A Case of Fluvoxamine Intoxication Demonstrating Nonlinear Elimination Pharmacokinetics

Spigset, Olav; Ohman, R

doi:10.1097/00004714-199606000-00012

Cited by 9 publications

(2 citation statements)

References 8 publications

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“…19 CYP1A2 has also been characterized by saturation kinetics for other drugs such as theophylline 20 and caffeine. 21 Several other studies [22][23][24] have shown nonlinear kinetics for FLV, which is considered to be caused by the saturation of CYP1A2 and CYP2D6. In our study, FLV concentration-to-dose ratio also increased with increasing treatment dose.…”

Section: Discussionmentioning

confidence: 99%

Dose-Dependent Effects of the 3435 C>T Genotype of ABCB1 Gene on the Steady-State Plasma Concentration of Fluvoxamine in Psychiatric Patients

Fukui¹,

Suzuki²,

Sawamura³

et al. 2007

Therapeutic Drug Monitoring

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Section: Discussionmentioning

confidence: 99%

Dose-Dependent Effects of the 3435 C>T Genotype of ABCB1 Gene on the Steady-State Plasma Concentration of Fluvoxamine in Psychiatric Patients

Fukui¹,

Suzuki²,

Sawamura³

et al. 2007

Therapeutic Drug Monitoring

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“…1 In a case report of fluvoxamine intoxication, in which fluvoxamine concentrations were followed for 1 week, nonlinearity was present at serum levels of more than 150 ng/mL. 2 This plasma concentration is well inside the range of steady-state concentrations reached after therapeutic dosages. 3 In a study with 10 healthy volunteers, fluvoxamine was administered in increasing doses.…”

Section: A Clinical Evaluationmentioning

confidence: 95%

Time-Dependent Clearance Decrements of Fluvoxamine in Depressed Inpatients

Broek¹,

Birkenhäger²,

Mulder³

et al. 2007

Journal of Clinical Psychopharmacology

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Non‐linear fluvoxamine disposition

Spigset¹,

Granberg²,

Hägg³

et al. 1998

Brit J Clinical Pharma

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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...

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A Case of Fluvoxamine Intoxication Demonstrating Nonlinear Elimination Pharmacokinetics

Cited by 9 publications

References 8 publications

Dose-Dependent Effects of the 3435 C>T Genotype of ABCB1 Gene on the Steady-State Plasma Concentration of Fluvoxamine in Psychiatric Patients

Dose-Dependent Effects of the 3435 C>T Genotype of ABCB1 Gene on the Steady-State Plasma Concentration of Fluvoxamine in Psychiatric Patients

Time-Dependent Clearance Decrements of Fluvoxamine in Depressed Inpatients

Non‐linear fluvoxamine disposition

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