Lorcaserin

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 selectively interacts with 5-HT_{2C receptors as compared to 5-HT2A and 5-HT2B receptors (see table), other 5-HT receptor subtypes, the 5-HT receptor transporter, and 5-HT reuptake sites.}

Lorcaserin Potency (EC50) and Binding Affinity (Ki) to Human 5-HT2A, 5-HT2B, and 5-HT2C Receptor Subtypes:

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.

Absorption

Lorcaserin film-coated tablet

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. 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 lorcaserin 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 C_max increased approximately 9% and exposure (AUC) increased approximately 5% under fed conditions. T_max was delayed approximately 1 hour in the fed state. Lorcaserin film-coated tablet can be administered with or without food.

Lorcaserin extended-release tablet

In an open label, randomized, crossover clinical trial, single dose and steady state pharmacokinetics of lorcaserin extended-release tablet 20 mg administered once daily were compared with lorcaserin film-coated tablet 10 mg administered twice daily under fasted conditions in 34 healthy subjects. At steady state, the time to reach peak plasma concentrations of lorcaserin (t_max) following lorcaserin extended-release tablet 20 mg once daily was approximately 10 hours compared with 1.5 hours for lorcaserin film-coated tablet 10 mg twice daily. A single dose administration of lorcaserin extended-release tablet 20 mg resulted in comparable total plasma exposure (AUC_0-∞), but approximately 25% lower peak exposures (C_max) relative to two doses of lorcaserin film-coated tablets administered 12 hours apart. At steady state, however, both C_max,ss and area under the plasma concentration versus time curve (AUC_0-24,ss) of lorcaserin extended-release tablet 20 mg administered once daily were bioequivalent to lorcaserin film-coated 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 lorcaserin extended-release tablet resulted in approximately 46% increase in C_max and 17% increase in AUC_0-∞ but no change in t_max. At steady state, however, there was no significant food effect on the rate or extent of absorption of lorcaserin extended-release tablet.

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 lorcaserin the major circulating metabolite is lorcaserin sulfamate (M1), with a plasma C_max that exceeds lorcaserin C_max 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. The terminal phase half-life for lorcaserin film-coated tablet/lorcaserin extended-release tablet is approximately 11 to 12 hours.

Specific Populations

Renal Impairment

The pharmacokinetics of lorcaserin was studied in patients with varying degrees of renal function. Creatinine clearance (CLcr) was calculated by Cockcroft-Gault equation based on ideal body weight (IBW). Impaired renal function decreased C_max 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.

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 Cockcroft-Gault calculation using the IBW:

female:

GFR (mL/min) = = 0.85 x (140-age) x ideal body weight (kg) / 72 x serum creatinine (mg/dL)

male:

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. Lorcaserin C_max 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.

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 C_max) was equivalent in the two groups. C_max was approximately 18% lower in the elderly group, and T_max 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 (C_max) by approximately 76% and exposure (AUC) by approximately 2-fold.