Pharmacokinetics of the Melanocortin Type 1 Receptor Agonist PL8177 After Subcutaneous Administration.

BACKGROUND AND OBJECTIVE: PL8177 is a selective melanocortin 1 receptor agonist in development for the treatment of various immunologic and inflammatory conditions. Here we describe the pharmacokinetics of PL8177 after subcutaneous (sc) delivery in animals and humans. METHODS: Mice, rats, and dogs were administered sc PL8177 at single doses of 1.0 and 3.0 mg/kg (mice); 1.0, 5.0, and 25.0 mg/kg/day (rats); or 1.5, 8.0, and 40.0 mg/day (dogs). Blood was collected over 24 h (mice) or 28 days (rats and dogs). Safety and pharmacokinetics of single and multiple sc doses were also examined in human volunteers. Two dose levels were tested in two dosing cohorts of 1.0 and 3.0 mg/day for 7 days. Blood samples were collected through Day 1 and on Days 2 to 6 at peak and trough times based on analysis of the first two single-dose cohorts. RESULTS: In mice, 3 mg/kg PL8177 resulted in an area under the plasma concentration-time curve from 0 to infinity (AUC(∞)) of 1727 ng·h/mL, a maximum plasma concentration (C(max)) of 2440 ng/mL, an elimination half-life (t(½)) of 0.5 h, and a time to maximum concentration (t(max)) of 0.25 h. Results for the 1-mg/kg dose were generally proportional. In rats, mean t(max) values were independent of dose and ranged from 0.25 to 1.0 h for single and multiple dosing. C(max) values ranged from 516 to 695 ng/mL (1-mg/kg dose) and from 666 to 1180 ng/mL (25-mg/kg dose). In dogs, mean t(max) values ranged from 0.4 to 1.3 h for single and multiple dosing. Values for t(max) decreased with increasing dose and mean plasma C(max) increased less than dose proportionally (96-129 ng·h/mL [1.5 mg], 275-615 ng·h/mL [8.0 mg], and 633-1280 ng·h/mL [40.0 mg]). In humans, PL8177 was observed in the plasma within 15 min after a single dose and persisted for up to 48 h at higher doses. The t(max) was 30-45 min (single dose) and 15-45 min (multiple doses). In multiple-dose studies, maximum steady-state plasma concentration (C(max,ss)) and AUC(∞) increased with dose. Geometric mean C(max,ss) values were 20.1 ng/mL (1.0 mg) and 57.2 ng/mL (3.0 mg). AUC(∞) values were 54.3 ng·h/mL (1.0 mg) and 199 ng·h/mL (3.0 mg). Unchanged PL8177 excreted in the urine was ≤ 1%, and accumulation was minimal. CONCLUSION: PL8177 administration resulted in a consistent pharmacokinetic profile. The measured exposure levels resulted in pharmacologically active PL8177 concentrations at the targeted MC1R. Rapid absorption was seen in healthy volunteers, and multiple-dose administration over 7 days resulted in pharmacokinetic characteristics similar to those observed after single-dose administration. Results support the continued development of PL8177 to treat immunologic and inflammatory conditions.