Lack of pharmacokinetic interaction when switching from fluoxetine to milnacipran.
The lack of a therapeutic effect or unsupportable side-effects can lead to substitution of one antidepressant by another. The present study investigated potential modifications to the pharmacokinetic profile of milnacipran at steady-state when it is substituted for fluoxetine without any washout period. The open-label, multiple dose, three-period study was carried out in 12 evaluable healthy volunteers. A reference period (period 1) comprising a 3.5-day treatment with milnacipran at 50 mg b.i.d. was followed, after a 5-10-day washout, by 3 weeks of administration of 20 mg fluoxetine once daily (period 2), immediately followed by a further 3.5 days of administration of milnacipran at 50 mg b.i.d. (period 3). Blood samples collected at each period were analysed for milnacipran, N-dealkyl milnacipran, fluoxetine and norfluoxetine. Potential drug-drug interactions were evaluated by comparing milnacipran pharmacokinetic parameters between periods 1 and 3. A steady-state of fluoxetine and its metabolite was effectively reached by the end of the 3-week period. A steady-state of milnacipran was reached on day 2 of both periods 1 and 3. Trough concentrations of milnacipran were 66 and 65 ng/ml before and after the fluoxetine administration period, respectively. Cmax values were 226 and 248 ng/ml. When comparing the kinetic parameters of milnacipran before and after fluoxetine treatment, all the 90% confidence intervals were in the 20% range. No significant difference in the adverse events of milnacipran was observed before or after fluoxetine administration.
Puozzo
Christian
C
Clinical Pharmacokinetic Department, Institut de Recherche Pierre Fabre, Castres, France. christian.puozzo@pierre-fabre.com
Hermann
Philippe
P
Chassard
Didier
D
D000328:Adult; D019540:Area Under Curve; D003521:Cyclopropanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008722:Methods; D000078764:Milnacipran; D009325:Nausea / Q000139:chemically induced; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced
D003521:Cyclopropanes; D019389:Cytochrome P-450 CYP2D6; D005473:Fluoxetine; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors; C514233:F 2800; C036139:norfluoxetine