Inside the body with Bremelanotide (PT-141)

After subcutaneous administration of the autoinjector product, absolute bioavailability is about 100% and median Tmax is about 1.0 hour (range 0.5-1.0 h). Injection into abdomen or thigh made no significant difference to systemic exposure. Mean Cmax and AUC are 72.8 ng/mL and 276 h*ng/mL. Exposure rises less than proportionally across the tested range.[src]

Plasma protein binding is 21%. Mean terminal half-life is about 2.7 hours (1.9-4.0 h) and mean apparent clearance (CL/F) is 6.5 L/h. As a seven-residue cyclic peptide it is metabolised by multiple hydrolyses of amide bonds rather than by cytochrome P450 enzymes.[src]

Bremelanotide is a non-selective melanocortin receptor agonist (potency MC1R, MC4R, MC3R, MC5R, MC2R); MC1R and MC4R binding is most relevant at therapeutic doses, and MC4R-expressing neurons are widespread in the CNS. A 3.1 A cryo-EM structure of bremelanotide-MC4R-Gs (PDB 7F55) shows the conserved binding mode of peptidic agonists at MC4R. Whether receptor activation in specific circuits explains the clinical effect in HSDD has not been established in humans.[src][src][src]

In female rats, PT-141 selectively increased solicitational (appetitive) behaviours without affecting lordosis, pacing or general motor activity, and without altering perceived sexual reward, suggesting a role for central melanocortin systems in sexual motivation. Systemic PT-141 also increased c-Fos in hypothalamic neurons in rats. These are animal findings; the FDA label states that the mechanism by which Vyleesi improves HSDD in women is unknown, and the RECONNECT trials did not test mechanism.[src][src][src]

In clinical studies each use produced a transient rise in systolic blood pressure of up to about 6 mmHg and diastolic up to about 3 mmHg, peaking 2-4 hours after the injection, with heart rate falling by up to about 5 beats per minute; values usually returned to baseline within 12 hours and no additive effect was seen with repeated daily use for up to 16 days. The label contraindicates use in uncontrolled hypertension or known cardiovascular disease. The precise receptor pathway for this effect is not stated in the label.[src]

MC1R is expressed on melanocytes, and agonism increases melanin expression. In the phase 3 trials focal hyperpigmentation (including face, gingiva and breasts) was reported in 1% of treated patients versus none on placebo; in a separate study, 38% developed focal hyperpigmentation after 8 days of daily use, with a higher risk in darker-skinned patients. Resolution was not confirmed in all patients after discontinuation.[src]

Nausea occurred in 40% of treated patients versus about 1% on placebo (highest after the first dose, 21%, then about 3%), lasted about two hours, and led to discontinuation in 8%. Pre-treatment with oral ondansetron did not reduce nausea in a phase 4 study. The label notes that bremelanotide may reduce the rate and extent of absorption of co-administered oral drugs, likely through slowed gastric motility; naltrexone and indomethacin exposure was affected.[src]

Following a radiolabelled dose, 64.8% of radioactivity was recovered in urine and 22.8% in faeces. Bremelanotide AUC rose 1.2-fold, 1.5-fold and 2-fold in mild, moderate and severe renal impairment respectively.[src]