Summary of clinical drug-drug interactions studies to evaluate the effect of milnacipran on the disposition of coadministered drugs
| Victim Drug | n a | Enzymeb | Treatment | Change in Pharmacokinetics of the Victim Drug | Reference |
|---|---|---|---|---|---|
| Sparteine | 25 | CYP2D6 | Milnacipran: 50 mg single dose (day 1), then 50 mg b.i.d. (days 2–8) Sparteine: 100 mg q.d. (days −2, 1, 8, 20) | 19.5% Increase in sparteine/metabolite ratio in CYP2C19EMsc | Puozzo et al., 2005 |
| Mephenytoin | 25 | CYP2C19 | Milnacipran: 50 mg single dose (day 1), then 50 mg b.i.d. (days 2–8) Mephenytoin: 100 mg q.d. (days −2, 1, 8, 20) | No increase in S/R-mephenytoin ratiod | Puozzo et al., 2005 |
| Caffeine | 25 | CYP1A2 | Milnacipran: 50 mg single dose (day 1), then 50 mg b.i.d. (days 2–8) Caffeine: 200 mg q.d. (days −2, 1, 8, 20) | No increase in the caffeine/paraxanthine AUC0–12 ratioe | Puozzo et al., 2005 |
| Warfarin | 25 | CYP2C9 for S-warfarin and CYP1A2/3A4 for R-warfarinf | Milnacipran: 25 mg bid (days 1–3), 50 mg bid (days 4–6), and 100 mg bid (days 7–11) Warfarin: 25 mg single dose on days 11 and 25 or Milnacipran: 25 mg b.i.d. (days 15–17), 50 mg b.i.d. (days 18–20), and 100 mg b.i.d. (days 21–25) Warfarin: 25 mg single dose on days 1 and 25 | No change in S- or R-warfarin pharmacokinetics or pharmacodynamics (INR) | FDA drug label; FRI, personal communication |
| Carbamazepine | 25 | CYP3A4 | Milnacipran: 50 mg b.i.d. (days 1–4) and days (29–35) Carbamazepine: 100 mg b.i.d. (days 8–11); 200 mg b.i.d. (days 12–35) | No change in the pharmacokinetics of carbamazepine or its epoxide metabolite | FDA drug label; FRI, personal communication |
FRI, Forest Research Institute.
↵a Number of subjects completing each study.
↵b Principal metabolizing enzyme.
↵c Before milnacipran treatment, the sparteine/metabolite ratio was 0.51 and 14.6 in CYP2C19 EMs and PMs, respectively.
↵d Before milnacipran treatment, the S/R-mephenytoin ratios were 0.066 and 1.56 in CYP2C19 EMs and PMs, respectively.
↵e Before milnacipran treatment, the caffeine/paraxanthine AUC ratio was 2.3.
↵f Two-sequence crossover design used.