BELVIQ XR (lorcaserin hydrochloride) extended-release tablets for oral use is a serotonin 2C receptor agonist for oral administration used for chronic weight management. Its chemical name is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H -3-benzazepine hydrochloride hemihydrate. The empirical formula is C11 H15 Cl2 N·0.5H2 O, and the molecular weight of the hemihydrate form is 241.16 g/mol.
The structural formula is:
Lorcaserin hydrochloride hemihydrate is a white to off-white powder with solubility in water greater than 400 mg/mL. Each BELVIQ XR tablet contains 20.8 mg of crystalline lorcaserin hydrochloride hemihydrate, equivalent to 20.0 mg anhydrous lorcaserin hydrochloride, and the following inactive ingredients: microcrystalline cellulose NF; mannitol USP; hypromellose 2208 USP; ethylcellulose dispersion Type B NF; hypromellose 2910 USP; colloidal silicon dioxide NF; polyvinyl alcohol USP; polyethylene glycol NF; titanium dioxide USP; talc USP; FD&C yellow #6/sunset yellow FCF; aluminum lake; iron oxide yellow NF; iron oxide red NF; and magnesium stearate NF.
Lorcaserin is believed to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus. The exact mechanism of action is not known.
Lorcaserin at the recommended daily dose selectively interacts with 5-HT2C receptors as compared to 5-HT2A and 5-HT2B receptors (see Table 5), other 5-HT receptor subtypes, the 5-HT receptor transporter, and 5-HT reuptake sites.
|Serotonin Receptor Subtype||EC 50 , nM||Ki, nM|
Cardiac Electrophysiology. The effect of multiple oral doses of immediate-release lorcaserin hydrochloride 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.
In an open label, randomized, crossover clinical trial, single dose and steady state pharmacokinetics of BELVIQ XR 20 mg administered once daily were compared with immediate-release lorcaserin hydrochloride 10 mg tablet administered twice daily under fasted conditions in 34 healthy subjects. At steady state, the time to reach peak plasma concentrations of lorcaserin (tmax ) following BELVIQ XR 20 mg once daily was approximately 10 hours compared with 1.5 hours for immediate-release lorcaserin hydrochloride 10 mg tablet twice daily. A single dose administration of BELVIQ XR 20 mg resulted in comparable total plasma exposure (AUC0-∞ ), but approximately 25% lower peak exposures (Cmax ) relative to two doses of immediate-release tablets administered 12 hours apart. At steady state, however, both Cmax,ss and area under the plasma concentration versus time curve (AUC0-24,ss ) of BELVIQ XR 20 mg administered once daily were bioequivalent to immediate-release lorcaserin hydrochloride 10 mg tablets administered twice daily under fasted conditions.
Effect of Food. Intake of high fat, high calorie breakfast before a single 20 mg oral dose of BELVIQ XR resulted in approximately 46% increase in Cmax and 17% increase in AUC0-∞ but no change in tmax . At steady state, however, there was no significant food effect on the rate or extent of absorption of BELVIQ XR.
Lorcaserin distributes to the cerebrospinal fluid and central nervous system in humans. Lorcaserin is moderately bound (~70%) to human plasma proteins.
Lorcaserin is extensively metabolized in the liver by multiple enzymatic pathways. After oral administration of lorcaserin, 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.
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. The plasma half-life of BELVIQ XR is approximately 12 hours.
Renal Impairment . The pharmacokinetics of lorcaserin was studied in patients with varying degrees of renal function following administration of immediate-release lorcaserin. Creatinine clearance (CLcr) was calculated by Cockcroft-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 [s ee Use in Specific Populations (8.6)].
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 Cock c roft-Gault calculation using the IBW:
GFR (mL/min) = 0.85 x (140-age) x ideal body weight (kg)
72 x serum creatinine (mg/dL)
GFR (mL/min) = (140-age) x ideal body weight (kg)
72 x serum creatinine (mg/dL)
Hepatic Impairment. The pharmacokinetics of lorcaserin was evaluated in patients with hepatic impairment and subjects with normal hepatic function following administration of immediate-release lorcaserin. 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 [s ee Use in Specific Populations (8.7)].
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 who were administered immediate-release lorcaserin, exposure (AUC and Cmax ) of lorcaserin 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 Interaction s
Lorcaserin inhibits CYP 2D6-mediated metabolism. In a clinical trial in 21 CYP 2D6 extensive metabolizers, concomitant administration of tablets of immediate-release lorcaserin hydrochloride (10 mg twice daily for 4 days) increased dextromethorphan peak concentrations (Cmax ) by approximately 76% and exposure (AUC) by approximately 2-fold [see Drug Interactions (7.2)].
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