 mg, oral, SD | ~0.20 | – | |
|
400 mg q.d., multiple doses, oral (PBPK modeling) |
Ibrutinib 38 | HVs | 560 mg, oral, SD | 0.18 | 0.14 | |
|
200 mg b.i.d., oral, 14 days, oral (PBPK modeling) |
Zanubrutinib 39 | HVs | 160 mg, oral, b.i.d. (day 7 to day 14) | 0.42 | 0.39 | |
| Enzalutamide | 160 mg q.d., 50 days, oral | Midazolam (as part of cocktail) 44 | Patients | 2 mg, oral, SD (day 50) | 0.14 | 0.23 |
| Ivosidenib | 500 mg q.d., 15 days, oral | Midazolam 51 | Patients | 5 mg, oral, SD (day 15) | 0.18 | 0.27 |
| Lumacaftor | 200 mg q.d., 14 days, oral | Ivacaftor 53 | HVs | 150 mg, oral, b.i.d. (14 days) | 0.19 | 0.24 |
| Lumacaftor + ivacaftor | LUMA, 200 mg + IVA, 250 mg (q12h) 21 days, oral | Itraconazole a , 53 | HVs | 200 mg, oral, QD (day 15 to day 21; 7 days) | 0.1 | 0.097 |
| Mitotane | 0.5–3.5 g, t.i.d., oral, n = 4 (patient 4: 0.5 g q.d. or 0.5 g b.i.d. every other day) | Midazolam 56 | Patients | 7.5 mg, oral, SD | 0.055 | N/A |
| Phenytoin | 300 mg q.d., 11 days, oral |
Lopinavir/ Ritonavir 59 |
HVs | 400 mg/100 mg, oral, b.i.d. (11 days) |
0.67 (Lopinavir) |
0.76 (Lopinavir) |
| 4 mg/kg q.d., 21 days, oral | Atorvastatin 61 | HVs | 40 mg, oral, MD (21 days) | 0.46 | 0.76 | |
| 100 mg t.i.d., 10 days, oral | Quetiapine 64 | Patients | 250 mg t.i.d., oral, 10 days (co‐administration with phenytoin, 250 mg q.d. day 13 to day 22) | 0.20 | 0.34 | |
| 100 mg, b.i.d. (until reaching a Ctrough of 5.5 μg/ml), oral | Sirolimus 85 | One patient | 5 mg q.d., oral, (required escalation to 15 mg q.d.) | 0.61 | 0.87 | |
| 200–450 mg, q.d./(with stable phenytoin concentration: 9.2–25.9 μg/ml), oral | Nisoladipine 62 | Patients and HVs | 40 mg in patients and 20 mg in HVs, oral, SD | 0.11 | 0.18 | |
| 150 mg, b.i.d., 5 days, oral | Ivabradine 60 | HVs | 10 mg, oral, SD (day 5) | 0.31 | 0.35 | |
| 150–300 mg, q.d., for at least 2 months, oral | Midazolam 63 | Patients and HVs | 15 mg, oral, SD | 0.057 | 0.074 | |
| Rifapentine | 5, 10, 15, 20 mg/kg q.d., 14 days (days 2 to days 15), oral | Midazolam 66 | HVs |
15 mg, oral, SD (day 15) |
<0.1 | ≤0.2 |
| St John's Wort | 300 mg t.i.d., 15 days, oral (standardized to 0.3% hypericin) | Eplerenone 98 | HVs | 100 mg, oral, SD (day 15) | 0.68 | 0.81 |
| 300 mg t.i.d., 15 days, oral | Ivabradine 99 | HVs | 10 mg, oral, SD (day 15) | 0.39 | 0.49 | |
| 300 mg t.i.d., 14 days, oral | Indinavir 100 | HVs | 800 mg, oral, SD (day 15) | 0.43 | 0.72 | |
| 300 mg t.i.d., 14 days, oral | Midazolam 101 | HVs |
5 mg, oral 0.05 mg/kg, intravenous, SD |
0.79 (intravenous) 0.48 (oral) | 0.57 (oral) | |
| 300 mg t.i.d., 14 days, oral | Midazolam 102 | HVs | 5 mg, oral, SD | 0.72 | 0.88 | |
| 300 mg t.i.d., 8 weeks, oral | Midazolam 103 | HVs |
5 mg, oral 0.05 mg/kg, intravenous, SD |
0.94 (intravenous) 0.59 (oral) |
0.79 (oral) | |
| LI 160, 300 mg per coated tablet of an 80% (vol/vol) methanolic dry extract (41 mg/day, 14 days) b , oral | Midazolam 71 | HVs |
7.5 mg, oral, SD (day 14) |
0.20 | 0.35 | |
|
300 mg t.i.d., 14 days, oral |
Simvastatin 104 | HVs |
10 mg, oral, SD (day 14) |
0.38 (acid) 0.52 (lactone) |
0.48 (acid) 0.69 (lactone) |
|
| 300 mg q.d., 18 days, oral | Tacrolimus 105 | HVs |
0.1 mg/kg, SD (day 15) |
0.65 | 0.77 | |
Abbreviations: AUC, area under the curve; Cmax, maximum plasma concentration; DDI, drug‐drug interaction; HV, healthy volunteers; IVA, ivacaftor; LUMA, lumacaftor; PBPK, physiologically‐based pharmacokinetic; SD, single dose; MD, multiple doses; N/A, not applicable.
Itraconazole is a CYP3A substrate but not sensitive CYP3A substrate.
Apart from the enriched extract presented, various doses of Hypericum powder with different contents of hyperforin tested in this study and midazolam AUC and Cmax ranged from 0.52–0.79 and 0.61–1, respectively.