Non‐linear fluvoxamine disposition

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Abstract
Aims To study the pharmacokinetics of fluvoxamine when given in increasing doses to healthy volunteers. Methods Ten healthy, non-smoking men were given maintenance treatment with fluvoxamine for 4 weeks. Eight subjects were CYP2D6 extensive metabolisers (EMs) and two were CYP2D6 poor metabolisers (PMs). As a measure of the CYP1A2 phenotype, the paraxanthine/caffeine ratio in saliva after intake of caffeine was studied. The fluvoxamine doses given were 25 mg day−1 the first week, 50 mg day−1 the second week, 100 mg day−1 the third week and 200 mg day−1 the fourth week, divided in two daily doses. On the seventh day every week, serum concentrations of fluvoxamine were followed for a dose interval of 12 h. After discontinuation of treatment, fluvoxamine concentrations were followed for 1 week. Results For each of the three two-fold increases in given dose, the mean AUC increased 3.25-fold, 3.17-fold and 3.14-fold, respectively (PPr=−0.56; P=0.095 for the correlation between the paraxanthine/caffeine ratio in saliva and fluvoxamine AUC at a dose of 50 mg day−1 ). The two CYP2D6 PMs had AUC values in the same range as the EMs. Conclusions The present study conclusively demonstrates that fluvoxamine exhibits non-linear kinetics within the therapeutic dose interval. The reason for non-linearity is not Michaelis-Menten saturation kinetics of a single metabolic pathway, but rather a complex involvement of multiple parallel pathways.