Non‐linear fluvoxamine disposition

Abstract

AimsTo 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 daythe 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 ( P<0.0001), indicating a decrease in oral clearance with increasing dose. The elimination half-life based upon the serum concentrations 12-48 h after discontinuation of fluvoxamine was 32.1±11.0 h whereas the half-life based upon the concentrations 3-7 days after discontinuation was significantly shorter, 15. 8±4.2 h (means±s.d.; P<0.001).There were no significant correlations between the CYP1A2 phenotype and fluvoxamine AUCs at different doses (r=−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.Keywords: CYP1A2, CYP2D6, fluvoxamine, non-linear, disposition, pharmacokinetics, adverse drug reactions (AUC) over a dose interval at steady-state (dose 50 mg ×2) Introduction was 30% higher than predicted from AUC from 0 to infinity after a single dose of 50 mg. Moreover, the terminal halfThe selective serotonin reuptake inhibitor fluvoxamine is used in the treatment of depression and obsessive compulsive lives were 20-50% longer at steady state than in the same subjects after a single dose [18]. In a study of nine patients disorder, and is currently evaluated in the treatment of a number of other psychiatric diseases [1,2]. Fluvoxamine is with depression, doubling the fluvoxamine dose from 100 to 200 mg day −1 caused a 3.3-fold increase in the mean extensively metabolised in the liver [3], and the limited data available indicate that it is a high clearance drug [4]. There steady state plasma concentration [19]. On the other hand, no indications of non-linearity were found in the dose range are some data to indicate that the isozymes CYP1A2 [5] and CYP2D6 [6], but not CYP2C19 [6], are important for 25-100 mg after single oral doses [20], and according t...

Comparison of In Vitro and In Vivo Inhibition Potencies of Fluvoxamine toward CYP2C19

“…Fluvoxamine average steady-state concentrations for each subject are shown in Table 4. These values are within the reported concentration ranges for these doses and consistent with the nonlinear disposition of this drug (Perucca et al, 1994b;Spigset et al, 1998). Fluvoxamine oral clearance decreased as the dose increased: oral clearances in the three phases were 94.7 Ϯ 78.7, 60.9 Ϯ 36.7, and 48.0 Ϯ 28.9 l/h, respectively.…”

“…The linearity and intercept values suggested that a good estimation of K i iv values can be obtained using only a single dose of inhibitor. Based on this observation, the results of a published study of fluvoxamine inhibition of the CYP2C19 catalyzed bioactivation of chloroguanide (Jeppesen et al, 1997) were used to calculate a K i iv of 25 nM (assuming that fluvoxamine plasma concentration at 100 mg/day is 199.3 nM; Spigset et al, 1998) and that only CYP2C19 catalyzes the formation of 4-chlorophenylbiguanide). This K i iv estimate is similar to the values obtained in the present study, which used a different probe of CYP2C19 and three doses of fluvoxamine.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Data are PHARMACOGENETICS, DRUG METABOLISM, AND CLINICAL PRACTICE conflicting regarding the effect of CYP2D6 on fluvoxamine concentrations, with a single-dose study reporting a 1.3-fold higher AUC in PMs , whereas in another no difference was observed (Christensen et al, 2002). Similar disparities were observed at steady state (Spigset et al, 1998;Christensen et al, 2002). Overall, the effect of the CYP2D6 genotype seems to be minor.…”

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

“…13,14 In the case of fluvoxamine, differences in concentration-time curves (AUCs) between CYP2D6 genotypes were described after single doses, 15,16 whereas multiple doses result in similar AUCs in PMs and in EMs indicating a strong inhibitory effect on CYP2D6 in EMs. 17 For fluoxetine undergoing enantioselective metabolism toward the S-enantiomer, impaired demethylation of Sfluoxetine in CYP2D6 PMs was observed. 18 However, since the metabolite desmethylfluoxetine is also an active antidepressant, no clinical implications should be expected with regard to variable metabolism of fluoxetine as the parent drug.…”