ntranasal 20 mg dose of bremelanotide co-administered with alcohol in 12 healthymale and 12 healthy female subjects. Intranasal bremelanotide or placebo spray was administered 10 minutes
after consumption of placebo drink or 0.6 g/kg ethanol (equivalent of three 12 ounce cans of beer containing 5%alcohol content, three 5 ounce glasses of wine containing 12% alcohol content, or three 1.5 ounce shots of 80-proof spirit in a 70 kg person).
The 20 mg intranasal dose achieves a 2.5-fold higher mean Cmax than that of VYLEESI. Alcohol consumptionhad no effect on the pharmacokinetic profile of bremelanotide. The incidence of flushing was higher withbremelanotide plus ethanol compared to ethanol alone, but similar to the incidence with bremelanotide alone.
The incidence of headache was higher with bremelanotide plus ethanol compared to bremelanotide alone, butsimilar to the incidence with ethanol alone. The incidence of other adverse reactions was similar across thetreatment groups. The incidence of abnormal orthostatic blood pressure reductions was comparable between the
bremelanotide plus ethanol group and the ethanol alone group. No participants discontinued due to adversereactions.
Cardiac Electrophysiology
A 20 mg intranasal dose of bremelanotide does not prolong the QTc interval to any clinically relevant extent.
12.3 Pharmacokinetics
Following subcutaneous administration of VYLEESI, the mean plasma Cmax and AUC of bremelanotide are72.8 ng/mL and 276 hr*ng/mL, respectively.
Mean plasmaconcentrations of bremelanotide increase in a lessthan dose proportional manner in the dose range of 0.3 to 10 mg, with mean Cmax levels reaching a plateau at the7.5 mg subcutaneous dose level (approximately 4.3 times the maximum recommended dose).
Absorption
Bremelanotide median Tmax is approximately 1.0 hour (range: 0.5 - 1.0 hours) in plasma. The absolutebioavailability of bremelanotide following subcutaneous administration of VYLEESI was about 100%. The siteof subcutaneous administration (abdomen and thigh) had no significant effect on the systemic exposure to
bremelanotide.
Distribution
Twenty-one percent of bremelanotide binds to human serum protein. The mean (SD) volume of distributionafter a single subcutaneous administration of VYLEESI is 25.0 ± 5.8 L.
Elimination
Following a single subcutaneous administration of VYLEESI, mean terminal half-life of bremelanotide isapproximately 2.7 hours (range: 1.9– 4.0 hours) and the mean (± SD) clearance (CL/F) is 6.5 ±1.0 L/hr.
Metabolism
As a peptide with 7 amino acids, the primary metabolic pathway of bremelanotide involves multiple hydrolysesof the amide bond of the cyclic peptide.
Excretion
Following administration of a radiolabeled dose, 64.8% of the total radioactivity was recovered in urine and22.8% in feces.
Specific Populations
Patients with Renal Impairment
Following a single subcutaneous dose of VYLEESI, bremelanotide exposure (AUC) increased 1.2-fold inpatients with mild (eGFR, 60 to 89 mL/min/1.73 m2) renal impairment, 1.5-fold in patients with moderate(eGFR, 30 to 59 mL/min/1.73 m2) renal impairment, and 2-fold in patients with severe (eGFR,<30 mL/min/1.73 m2) renal impairment [see Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
Following a single subcutaneous dose of VYLEESI, bremelanotide exposure (AUC0-inf) increased 1.2-fold inpatients with mild (Child-Pugh A; score of 5-6) hepa |
