Mechanism of Action

Lorcaserin is believed to decrease food consumption and promote satiety by selectively activating 5-HT_2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus. The exact mechanism of action is not known.

Lorcaserin at the recommended daily dose selectivity interacts with 5-HT_2C receptors as compared to 5-HT_2A and 5-HT_2B receptors (see Table 5), other 5-HT receptor subtypes, the 5-HT receptor transporter, and 5-HT reuptake sites.

Table 5: Lorcaserin Potency (EC50) and Binding Affinity (Ki) to Human 5-HT_2A, 5-HT_2B, and 5-HT_2C Receptor Subtypes

Pharmacodynamics

Cardiac Electrophysiology

The effect of multiple oral doses of lorcaserin 15 mg and 40 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- (moxifloxacin 400 mg) controlled four-treatment arm parallel thorough QT study in 244 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern.

Pharmacokinetics

Absorption

Lorcaserin is absorbed from the gastrointestinal tract with peak plasma concentration occurring 1.5 - 2 hours after oral dosing. The absolute bioavailability of lorcaserin has not been determined. Lorcaserin has a plasma half life of ~11 hours; steady state is reached within 3 days after twice daily dosing, and accumulation is estimated to be approximately 70%.

Effect of Food. Twelve adult volunteers (6 men and 6 women) were given a single 10 mg oral dose of BELVIQ in a fasted state and after administration of a high fat (approximately 50% of total caloric content of the meal) and high-calorie (approximately 800–1000 calories) meal. The Cmax increased approximately 9% and exposure (AUC) increased approximately 5% under fed conditions. Tmax was delayed approximately 1 hour in the fed state. BELVIQ can be administered with or without food.

Distribution

Lorcaserin distributes to the cerebrospinal fluid and central nervous system in humans. Lorcaserin hydrochloride is moderately bound (~70%) to human plasma proteins.

Metabolism

Lorcaserin is extensively metabolized in the liver by multiple enzymatic pathways. After oral administration of BELVIQ, the major circulating metabolite is lorcaserin sulfamate (M1), with a plasma Cmax that exceeds lorcaserin Cmax by 1- to 5-fold. N-carbamoyl glucuronide lorcaserin (M5) is the major metabolite in urine; M1 is a minor metabolite in urine, representing approximately 3% of dose. Other minor metabolites excreted in urine were identified as glucuronide or sulfate conjugates of oxidative metabolites. The principal metabolites exert no pharmacological activity at serotonin receptors.

Elimination

Lorcaserin is extensively metabolized by the liver and the metabolites are excreted in the urine. In a human mass balance study in which healthy subjects ingested radiolabeled lorcaserin, 94.5% of radiolabeled material was recovered, with 92.3% and 2.2% recovered from urine and feces, respectively.

Specific Populations

Renal Impairment. The disposition of lorcaserin was studied in patients with varying degrees of renal function. Creatinine clearance (CLcr) was calculated by Cockgroft-Gault equation based on ideal body weight (IBW). Impaired renal function decreased Cmax of lorcaserin, with no change in AUC.

Exposure of lorcaserin sulfamate metabolite (M1) was increased in patients with impaired renal function by approximately 1.7-fold in mild (CLcr = 50-80 mL/min), 2.3-fold in moderate (CLcr = 30-50 mL/min) and 10.5-fold in severe renal impairment (CLcr = < 30 mL/min) compared to normal subjects (CLcr > 80 mL/min).

Exposure of the N-carbamoyl-glucuronide metabolite (M5) was increased in patients with impaired renal function by approximately 1.5-fold in mild (CLcr = 50-80 mL/min), 2.5-fold in moderate (CLcr = 30-50 mL/min) and 5.1-fold in severe renal impairment (CLcr = < 30 mL/min) compared to normal subjects (CLcr > 80 mL/min).

The terminal half-life of M1 is prolonged by 26%, 96%, and 508% in mild, moderate, and severe renal impairment, respectively. The terminal half-life of M5 is prolonged by 0%, 26%, and 22% in mild, moderate, and severe renal impairment, respectively. The metabolites M1 and M5 accumulate in patients with severely impaired renal function.

Approximately 18% of metabolite M5 in the body was cleared from the body during a standard 4-hour hemodialysis procedure. Lorcaserin and M1 were not cleared by hemodialysis. Lorcaserin is not recommended for patients with severe renal impairment (CLcr < 30 mL/min) or patients with end stage renal disease [see Use In Specific Populations].

Estimate Ideal Body Weight (IBW) in (kg)

Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.

The Cockroft-Gault calculation using the IBW:

Hepatic Impairment. The disposition of lorcaserin was evaluated in patients with hepatic impairment and subjects with normal hepatic function. Lorcaserin Cmax was 7.8% and 14.3% lower, in subjects with mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) hepatic impairment, respectively, than that in subjects with normal hepatic function. The half-life of lorcaserin is prolonged by 59% to 19 hours in patients with moderate hepatic impairment. Lorcaserin exposure (AUC) is approximately 22% and 30% higher in patients with mild and moderate hepatic impairment, respectively. Dose adjustment is not required for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on lorcaserin was not evaluated [see Use In Specific Populations].

Gender. No dosage adjustment based on gender is necessary. Gender did not meaningfully affect the pharmacokinetics of lorcaserin.

Geriatric. No dosage adjustment is required based on age alone. In a clinical trial of 12 healthy elderly (age greater than 65 years) subjects and 12 matched adult patients, lorcaserin exposure (AUC and Cmax) was equivalent in the two groups. Cmax was approximately 18% lower in the elderly group, and Tmax was increased from 2 hours to 2.5 hours in the elderly group as compared to the non-elderly adult group.

Race. No dosage adjustment based on race is necessary. Race did not meaningfully affect the pharmacokinetics of lorcaserin.

Drug-Drug Interactions

Lorcaserin inhibits CYP 2D6-mediated metabolism. In a clinical trial in 21 CYP 2D6 extensive metabolizers, concomitant administration of lorcaserin (10 mg BID for 4 days) increased dextromethorphan peak concentrations (Cmax) by approximately 76% and exposure (AUC) by approximately 2-fold [see DRUG INTERACTIONS].

Clinical Studies

The safety and efficacy of BELVIQ for chronic weight management in conjunction with reduced caloric intake and increased physical activity were evaluated in 3 randomized, double-blind, placebo-controlled trials with durations ranging from 52 to 104 weeks. Two trials in adults without type 2 diabetes mellitus (Study 1 and Study 2) and one study in adults with type 2 diabetes mellitus (Study 3) evaluated the effect of BELVIQ 10 mg twice daily. The primary efficacy parameter in these studies was weight loss at 1 year, which was assessed by percent of patients achieving greater than or equal to 5% weight loss, percent of patients achieving greater than or equal to 10% weight loss, and mean weight change. All patients received one-on-one instruction for a reduced-calorie diet and exercise counseling that began with the first dose of study medication and continued every four weeks throughout the trial.

Study 1 was a 2-year study that enrolled 3182 patients who were obese (BMI 30-45 kg/m²), or who were overweight (BMI 27-29.9 kg/m²) and had at least one weight-related comorbid condition such as hypertension or dyslipidemia. In Year 2, placebo patients were continued on placebo and BELVIQ patients were re-randomized in a 2:1 ratio to continue BELVIQ or to switch to placebo. The mean age was 44 (range 18-65); 83.5% were women. Sixty-seven percent were Caucasian, 19% were African American and 12% were Hispanic. Mean baseline body weight was 100.0 kg and mean BMI was 36.2 kg/m².

Study 2 was a 1-year study that enrolled 4008 patients who were obese (BMI 30-45 kg/m²) or were overweight (BMI 27-29.9 kg/m²) with at least one comorbid condition such as hypertension or dyslipidemia. The mean age was 44 (range 18-65); 80% were women. Sixty-seven percent were Caucasian, 20% were African American and 11% were Hispanic. Mean baseline body weight was 100.2 kg and mean BMI was 35.9 kg/m².

Study 3 was a 1-year study that enrolled 604 adult patients with BMI greater than or equal to 27 kg/m² and inadequately controlled type 2 diabetes (HbA1c range 7-10%) being treated with metformin and/or a sulfonylurea. Mean age was 53 (range 21-65); 54% were women. Sixty-one percent were Caucasian, 21% African American and 14% were Hispanic. Mean BMI was 36 kg/m² and mean HbA1C was 8.1%.

A substantial percentage of randomized subjects withdrew from each study prior to week 52: 50% in Study 1, 45% in Study 2 and 36% in Study 3.

One-Year Weight Management in Patients without Diabetes Mellitus

Weight loss at 1 year in Studies 1 and 2 is presented in Table 6. The pooled data are reflective of the individual study results.

Statistically significantly greater weight loss was achieved with BELVIQ compared to placebo at week 52. The Year 1 placebo-adjusted weight loss achieved in patients treated with BELVIQ was 3.3 kg by ITT/LOCF analysis. The time course of weight loss with BELVIQ and placebo through week 52 is depicted in Figure 1.

Patients who did not lose at least 5% of baseline body weight by week 12 were unlikely to achieve at least 5% weight loss at week 52.

Table 6: Weight Loss at 1 Year in Studies 1 and 2 Combined

Figure 1: Longitudinal Weight Change (kg) in Completer Population: Studies 1 and 2

Two-Year Weight Management in Patients without Diabetes Mellitus

The safety and efficacy of BELVIQ for weight management during 2 years of treatment were evaluated in Study 1. Of the 3182 patients who were randomized in Year 1, 1553 (48.8%) were randomized in Year 2. Patients in all three Year 2 patient groups (BELVIQ Year 1/ BELVIQ Year 2, BELVIQ Year 1/placebo Year 2, and placebo Year 1/placebo Year 2) regained weight in Year 2 but remained below their Year 1 mean baseline weight (Figure 2).

Figure 2: Body Weight Changes during Study 1 in the Completers Population

Effect of BELVIQ on Cardiometabolic Parameters and Anthropometry

Changes in lipids, fasting glucose, fasting insulin, waist circumference, heart rate, and blood pressure with BELVIQ are shown in Table 7.

In a substudy of 154 patients conducted as part of Study 2, DEXA analysis showed a 9.9% reduction in fat mass from a baseline of 45.0 kg in patients treated with BELVIQ compared to a 4.6% reduction from a baseline of 44.5 kg in patients treated with placebo. The placebo-adjusted reduction in fat mass achieved on BELVIQ was -5.3%. Reductions in lean body mass were 1.9% and 0.3% from baseline values of 48.0 kg and 51.0 kg, respectively, for BELVIQ- and placebo-treated patients.

Table 7: Mean Changes in Cardiometabolic Parameters and Waist Circumference in Year 1 of Studies 1 and 2

One-Year Weight Management in Patients with Type 2 Diabetes Mellitus

Weight loss among patients with type 2 diabetes mellitus who were treated with BELVIQ was statistically significantly greater than that among patients treated with placebo (Table 8).

Table 8: Weight Loss at 1 Year in Study 3 (Type 2 Diabetes Mellitus)

Effect of BELVIQ on Cardiometabolic Parameters and Anthropometry in Patients with Type 2 Diabetes Mellitus

Patients in Study 3 were taking either metformin and/or a sulfonylurea at study start, and had inadequate glycemic control (HbA1c range 7-10%). Changes in HbA1c and fasting glucose with BELVIQ use are shown in Table 9.

Table 9: Mean Changes in Cardiometabolic Parameters and Waist Circumference in Patients with Type 2 Diabetes Mellitus

Last reviewed on RxList: 7/5/2012
This monograph has been modified to include the generic and brand name in many instances.