PMON70 Systemic Delivery of Leuprolide via Oral Administration
Authors: Shangold Gary , Rubin Arkady , Daggs Thomas , Vrettos John , Rasums Andrejs , Consalvo Angelo , Skeet Nicola , Shields Paul 
Published: November 2022

We have developed a technology platform employing enteric coating and permeation enhancement to enable systemic delivery of peptides via the oral route. To determine whether this platform can deliver therapeutic doses of the GnRH agonist leuprolide, we conducted a randomized, four-period, four-treatment, crossover pharmacokinetic and food effect study in 14 healthy female volunteers, which compared PK profiles following single administrations of 1 and 4 mg of leuprolide --- the latter under both fasting and fed conditions --- to that of a single subcutaneous injection of 1 mg of leuprolide acetate. Study objectives were to assess the relative bioavailability, dose proportionality, safety and tolerability of orally administered leuprolide, as well as the effect of food on drug absorption. Frequent blood sampling for 24 hours followed each dose, and each treatment was separated by 7 days. Of the 14 subjects enrolled and dosed, 12 completed the study. Mean Tmax occurred at 2.24 ±0.38, 2.77 ±0.46, and 3.49 ±0.23 hrs, for 1 mg po, 4 mg po (fasting), and 1 mg sc leuprolide, respectively. Mean Cmax was 1.9 ±1.3, 10.2 ±9.6, and 59.4 ±9.1 ng/mL, for the aforementioned treatments. Mean AUC0-24h was 3.5 ±2.1, 19.3 ±16.8, and 163.0 ±18.8 ng*h/mL, respectively. Relative to 1 mg sc leuprolide, oral doses of 1 mg and 4 mg (fasted) achieved 2.2 ±1.3% and 3.0 ±2.5% bioavailability. While differences in the dose-normalized parameters were not statistically significant, formal criterion of dose-proportionality (i.e. 90% CI within 80-125%) was not met. 'Fasting' conditions included an overnight (10-hr) fast prior to dosing, and no food consumption for 4 hours following dosing. The 'fed' condition involved consumption of a high-fat, high-calorie meal 30 minutes prior to drug administration. Significant negative impact of food on both rapidity and extent of drug absorption was observed in nearly all subjects, with measurable leuprolide levels sufficiently sparse as to prevent robust PK assessments in this group. The subject incidence of treatment-emergent adverse events (TEAEs) was comparable across all four treatment groups, including sc leuprolide, and was not dose-dependent. The most commonly observed TEAEs across all treatment groups combined were nausea (43%), headache (43%), and increased libido (21%). All other TEAEs were reported by only one or two subjects. The study drugs were well tolerated; most AEs were mild in severity (none were severe or serious), and 30 of 53 (57%) deemed unrelated to study drug. No notable changes were observed in laboratory values or vital signs. This study thus confirmed the successful oral delivery of leuprolide, a 1209-dalton nonapeptide, via the oral route. Investigations now in progress are assessing the feasibility of delivering substantially greater amounts of the drug orally, in order to provide an alternative to parenteral administration of this widely used therapeutic.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.