Sublingual absorption of leuprolide: comparison between human and animal models

Leuprolide is a potent luteinizing hormone releasing hormone agonist used f or the treatment of hormone-dependent diseases. It is a decapeptide drug cu rrently administered by subcutaneous and intramuscular injection because it is not orally bioavailable. In the present study, sublingual gel formulati ons of leuprolide were administered to dogs, monkeys and humans. Plasma sam ples were analyzed by radioimmunoassay. Absorption and pharmacokinetics of leuprolide following sublingual administration were compared and evaluated. It was found that the extent and rate of absorption were similar between h umans and monkeys following sublingual dosing of leuprolide formulations. A prolonged absorption of up to approximately 6 h after dosing was observed in both humans and monkeys. The rate and extent of absorption were signific antly higher in dogs than in humans. The estimate of absolute bioavailabili ty of leuprolide was 46.7% in dogs compared with 2.7% in monkeys at an equi valent dose of 0.45 mg/kg. Absolute bioavailabilities in humans were 2.0, 2 .3 and 2.4% at doses of 1.125, 2.25 and 4.5 mg, respectively. Based on thes e results, the dog is not an appropriate animal model for evaluating sublin gual absorption of leuprolide. This work suggests that monkey is a preferre d model for the development and assessment of sublingual formulations of le uprolide. (C) 1999 Elsevier Science B.V. All rights reserved.