BIOAVAILABILITY OF LEUPROLIDE ACETATE FOLLOWING NASAL AND INHALATION DELIVERY TO RATS AND HEALTHY HUMANS

Systemic delivery of leuprolide acetate, a luteinizing hormone releasing hormone (LHRH) agonist, was compared after inhalation (i.h.) and intranasal (i.n.) administration. The i.n. bioavailability in rats was significantly increased by alpha-cyclodextrin (CD), EDTA, and solution volume. Intraanimal variability was 30-60%, and absorption ranged from 8 to 46% compared to i.v. controls. Studies in healthy human males were conducted with leuprolide acetate i.n. by spray, or inhalation aerosol (i.h.), and subcutaneous (s.c.) and intravenous (i.v.) injection. The s.c. injection was 94% bioavailable compared with i.v. The i.n. bioavailability averaged 2.4%, with significant subject-to-subject variability. Plasma peak concentrations (C(max)) with 1- and 3-mg dosages ranged between 0.24-1.6 and 0.10-11.0 ng/ml, respectively. The low human bioavailability may be due to physical loss of drug down the oral cavity and differences between human and rat nasal mucosa. Inhalation delivery gave a slightly lower intersubject variability. Mean C(max) with a 1-mg dose of solution aerosol was 0.97 ng/ml, compared with 4.4 and 11.4 ng/ml for suspension aerosols given at 1- and 2-mg bolus dosages, respectively. The mean bioavailability of the suspension aerosols (28% relative to s.c. administration) was fourfold greater than that of the solution aerosol (6.6%), suggesting that LHRH analogues may be delivered systemically via the lung as aerosol dispersions.