Detirelix acetate

The unanesthetized awake sheep was employed as large animal model for the determination of bioavailability and pharmacokinetics following the pulmonary instillation of the decapeptide detirelix. After intratracheal administration of a 80 micrograms/kg dose, the average t1/2 of elimination was 9.8 +/- 1.3 hours (n = 5) which was similar to the elimination kinetics of a 30 micrograms/kg i.v. dose (7.2 +/- 2.9 hours). Mean residence time (MRT) was prolonged to 10.3 +/- 2.0 hours vs. 2.7 +/- 0.8 hours i.v., and mean absorption time (MAT) was calculated to be 7.5 +/- 1.8 hours. Maximum plasma levels (cmax) of 9.2 ng/ml were reached after 2 hours. The average bioavailability was 9.8 +/- 3.9% of the dose. The pharmacokinetic profile was found to be similar after aerosol administration. It was concluded that detirelix was absorbed systemically when administered by pulmonary instillation or aerosolization and that the unanesthetized awake sheep is a suitable model to study resulting drug profiles.

Pulmonary delivery of the decapeptide detirelix was studied in briefly anesthetized dogs and the pharmacokinetics were examined following intravenous administration, intratracheal instillation, and aerosol inhalation. Detirelix administrations to the lung gave plasma profiles that were extended over two days, and that differed markedly from those of similarly sized peptides. Absorption from the lung after instillation was slow (Tmax = 6.5 +/- 3.6 h) with a relative bioavailability of 29 +/- 10%. Administration of detirelix-containing aerosols resulted in similar plasma profiles as for administration by instillation. Compartmental and non-compartmental methods of pharmacokinetic analysis indicated no faster absorption from aerosols than from instilled solutions; an absorption rate limiting process may be an explanation. Plasma profiles were not affected by the use of detirelix liquid crystal favoring formulations or destabilizing formulations, and suggested that in situ liquid crystal formation was not an explanation for the slow absorption. No significant changes in pharmacokinetics or systemic uptake were observed during the five-month period of repeated pulmonary administrations. Histopathologic examination revealed the lungs to be essentially normal.