The Use of Pharmacokinetics in the Assessment of Dexfenfluramine Safety

Publisher Summary This chapter focuses on studies that use pharmacokinetics in the safety assessment of dexfenfluramine. Some investigators suggest that dexfenfluramine is neurotoxic, because of observed reductions in central 5-HT levels, particularly in the cortex. Several studies have been conducted regarding the indications of neurodegeneration following changes in 5-HT levels. The plasma pharmacokinetics and metabolism of dexfenfluramine has been studied in at least eight species, including human. The long-term 5-HT/5-HIAA reductions with fenfluramine at high doses cannot be readily explained and, when comparing these effects in different species in terms of dosage, the primate appears to be more sensitive compared with the rat, whereas the mouse is the least sensitive. It is well documented for many drugs that there are major species differences in the kinetics and clearance from the body in terms of both rate and route. From allometric or body size considerations, it can be expected that small animals will remove drugs more rapidly from the body because of their relatively faster tissue blood flows and larger organs when expressed as a percentage of body size. Thus, the common method of extrapolating a dosage that exhibits an effect in animals to the dosage used in humans, and expecting the same effect to occur without at least blood or tissue levels of the active components, is often a misrepresentation of the data. Dexfenfluramine is no exception. The uptake of dexfenfluramine and exnorfenfluramine into the brain appears to be related to the species body weight.