Vyleesi Pharmacokinetics (ADME): How Bremelanotide Is Absorbed, Distributed, Metabolized, and Eliminated

Absorption: fast, near-complete, peaking near one hour

Vyleesi is the FDA-approved bremelanotide product (NDA 210557, approved June 21, 2019) and is a 1.75 mg/0.3 mL subcutaneous injection given with a prefilled autoinjector into the abdomen or thigh [1][2]. After a subcutaneous dose, median Tmax is about 1.0 hour (range 0.5 to 1.0 hour) and absolute bioavailability is about 100% [1]. Mean Cmax is 72.8 ng/mL and mean AUC is 276 hr*ng/mL [1].

The dosing instruction is to inject at least 45 minutes before anticipated sexual activity, and the same section says the duration of efficacy after each dose is unknown and the optimal administration window has not been fully characterized [1]. A median Tmax near one hour describes when plasma levels peak; the label does not present it as an onset time for clinical effect [1].

Dose: concentrations rise less than proportionally

Across subcutaneous doses from 0.3 to 10 mg, mean plasma concentrations rose less than proportionally with dose, and mean Cmax reached a plateau at the 7.5 mg subcutaneous dose, about 4.3 times the maximum recommended dose [1]. That 0.3 to 10 mg range was studied with subcutaneous PT-141 in healthy men, while men with erectile dysfunction who responded inadequately to sildenafil received placebo, 4 mg or 6 mg in a crossover design [3].

Receptor activity

Bremelanotide is a cyclic peptide of seven amino acids and a nonselective melanocortin receptor agonist. It activates receptor subtypes in this order of potency: MC1R, MC4R, MC3R, MC5R, MC2R, and at therapeutic doses binding to MC1R and MC4R is most relevant [1]. The label states that the mechanism by which Vyleesi improves hypoactive sexual desire disorder is unknown [1]. A 2023 review describes the idea that bremelanotide triggers excitatory brain pathways as a hypothesis rather than an established mechanism [4].

Metabolism: hydrolysis of amide bonds

Bremelanotide is metabolized by hydrolysis of amide bonds [1].

Elimination: a 2.7-hour half-life

After a single subcutaneous dose, mean terminal half-life is about 2.7 hours (range 1.9 to 4.0 hours) [1]. In a radiolabeled study, 64.8% of total radioactivity was recovered in urine and 22.8% in feces [1]. Those percentages describe total radioactivity, not the fraction of unchanged bremelanotide, so they cannot be read as the amount of parent drug excreted by each route [1].

A 2.7-hour half-life does not define how long a dose works. The label says the duration of efficacy after each dose is unknown [1], and the blood pressure and heart rate changes that follow each dose usually return to baseline within 12 hours [1].

Kidney and liver impairment

AUC rises 1.5-fold in moderate renal impairment and 2-fold in severe renal impairment, and 1.2-fold with mild and 1.7-fold with moderate hepatic impairment [1]. The label recommends no dosing adjustment in mild to moderate renal impairment (eGFR 30-89) or mild to moderate hepatic impairment (Child-Pugh A and B), and says to use with caution in severe renal impairment (eGFR below 30) and severe hepatic impairment (Child-Pugh C) [7].

Oral medicines and slowed stomach emptying

Vyleesi may slow gastric emptying, which can reduce the rate and extent of absorption of oral medicines [1]. The label instructs patients to avoid Vyleesi when taking oral drugs that depend on threshold concentrations for efficacy, such as antibiotics [1]. If an oral medicine such as indomethacin has a delayed effect when a quick effect is needed, the Vyleesi label says to consider discontinuing Vyleesi [1]. In clinical pharmacology studies, only naltrexone and indomethacin were meaningfully affected [1].

Vyleesi may significantly decrease the systemic exposure of orally administered naltrexone, and the label says to avoid the combination with naltrexone-containing products intended to treat alcohol or opioid addiction because of the severe consequence of naltrexone treatment failure [1].

Does alcohol change bremelanotide levels?

In a crossover study of 24 healthy volunteers, alcohol at 0.6 g/kg did not change the pharmacokinetic profile of bremelanotide [1]. That study used a 20 mg intranasal dose, which produces a mean Cmax about 2.5-fold higher than Vyleesi [1]. Flushing and headache rates with the combination were similar to the higher of the two single-agent rates [1].

Blood pressure and heart rate are pharmacodynamics, not ADME

Each dose transiently raises blood pressure and lowers heart rate [1]. Maximal increases in clinical studies were 6 mmHg systolic and 3 mmHg diastolic, peaking 2 to 4 hours after the dose, with a heart rate reduction of up to 5 beats per minute; values usually returned to baseline within 12 hours [1]. In an open-label ambulatory study of 127 premenopausal women dosed once daily for 8 days, mean daytime blood pressure rose 1.9 mmHg systolic (95% CI 1.0 to 2.7) and 1.7 mmHg diastolic (95% CI 0.9 to 2.4), with a mean heart rate decrease of 0.5 beats per minute [1]. No additive effect on blood pressure or heart rate was seen with repeat daily dosing 24 hours apart for up to 16 days [1].

Why the dose limits exist

The label says not to administer more than one dose within 24 hours, and that more than 8 doses per month is not recommended [1]. It gives the reasons: the efficacy of consecutive doses within 24 hours has not been established, doses given close together may add to blood pressure effects, and more frequent monthly dosing increases the risk of focal hyperpigmentation and the length of time each month that blood pressure is raised [1]. Most patients in the phase 3 program used Vyleesi two to three times per month and no more than once a week [1].

In the two identical 24-week RECONNECT trials, 1,267 premenopausal women were randomized to bremelanotide 1.75 mg as needed or placebo [5], and the 52-week open-label extension enrolled 684 women, of whom 272 completed it [6]. The label also says to stop after 8 weeks if symptoms have not improved [1].