CLINICAL PHARMACOKINETICS OF FLUVOXAMINE - APPLICATIONS TO DOSAGE REGIMEN DESIGN

Background: The disposition characteristics and pharmacokinetic parame ters of drugs provide fundamental data for designing safe and effectiv e dosage regimens. A drug's volume of distribution, clearance, and the derived parameter, half-life, are particularly important, as they det ermine the degree of fluctuation between a maximum and minimum plasma concentration during a dosage interval, the magnitude of the steady-st ate concentration, and the time to reach a steady-state plasma concent ration upon chronic dosing. Potential drug-drug interactions can be pr edicted with knowledge of affinities for various cytochrome P450 (CYP) isozymes. Method: The literature was searched for information related to the pharmacokinetic properties of fluvoxamine and reports of its i nvolvement in drug interactions. Results: The primary pharmacokinetic variables for fluvoxamine have been estimated in single and multiple d ose studies in animals, healthy volunteers, and patients. Fluvoxamine is well absorbed after oral administration, widely distributed in the body, and eliminated with a mean half-life of 15 hours and a range fro m 9 hours to 28 hours. Its disposition is altered in hepatic, but not renal, disease. Data from elderly subjects reflect a modest need for d osage adjustment in this population. Fluvoxamine produces no active me tabolites. The specific cytochrome isozymes involved in the hepatic el imination of the drug are undefined. Data from studies relating the pl asma concentration of fluvoxamine to its clinical effects do not suppo rt routine plasma concentration monitoring in depression or anxiety di sorders. Fluvoxamine has prominent affinity for the CYP1A2 isozyme, le sser affinity for the CYP3A4 and CYP2C isozymes, and minimal affinity for CYP2D6. This profile suggests the need for careful dosage adjustme nt when used together with some drugs that have a narrow therapeutic r ange in order to minimize inhibiting their metabolism. Conclusion: Ove rall, the pharmacokinetic profile of fluvoxamine is adequately defined to provide guidelines for developing safe and effective dosage regime ns for most types of patients.