Chemical formula: C₄₉H₆₈N₁₈O₉S₂ Molecular mass: 1,117.32 g/mol PubChem compound: 11993702
Setmelanotide is a selective MC4 receptor agonist. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. In genetic forms of obesity associated with insufficient activation of the MC4 receptor, setmelanotide is believed to re-establish MC4 receptor pathway activity to reduce hunger and promote weight loss through decreased caloric intake and increased energy expenditure.
Setmelanotide is a selective MC4 receptor agonist with less activity at the melanocortin 1 (MC1) receptor. The MC1 receptor is expressed on melanocytes, and activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently of ultraviolet light.
The mean steady state setmelanotide Cmax,ss, AUCtau, and trough concentration for a 3 mg dose administered subcutaneously to otherwise healthy volunteers with obesity (N=6) once daily for 12 weeks were 37.9 ng/mL, 495 h*ng/mL, and 6.77 ng/mL, respectively. Steady-state plasma concentrations of setmelanotide were achieved within 2 days with daily dosing of 1-3 mg setmelanotide. The accumulation of setmelanotide in the systemic circulation during once-daily dosing over 12 weeks was approximately 30%. Setmelanotide AUC and Cmax increased proportionally following multiple-dose subcutaneous administration in the proposed dose range (1-3 mg).
A population PK model comprised of 120 subjects in 8 studies with otherwise healthy volunteers with obesity or patients with rare genetic diseases of obesity was conducted. The study population consisted of 51 males and 69 females with ages ranging from 10 to 65 years and weights ranging from 55.9 to 209 kg. There were 4 children ages 10 to <12 years and 19 adolescents ages 12 to <17 years in the dataset. Studies enrolled 29 otherwise healthy volunteers with obesity and 91 patients with rare genetic diseases of obesity.
After subcutaneous injection of setmelanotide, steady-state plasma concentrations of setmelanotide increased slowly, reaching maximum concentrations at a median tmax of 8.0 hours after dosing. The absolute bioavailability following subcutaneous administration of setmelanotide has not been investigated in humans. Estimate of the inter-individual variability (CV%) from the population PK model was 28.7% (CL/F) and intraindividual variability was 27.6%.
The PK of setmelanotide in patients with BBS was similar to that obtained in the population of patients with POMC, PCSK1, and LEPR deficiency, suggesting the disease state alone does not impact the PK of setmelanotide.
The mean apparent volume of distribution of setmelanotide after subcutaneous administration of setmelanotide 3 mg once daily was estimated from the population PK model to be 48.7L. Setmelanotide binding to human plasma protein is 79.1%.
In vitro experiments indicate that setmelanotide is not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.
In vitro data indicate that setmelanotide is very unlikely a P-gp or BCRP substrate.
Setmelanotide did not appear to be metabolised by rat, monkey, or human hepatic microsomes or hepatocytes, or kidney microsomes.
The effective elimination half-life (t½) of setmelanotide was approximately 11 hours. The total apparent steady state clearance of setmelanotide following subcutaneous administration of 3 mg once daily was estimated from the population PK model to be 4.86 L/h.
Approximately 39% of the administered setmelanotide dose was excreted unchanged in urine during the 24-hour dosing interval following subcutaneous administration of 3 mg once daily.
Setmelanotide AUC and Cmax increased approximately linearly with dose following multiple-dose subcutaneous administration in the proposed dose range (1-3 mg).
Setmelanotide has been evaluated in paediatric patients (aged 6 to 17 years). Simulations from the population PK analyses suggest slightly higher exposure in younger patients (who also have lower body weight) and provide support for the dosing regimen in patients 6 years and older.
Available data in a small sample of elderly patients suggest no marked changes in setmelanotide exposure with increased age. However, these data are too limited to draw definite conclusions.
Pharmacokinetic analysis showed a 12%, 26%, and 49% lower clearance (CL/F) of setmelanotide in patients with mild, moderate, and severe renal impairment, respectively, as compared to patients with normal renal function.
POMC, including PCSK1, deficiency and LEPR deficiency:
No dose adjustments for patients with mild (estimated glomerular filtration rate [eGFR] of 60-89 ml/min/1.73 m²) or moderate renal impairment (eGFR of 30-59 ml/min/1.73 m²) are needed. Dose adjustments are recommended for patients with severe renal impairment (eGFR 15-29 ml/min/1.73 m²). Setmelanotide should not be administered to patients with end-stage renal disease (eGFR <15 ml/min/1.73 m²).
Bardet-Biedl Syndrome:
No dose adjustments for patients with mild (estimated glomerular filtration rate [eGFR] of 60-89 ml/min/1.73 m²) or moderate renal impairment (eGFR of 30-59 ml/min/1.73 m²) are needed. Dose adjustments are recommended for patients with severe renal impairment (eGFR 15-29 ml/min/1.73 m²). Setmelanotide should not be administered to patients with end-stage renal disease (eGFR <15 ml/min/1.73 m²).
Setmelanotide is stable in human, rat, and monkey hepatocytes; therefore, a study in patients with hepatic impairment was not conducted. Setmelanotide should not be used in patients with hepatic impairment.
Setmelanotide CL/F varied with body weight according to a fixed allometric relationship.
No clinically significant differences in the pharmacokinetics of setmelanotide were observed based on sex.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenicity, fertility, teratogenicity, or postnatal development.
A developmental reproduction study in rabbits revealed increases in embryo-foetal resorption and post-implantation loss in pregnant rabbits treated with setmelanotide. These effects were attributed to extreme reductions in maternal food consumption related to the primary pharmacodynamic activity of setmelanotide. Similar reductions in food consumption and related embryo-foetal loss were not observed in a developmental reproduction study in rats. No teratogenic effects were observed in either species.
Dose-related setmelanotide concentrations were observed in milk 2 hours after subcutaneous injection in the pre-weaning phase of a pre- and postnatal development study in rats. No quantifiable setmelanotide concentrations were detected in plasma from nursing pups at any dose.
In contrast to primates, variable cardiovascular effects, such as increased heart rate and blood pressure, were observed in rats and minipigs. The reason underlying those species differences remains unclear. In rat, the dose-dependent effects of setmelanotide on heart rate and blood pressure were linked to an increase in sympathetic tone and they were found to progressively diminish upon repeated daily dosing.
Minimal cytoplasmic vacuolation related to the excipient mPEG-DSPE was observed in the choroid plexus after chronic administration in adult rats and monkeys. Choroid plexus vacuolation was not observed in juvenile rats treated with setmelanotide/mPEG-DSPE from post-natal Days 7 to 55 at 9.5-times the human dose of mPEG-DSPE from 3 mg of setmelanotide on a mg/m²/day basis.
The available carcinogenicity data in Tg.rasH2 mice indicate that setmelanotide/mPEG-DSPE does not pose a carcinogenic risk to patients, with a safety margin of 17 for setmelanotide based on AUC and a dose margin of 16 for mPEG DSPE on a mg/m²/day basis, at the clinical dose of 3 mg/day. Due to the lack of pro-carcinogenic concern from the available non-clinical and clinical data on setmelanotide, a 2-year carcinogenicity study in rats has not been performed.
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