Compounds / Sexual health

PT-141

Bremelanotide (Vyleesi), synthetic α-MSH analog, melanocortin receptor agonist

Cyclic heptapeptide melanocortin receptor agonist developed by Palatin Technologies. FDA-approved June 2019 (NDA 210557, Vyleesi) for premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD). Sold as a 1.75 mg single-dose autoinjector for SC use. Off-label use for male erectile dysfunction (especially PDE5-inhibitor non-responders) is widespread in TRT clinics and biohacker communities.

At a glance

Half-life

~2.7 h Terminal t½ 2.7h (range 1.9-4.0h) per FDA Vyleesi label. Tmax ~1h. Cmax 72.8 ng/mL after 1.75 mg SC. AUC 276 ng·h/mL. Absolute SC bioavailability ~100%. Vd 25.0 ± 5.8 L. Clearance 6.5 ± 1.0 L/h. Protein binding 21%. Excretion 64.8% urinary, 22.8% fecal.

Routes

SubQ

Vial sizes

10 mg

Evidence base

4 studies 4 human

Mechanism

Non-selective melanocortin receptor agonist: potency MC1R > MC4R > MC3R > MC5R > MC2R. Sexual desire/arousal effect attributed primarily to MC4R agonism in hypothalamic neurons (medial preoptic area, paraventricular nucleus); rapid dose-dependent c-Fos expression in these regions demonstrated in animal models. MC1R agonism on melanocytes drives focal hyperpigmentation. Mechanism is centrally mediated, distinct from PDE5 inhibitors (sildenafil, tadalafil) which act peripherally on penile vascular smooth muscle. PT-141 works in PDE5 non-responders and is additive when combined. FDA approval for HSDD in premenopausal women (phase 3 RECONNECT). Pigmentation risk increases substantially with frequent dosing.

Dosing

Where a study reports an amount, it appears in that study's entry below, attributed to the source.

Published evidence

1. Human RCT 2019

   Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials

   Kingsberg SA, Clayton AH, Portman D, et al. Obstet Gynecol

   Pivotal Phase 3 RECONNECT: two identical 24-week RCTs in premenopausal women with HSDD. Bremelanotide 1.75 mg SC PRN improved Female Sexual Function Index Desire and Female Sexual Distress Scale-DAO Item 13 vs placebo. Basis of FDA approval.

   PMID 31403597

2. Human RCT 2016

   Phase II Randomized Study of the Efficacy and Safety of Bremelanotide in Premenopausal Women with Female Sexual Dysfunction

   Clayton AH, Lucas J, DeRogatis LR, Jordan R J Sex Med

   Phase II dose-finding: established 1.75 mg SC as the dose carried into Phase III.

3. Human RCT 2004

   Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141 in healthy male subjects and in patients with an inadequate response to Viagra

   Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB Int J Impot Res

   Dose range 0.3-10 mg SC. Statistically significant erectile response above 1 mg in healthy men; ED patients (sildenafil non-responders) responded at 4 and 6 mg. Established SC PK and dose-response for later development.

   PMID 14999221

4. Human observational 2019

   Long-term safety and efficacy of bremelanotide for hypoactive sexual desire disorder

   Simon JA, Kingsberg SA, Portman D, et al. Obstet Gynecol

   52-week open-label safety extension. Documented persistent safety profile, pigmentation risk with frequent use, single hepatitis case. Basis for 'max 8 doses/month' labeling.

   PMID 31599847

Reported side effects

Nausea

Very common Moderate · 40.0% of patients in pivotal trials (vs 1.3% placebo). Worst with first dose; ~13% required anti-emetic. Peaks 30-90 min post-dose, resolves 2-4h.

Flushing

Very common Mild · 20.3% (vs 0.3% placebo). Facial / upper body flushing, transient.

Injection site reactions

Common Mild · 13.2% (vs 8.4% placebo). Redness, mild pain, occasional bruising.

Headache

Common Mild · 11.3% (vs 1.9% placebo).

Vomiting

Occasional Moderate · 4.8% (vs 0.2% placebo).

Transient blood pressure increase

Very common Moderate · Systolic +6 mmHg, diastolic +3 mmHg peaks 2-4h post-dose, resolves within 12h. Contraindicated in uncontrolled hypertension or known cardiovascular disease.

Focal hyperpigmentation

Occasional Moderate · 1% in pivotal trials (≤8 doses/month): face, gingiva, breasts most common. Risk much higher in darker skin and with daily/frequent dosing, and is reported to be greater in Fitzpatrick IV-VI skin types. Separate study showed 38% incidence at 8 consecutive daily doses. Resolution after stopping not guaranteed.

Hepatotoxicity (rare)

Rare Serious · One published case of acute hepatitis after 10 injections over a year: marked AST/ALT elevation, mild jaundice, resolved post-discontinuation. LiverTox category D.

Interactions

• PDE5 inhibitors Synergy

  Central (MC4R) + peripheral (PDE5) mechanisms are additive; co-administration produces stronger erectile response than either alone (PMID 14999221). However, both raise BP transiently, an additive hypertensive effect; risk of priapism from synergistic vasodilation + central activation.

• Oral naltrexone Absorption interference

  Vyleesi may significantly decrease systemic exposure of orally-administered naltrexone (FDA label warning).

• Melanotan II Redundant

  Both are MCR agonists with overlapping pharmacology. MT-II is non-selective with stronger MC1R activity (more pigmentation). Stacking is redundant and amplifies MC1R-mediated hyperpigmentation.

• Antihypertensives Caution

  PT-141 transiently raises BP (~6/3 mmHg). Generally not a problem with controlled hypertension on stable regimen, but contraindicated in uncontrolled hypertension or known CV disease.

Reconstitution and storage

Brand Vyleesi: pre-filled autoinjector: no reconstitution. Compounded research-grade: 10 mg vial + 2 mL BAC water = 5 mg/mL = 1.75 mg per 0.35 mL (35 units on insulin syringe). For microdose (15-20 mcg), 10 mg + 5 mL = 2 mg/mL = 20 mcg per 0.01 mL (1 unit): extremely small volume, requires precise syringe handling.

Vyleesi autoinjector: store ≤25°C, do not freeze, protect from light. Compounded reconstituted: refrigerate 2-8°C, use within 28 days.

Open the reconstitution calculator for PT-141