Meridia (Sibutramine Hydrochloride) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

MODE OF ACTION

Sibutramine produces its therapeutic effects by norepinephrine, serotonin and dopamine reuptake inhibition. Sibutramine and its major pharmacologically active metabolites (M₁ and M₂) do not act via release of monoamines.

PHARMACODYNAMICS

Sibutramine exerts its pharmacological actions predominantly via its secondary (M₁) and primary (M₂) amine metabolites. The parent compound, sibutramine, is a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake in vivo, but not in vitro. However, metabolites M₁ and M₂ inhibit the reuptake of these neurotransmitters both in vitro and in vivo.

In human brain tissue, M₁ and M₂ also inhibit dopamine reuptake in vitro, but with ~3-fold lower potency than for the reuptake inhibition of serotonin or norepinephrine.

A study using plasma samples taken from sibutramine-treated volunteers showed monoamine reuptake inhibition of norepinephrine > serotonin > dopamine; maximum inhibitions were norepinephrine = 73%, serotonin = 54% and dopamine = 16%.

Sibutramine and its metabolites (M₁ and M₂) are not serotonin, norepinephrine or dopamine releasing agents. Following chronic administration of sibutramine to rats, no depletion of brain monoamines has been observed.

Sibutramine, M₁ and M₂ exhibit no evidence of anticholinergic or antihistaminergic actions. In addition, receptor binding profiles show that sibutramine, M₁ and M₂ have low affinity for serotonin (5-HT₁, 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C), norepinephrine ((beta), (beta)₁, (beta)₃, (alpha)₁ and (alpha)₂), dopamine (D₁ and D₂), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.

PHARMACOKINETICS

ABSORPTION

Sibutramine is rapidly absorbed from the GI tract (T_max of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/h and half-life of 1.1 h) to form the pharmacologically active mono- and di-desmethyl metabolites M₁ and M₂. Peak plasma concentrations of M₁ and M₂ are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined.

DISTRIBUTION

Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney. In vitro, sibutramine, M₁ and M₂ are extensively bound (97%, 94% and 94%, respectively) to human plasma proteins at plasma concentrations seen following therapeutic doses.

METABOLISM

Sibutramine is metabolized in the liver principally by the cytochrome P450(3A₄) isoenzyme, to desmethyl metabolites, M₁ and M₂. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M₅ and M₆. Following oral administration of radiolabeled sibutramine, essentially all of the peak radiolabeled material in plasma was accounted for by unchanged sibutramine (3%), M₁(6%), M₂(12%), M₅(52%), and M₆(27%).

M₁ and M₂ plasma concentrations reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of M₁ and M₂, 14 and 16 hours, respectively, were unchanged following repeated dosing.

EXCRETION

Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. Major metabolites in urine were M₅ and M₆; unchanged sibutramine, M₁, and M₂ were not detected. The primary route of excretion for M₁ and M₂ is hepatic metabolism and for M₅ and M₆ is renal excretion.

SUMMARY OF PHARMACOKINETIC PARAMETERS

EFFECT OF FOOD

Administration of a single 20 mg dose of sibutramine with a standard breakfast resulted in reduced peak M₁ and M₂ concentrations (by 27% and 32%, respectively) and delayed the time to peak by approximately three hours. However, the AUCs of M₁ and M₂ were not significantly altered.

SPECIAL POPULATIONS

Geriatric: Plasma concentrations of M₁ and M₂ were similar between elderly (ages 61 to 77 yr) and young (ages 19 to 30 yr) subjects following a single 15-mg oral sibutramine dose. Plasma concentrations of the inactive metabolites M₅ and M₆ were higher in the elderly; these differences are not likely to be of clinical significance. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatric: The safety and effectiveness of MERIDIA in pediatric patients under 16 years old have not been established.

Gender: Pooled pharmacokinetic parameters from 54 young, healthy volunteers (37 males and 17 females) receiving a 15-mg oral dose of sibutramine showed the mean C_max and AUC of M₁ and M₂ to be slightly ( DOSAGE AND ADMINISTRATION ").

Race: The relationship between race and steady-state trough M₁ and M₂ plasma concentrations was examined in a clinical trial in obese patients. A trend towards higher concentrations in Black patients over Caucasian patients was noted for M₁ and M₂. However, these differences are not considered to be of clinical significance.

Renal Insufficiency: The effect of renal disease has not been studied. However, since sibutramine and its active metabolites M₁ and M₂ are eliminated by hepatic metabolism, renal disease is unlikely to have a significant effect on their disposition. Elimination of the inactive metabolites M₅ and M₆, which are renally excreted, may be affected in this population. MERIDIA should not be used in patients with severe renal impairment.

Hepatic Insufficiency: In 12 patients with moderate hepatic impairment receiving a single 15-mg oral dose of sibutramine, the combined AUCs of M₁ and M₂ were increased by 24% compared to healthy subjects while M₅ and M₆ plasma concentrations were unchanged. The observed differences in M₁ and M₂ concentrations do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. MERIDIA should not be used in patients with severe hepatic dysfunction.

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 MERIDIA Capsules on the morbidity and mortality associated with obesity have not been established. Weight loss was examined in 11 double-blind, placebo-controlled obesity trials (BMI range across all studies 27-43) with study durations of 12 to 52 weeks and doses ranging from 1 to 30 mg once daily. Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5 to 20 mg once daily. In two 12-month studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of placebo-subtracted weight loss achieved on MERIDIA was consistent across studies.

Analysis of the data in three long-term (>/=6 months) obesity trials indicates that patients who lose at least 4 pounds in the first 4 weeks of therapy with a given dose of MERIDIA are most likely to achieve significant long-term weight loss on that dose of MERIDIA. Approximately 60% of such patients went on to achieve a placebo-subtracted weight loss of >/=5% of their initial body weight by month 6. Conversely, of those patients on a given dose of MERIDIA who did not lose at least 4 pounds in the first 4 weeks of therapy, approximately 80% did not go on to achieve a placebo-subtracted weight loss of >/=5% of their initial body weight on that dose by month 6.

Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months in placebo-controlled clinical trials. In a 12-week placebo-controlled study of non-insulin dependent diabetes mellitus patients randomized to placebo or 15 mg per day of MERIDIA, Dual Energy X-Ray Absorptiometry (DEXA) assessment of changes in body composition showed that total body fat mass decreased by 1.8 kg in the MERIDIA group versus 0.2 kg in the placebo group (p<0.001). Similarly, truncal (android) fat mass decreased by 0.6 kg in the MERIDIA group versus 0.1 kg in the placebo group (p<0.01). The changes in lean mass, fasting blood sugar, and HbA₁ were not statistically significantly different between the two groups.

Eleven double-blind, placebo-controlled obesity trials with study durations of 12 to 52 weeks have provided evidence that MERIDIA does not adversely affect glycemia, serum lipid profiles, or serum uric acid in obese patients. Treatment with MERIDIA (5 to 20 mg once daily) is associated with mean increases in blood pressure of 1 to 3 mm Hg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo. These findings are similar in normotensives and in patients with hypertension controlled with medication. Those patients who lose significant (>/= 5% weight loss) amounts of weight on MERIDIA tend to have smaller increases in blood pressure and pulse rate (see " WARNINGS ").

In Study 1, a 6-month, double-blind, placebo-controlled study in obese patients, Study 2, a 1-year, double-blind, placebo-controlled study in obese patients, and Study 3, a 1-year, double-blind, placebo-controlled study in obese patients who lost at least 6 kg on a 4-week very low calorie diet (VLCD), MERIDIA produced significant reductions in weight, as shown below. In the two 1-year studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months.

Maintenance of weight loss with Meridia® (sibutramine hydrochloride monohydrate) was examined in a 2-year, double-blind, placebo-controlled trial. After a 6-month run-in phase in which all patients received sibutramine 10 mg (mean weight loss, 26 lbs.), patients were randomized to sibutramine (10 to 20 mg, 352 patients) or placebo (115 patients). The mean weight loss from initial body weight to endpoint was 21 lbs. and 12 lbs. for sibutramine and placebo patients, respectively. A statistically significantly (p<0.001) greater proportion of sibutramine treated patients, 75%, 62%, and 43%, maintained at least 80% of their initial weight loss at 12, 18, and 24 months, respectively, compared with the placebo group (38%, 23%, and 16%). Also 67%, 37%, 17%, and 9% of sibutramine treated patients compared with 49%, 19%, 5%, and 3% of placebo patients lost >/=5%, >/=10%, >/=15%, and >/=20%, respectively, of their initial body weight at endpoint. From endpoint to the post-study follow-up visit (about 1 month), weight regain was approximately 4 lbs for the sibutramine patients and approximately 2 lbs for the placebo patients.

MERIDIA (sibutramine hydrochloride monohydrate) induced weight loss has been accompanied by beneficial changes in serum lipids that are similar to those seen with nonpharmacologically-mediated weight loss. A combined, weighted analysis of the changes in serum lipids in 11 placebo-controlled obesity studies ranging in length from 12 to 52 weeks is shown below for the last observation carried forward (LOCF) analysis.

MERIDIA induced weight loss has been accompanied by reductions in serum uric acid.

Certain centrally-acting weight loss agents that cause release of serotonin from nerve terminals have been associated with cardiac valve dysfunction. The possible occurrence of cardiac valve disease was specifically investigated in two studies. In one study 2-D and color Doppler echocardiography were performed on 210 patients (mean age, 54 years) receiving MERIDIA 15 mg or placebo daily for periods of 2 weeks to 16 months (mean duration of treatment, 7.6 months). In patients without a prior history of valvular heart disease, the incidence of valvular heart disease was 3/132 (2.3%) in the sibutramine treatment group (all three cases were mild aortic insufficiency) and 2/77 (2.6%) in the placebo treatment group (one case of mild aortic insufficiency and one case of severe aortic insufficiency). In another study, 25 patients underwent 2-D and color Doppler echocardiography before treatment with MERIDIA and again after treatment with MERIDIA 5 to 30 mg daily for three months; there were no cases of valvular heart disease.

The effect of sibutramine 15 mg once daily on measures of 24-hour blood pressure was evaluated in a 12-week placebo-controlled study. Twenty-six male and female, primarily Caucasian individuals with an average BMI of 34 kg/m² and an average age of 39 years underwent 24-hour ambulatory blood pressure monitoring (ABPM). The mean changes from baseline to Week 12 in various measures of ABPM are shown in the following table.