New Ultra-Sensitive Method Quantifies Oral Bremelanotide Pharmacokinetics

Bremelanotide is a therapeutic cyclic peptide primarily known for treating hypoactive sexual desire disorder (HSDD) in premenopausal women. While effective, its current administration is via subcutaneous injection, which can be inconvenient for long-term use. Developing an oral formulation for peptides like bremelanotide is a significant challenge due to their susceptibility to enzymatic degradation and poor absorption in the gastrointestinal tract. This often results in very low plasma concentrations, necessitating highly sensitive and robust analytical methods to accurately measure the drug's presence after oral dosing and evaluate its pharmacokinetic profile.

The developed UHPLC-MS/MS method demonstrated exceptional sensitivity and specificity for bremelanotide, achieving a remarkably low lower limit of quantification (LLOQ) of 0.05 ng/mL, which is significantly more sensitive than previously reported methods, making it suitable for detecting trace amounts. The method exhibited excellent linearity over a wide concentration range (0.05-500 ng/mL) with a high correlation coefficient (R² > 0.998), and consistently high accuracy (95-105%) and precision (intra-day and inter-day coefficient of variation (CVs) < 8%). Matrix effects were found to be negligible, and the extraction recovery of bremelanotide from plasma was consistently high, averaging 87%. This robust performance allowed for reliable pharmacokinetic analysis. The study revealed that despite the inherent challenges of oral peptide delivery, bremelanotide exhibited detectable, albeit low, systemic absorption in rats after oral administration, with an estimated oral bioavailability of approximately 2.5% when compared to intravenous administration. Peak plasma concentrations (Cmax) after oral dosing reached 15.2 ± 3.1 ng/mL at a Tmax of 2 hours, indicating a relatively rapid, though limited, absorption.