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Pharmacokinetic evaluation of combined duloxetine and fluvoxamine dosing in CYP2D6 poor metabolizers
Author(s) -
Small D.,
Loghin C.,
Lucas R.,
Knadler M. P.,
Zhang L.,
Chappell J.,
Bergstrom R.,
Callaghan J. T.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.036
Subject(s) - duloxetine , fluvoxamine , cmax , duloxetine hydrochloride , pharmacology , cyp2d6 , pharmacokinetics , medicine , fluoxetine , chemistry , serotonin , cytochrome p450 , alternative medicine , receptor , pathology , metabolism
Background/Aims The effect of CYP1A2 inhibition in CYP2D6 PMs was assessed on duloxetine steady‐state Cmax and AUC using fluvoxamine. The aim was to study dual CYP1A2 and CYP2D6 inhibition without introducing confounding effects of two inhibitors. Methods A multicenter, open‐label, multiple‐dose study in 15 healthy CYP2D6 PMs. Duloxetine 40 mg BID was given on Days 1–18 and once in the morning of Day 19. Fluvoxamine was dosed in the evening as 50 mg QD on Days 5–6, 100 mg QD on Days 7–20, and 50 mg QD on Days 21–22. The pharmacokinetic profile on Days 5 and 19 and safety profile (vital signs, ECGs, lab tests) were assessed. Results At steady state on Day 19, duloxetine's AUC and Cmax were increased 540% and 471%, respectively, versus duloxetine on Day 5, an increase similar in magnitude to that previously measured during CYP1A2 inhibition alone. Adverse events with duloxetine were typical and not worse at higher concentrations. Nausea and headache were most commonly reported. Conclusions Duloxetine was generally well tolerated, even during potent inhibition. CYP1A2 inhibition is the largest component of dual inhibition. Clinical Pharmacology & Therapeutics (2005) 77 , P37–P37; doi: 10.1016/j.clpt.2004.12.036