Vyleesi Renal Protection or Renal Risk: What Patients and Prescribers Need to Know

Does bremelanotide protect the kidneys?

Bremelanotide is a melanocortin receptor agonist that activates several receptor subtypes in this order of potency: MC1R, MC4R, MC3R, MC5R, MC2R. At the approved dose, binding at MC1R and MC4R is the most relevant [1]. The label places MC1R on pigment cells and MC4R on neurons in the central nervous system, and states that how the drug improves HSDD is unknown [1]. Kidney tissue is not part of that description [1].

Kidney-protection findings exist for a related peptide, alpha-melanocyte-stimulating hormone (alpha-MSH). It limited kidney injury in mice subjected to 40 minutes of ischemia and 24 hours of reperfusion, and it still did so in mice lacking ICAM-1, which had about 75% less neutrophil infiltration than controls [2]. In isolated ischemic kidneys perfused without neutrophils, alpha-MSH preserved glomerular filtration rate and tubular sodium reabsorption, and it reduced nitrite production by 20% in cultured mouse cortical tubule cells [2]. Those are mouse and isolated-kidney experiments with alpha-MSH, not bremelanotide, and they do not demonstrate kidney protection from Vyleesi in people [2].

What the Vyleesi label says about kidney function

The contraindications section lists two items: uncontrolled hypertension and known cardiovascular disease [1]. Kidney impairment is not one of them.

The kidney-related content in the label is pharmacokinetic. Exposure to bremelanotide, measured as AUC, is about 1.5-fold higher in moderate renal impairment and about 2-fold higher in severe renal impairment [1]. The label sets the dose at 1.75 mg subcutaneously, at least 45 minutes before anticipated sexual activity, with no more than one dose within 24 hours, and says more than 8 doses per month is not recommended [1].

How the drug is cleared

After a 1.75 mg subcutaneous dose, mean peak plasma concentration is 72.8 ng/mL and AUC is 276 hr*ng/mL, with a median time to peak of about 1.0 hour, absolute bioavailability of about 100%, and a mean terminal half-life of about 2.7 hours (range 1.9 to 4.0) [1]. Bremelanotide is metabolized by hydrolysis of amide bonds, and 64.8% of the radioactivity from a dose is recovered in urine while 22.8% is recovered in feces [1].

Blood pressure is the label's main concern

Each dose transiently raises blood pressure and lowers heart rate. Maximal increases 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, and no additive effect appeared with once-daily dosing 24 hours apart for up to 16 days [1]. Those are maximal figures, not averages. In an open-label ambulatory blood pressure study of 127 premenopausal women dosed once daily for 8 days, the mean daytime increase was 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].

The label says to assess cardiovascular risk and make sure blood pressure is well controlled before starting and periodically during treatment. It states that Vyleesi is not recommended in patients at high risk for cardiovascular disease, and it contraindicates the drug in uncontrolled hypertension or known cardiovascular disease [1].

Other label cautions

Vyleesi may slow gastric emptying and reduce absorption of oral medicines. The label says to avoid it with oral drugs that depend on threshold blood concentrations, such as antibiotics, and to consider skipping it when a quick onset of an oral medicine such as indomethacin is wanted [1]. In the clinical pharmacology studies, only naltrexone and indomethacin were meaningfully affected [1]. Vyleesi may significantly decrease the exposure to oral naltrexone, and the label says to avoid the combination with naltrexone products intended to treat alcohol or opioid addiction because of the consequences of treatment failure [1].