Pharmacokinetics of Fenfluramine and Neuroleptics

Authors: John W Hubbard Barringer D Marshall Nuggehally R Srinivas Linda L Bowen John K Cooper Robert P Liberman K K Midha

Publish Date: 2012/10/26

Volume: 4, Issue: 2, Pages: 99-111

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Abstract

This study was designed to investigate whether the addition of fenfluramine to neuroleptic therapy could produce an improvement in chronic schizophrenics who were limited responders to neuroleptics Initially each of 9 inpatients received at least 6 weeks’ treatment with placebo fenfluramine for baseline data collection Thereafter active fenfluramine therapy commenced at 60 mg/day with increments of 20 mg/day implemented every 2 weeks until a maximum daily dose of 120mg of fenfluramine was attained This dosage level was maintained until fenfluramine was withdrawn by stepwise decrements so that the duration of fenfluramine treatment did not exceed 12 weeks The patients then continued to receive placebo fenfluramine for a minimum of 4 weeks for further evaluation and data collection Throughout the study each patient was maintained on a constant dose of a neuroleptic drugThe stepwise addition of fenfluramine revealed significant correlations between dose and plasma concentrations for both isomers of fenfluramine and its pharmacologically active metabolite norfenfluramine Dose proportionality with the plasma concentrations of the isomers of parent and metabolite was also maintained during dose tapering The plasma concentrations of the lisomers of both fenfluramine and norfenfluramine were significantly higher than those of the corresponding disomers Moreover the l d optical isomer ratios were constant at 19 for fenfluramine and 14 for norfenfluramine Thus it would appear that the enantioselective aspects of fenfluramine and its metabolite norfenfluramine were not affected by changes in the dose of fenfluramine The presence of fenfluramine had no consistent effects on the steadystate plasma concentrations of either the neuroleptic drugs or metabolites

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