Protein Binding and Distribution: At a dexfenfluramine plasma concentration of 100 ng/mL, 36% is bound to plasma proteins. Dexfenfluramine is distributed into body tissue in non-obese subjects, with a volume of distribution of 839 L.

Metabolism: Dexfenfluramine is metabolized in the liver. The first steps in the metabolism of dexfenfluramine are dealkylation, resulting in formation of the active metabolite, d-norfenfluramine and deamination to an inactive d-hydroxy derivative. In a study of drug metabolism using radiolabeled dexfenfluramine, levofenfluramine and d,l-fenfluramine in two healthy subjects, 92% of the administered radioactivity was found in urine and 1% in feces over 6 days. Fenfluramine accounted for 7% to 19% and norfenfluramine accounted for 4% to 11% of the urine radioactivity. Other metabolites (inactive) included 1-(m-trifluoromethylphenyl)-1,2-propane diol (21 to 38%), m-trifluoromethyl benzoic acid (7 to 22%), m-trifluoromethyl hippuric acid (<1 to 11%), and 1-(m-trifluoromethylphenyl)-propan-2-ol (2 to 4%).

Renal Disease and Liver Disease: Specific studies in patients with renal and hepatic impairment have not been conducted.

Obese Patients: In obese patients who received a single 30-mg dose, a mean peak plasma dexfenfluramine concentration of about 22.3 ng/mL is reached after about 5.2 hours. In a parallel-group, multiple-dose pharmacokinetic study of dexfenfluramine (15 mg twice daily) there were no significant differences in steady-state pharmacokinetic parameters between obese and non-obese subjects.

Age: The pharmacokinetics of a single 30-mg dose of dexfenfluramine in eight elderly patients, ranging from 66 to 83 years of age, have been examined in one study. The mean maximal plasma concentration was 21.8 ng/mL, and ranged from 9.7 to 33.0 ng/mL in individual patients. Time to maximal plasma concentration was about 5 hours and ranged from 3 hours to 10 hours. Area-under-the-curve to infinity was 615 ng·hr/mL and ranged from 16 to 1205 ng·hr/mL. Mean (±SD) steady-state plasma concentrations of dexfenfluramine and d-norfenfluramine after six months of treatment (15 mg twice daily) in 18 obese patients over 60 years old were 27.3 (±16.3) ng/mL and 14.0 (±7.4) ng/mL, respectively, compared to values of 24.1 (±15.9) and 15.6 (±11.2), respectively, in 268 patients under 60 years old. In a cohort of these patients followed through 12 months of treatment (15 mg twice daily) mean (±SD) steady-state plasma concentrations of dexfenfluramine and d-norfenfluramine in 17 obese patients over 60 years old were 32.9 (±16.8) ng/mL and 18.0 (±8.0) ng/mL, respectively, compared to values of 23.9 (±12.9) and 14.4 (±8.2), respectively, in 186 obese patients under 60 years old.

CLINICAL STUDIES

Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases.

The long-term effects of dexfenfluramine on the morbidity and mortality associated with obesity have not been established. Short-term (<4 months), placebo-controlled, double-blind studies have provided evidence that dexfenfluramine does not adversely affect glycemia, lipid profile, or blood pressure control in obese patients. Some short-term studies have suggested that weight loss with dexfenfluramine may be associated with a reduction in hyperglycemia in obese diabetic patients, a reduction in blood pressure in obese hypertensive patients, and improvement in the lipid profile in obese hyperlipidemic patients.

Dexfenfluramine has been shown to be effective in reducing excess body weight in obese patients. In 16 of 17 double-blind, placebo-controlled trials, of various treatment durations and with different design features, where all patients were on reduced-calorie diets, dexfenfluramine-treated patients lost statistically significantly more weight on average than those treated with placebo. In these studies, weight loss was evident within 4 weeks of initiating treatment, even in some patients where reduced-calorie diet alone had failed to induce a significant weight loss.

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