Two days of fluvoxamine dosing significantly inhibits CYP1A2

Abstract

Fluvoxamine (FLV) is frequently used in drug-drug interaction studies as an inhibitor of CYP1A2. FLV administration is known to produce adverse events that may result in subject discontinuation. Therefore, minimizing FLV dose and duration is an important consideration in designing interaction studies. Fifteen healthy male and female subjects were enrolled and 12 subjects completed a sequential-design, placebo-controlled, FLV drug interaction study where an N3-demethylation urinary caffeine (CAF) molar metabolic ratio1 was used to determine CYP1A2 activity levels. Subjects were checked into the clinic for a 48-hour methylxanthine washout. At baseline, a single 100 mg dose of CAF was then admin-istered and urine collected for 24 hours. Subsequently, FLV, 50 mg BID, was given for 5 days. A single 100 mg dose of CAF was administered on the second day of FLV treatment and 84-hours after the last dose of FLV. Urine was collected for 24 hours after each CAF dose. HPLC with ultraviolet detection was used to determine urine concentrations of CAF and its metabolites. Mean (SD) values of the CAF metabolic ratio are presented in the Table. On the second day of FLV dosing, CYP1A2 activity was significantly decreased by 83%. CYP1A2 activity was fully recovered 84h after the last dose of FLV. Clinical Pharmacology & Therapeutics (2005) 77, P78–P78; doi: 10.1016/j.clpt.2004.12.191 Table 1. 100 mg CAF CAF + FLV 100 mg CAF after Baseline (n = 7) (n = 11) 84 h FLV washout (n = 8) 18.6 (5.4) 3.2 (1.4) 19.5 (8.7)