No abstract

No abstract

No abstract

Clinical Pharmacology & Therapeutics (1999) 65, 159–159; doi:

No abstract

1. Large doses of dexfenfluramine in animals cause a decrease of serotoninergic markers but none of the species so far investigated shows sufficient kinetic and metabolic similarity with man to be a valid model for safety studies. The plasma kinetics of dexfenfluramine and its active metabolite dexnorfenfluramine were therefore studied in baboon, rhesus and cynomolgus monkeys given dexfenfluramine hydrochloride orally (2 mg/kg) in order to investigate whether any of these primates have a biodisposition particularly similar to man. 2. The drug was rapidly N-deethylated to dexnorfenfluramine achieving comparatively low mean maximum plasma levels (Cmax) of 12-14 ng/ml in all primates, and rapidly disappeared thereafter with half-lives (t1/2) ranging from 2 to 3 h in the baboon and rhesus monkey to 6 h in the cynomolgus monkey. Its normetabolite reached higher mean Cmax (52-97 ng/ml) and the t1/2's were longer, varying from about 11 h in the rhesus monkey to 22 h in the cynomolgus monkey. The metabolite-to-parent drug ratio (14-37), in terms of plasma area under curve (AUC), greatly exceeded that in man (< 1), being higher than in all species investigated so far. 3. Comparative repeat dose simulation in monkey and man indicated that the dosage in primates would need to be increased 10-fold to achieve comparable dexfenfluramine steady-state plasma Cmax, producing nor-metabolite levels several times those in man, whilst for comparable metabolite Cmax, those of the parent drug would be correspondingly too low. 4. In view of the different mechanism of action of dexfenfluramine and dexnorfenfluramine within the serotoninergic system none of these primates is therefore a suitable model for safety assessment in terms of exposure of the active moieties in comparison with man.

No abstract

IT HAS LONG BEEN known that animals metabolize and excrete drugs faster than man and that safety comparison across and within species, using dosage, provides insufficient measures of relative exposure. Measurement of blood drug levels during toxicological studies (toxicokinetics), however, can provide a better appreciation of the total body load, but at the moment there are no regulatory guidelines to provide a framework for undertaking such studies for registration. In an attempt to rationalize this knowledge, it has been decided by those working for international harmonization that new guidelines should be drawn up and discussed at the forthcoming International Conference for Harmonization (ICH2). It was, therefore, felt opportune that the DIA should bring together scientists from industry, academia, and the regulatory agencies to address this new issue and hopefully provide support for the current discussions.A total of approximately 170 people listened to 35 speakers and chairmen from 14 countries over the two and one half days of the meeting which was held in Nice, France, February 24-26, 1993.All aspects of toxicokinetics were discussed with session themes dealing with: