Bremelanotide (PT-141)

1. 01Skin

   Injected under the skin and absorbed

   The medicine is given as a small injection just under the skin. From there almost all of it passes into the bloodstream, and levels peak in about an hour.

   For experts

   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]

2. 02Bloodstream

   Travels in the blood for a few hours

   In the blood the peptide is mostly free rather than stuck to proteins. Half of it is gone in about two and a half hours, so its effects are short-lived.

   For experts

   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]

3. 03Brain

   Switches on melanocortin receptors in the brain

   Bremelanotide copies a natural hormone called alpha-MSH. It fits into melanocortin receptors, especially one called MC4R that is found on nerve cells in many brain areas, and turns them on. Scientists have taken 3D pictures of this fit.

   For experts

   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]

4. 04Brain

   Changes brain signalling linked to sexual desire (animal evidence)

   In female rats, the drug made the animals more likely to start sexual behaviour, without changing other behaviours. That points to brain melanocortin systems, but it is animal evidence. In women, doctors do not know exactly how the drug improves desire.

   For experts

   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]

5. 05Heart

   Briefly raises blood pressure and slows the heart

   After each use, blood pressure goes up a little and heart rate goes down a little for several hours, then returns to normal. This is why people with uncontrolled high blood pressure or known heart disease should not use it.

   For experts

   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]

6. 06Skin

   Can darken patches of skin (MC1R)

   Skin pigment cells also carry a melanocortin receptor, MC1R. Switching it on can make some spots of skin, gums or breast tissue darker. In some people it was not confirmed to fade after stopping.

   For experts

   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]

7. 07Stomach

   Often causes nausea and may slow the stomach

   Nausea is the most common side effect, mostly after the first use. The drug can also slow how quickly the stomach moves food along, which may change how quickly some pills are absorbed.

   For experts

   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]

8. 08Kidneys

   Broken down and removed, mostly through urine

   The body chops the peptide into small pieces. Most of what leaves goes out in urine, the rest in stool. When the kidneys work poorly, more of the drug stays in the blood.

   For experts

   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]

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