PULMONARY BIOAVAILABILITY OF LEUPROLIDE ACETATE FOLLOWING MULTIPLE DOSING TO BEAGLE DOGS - SOME PHARMACOKINETIC AND PRECLINICAL ISSUES

Localized delivery of drugs to the lung- has long been known as an effective and rapid modality for treating various pulmonary diseases. Because of its large surface area, the lung serves also as a port of drug entry to the systemic circulation. However, lung deposition of pharmaceutical aerosols is generally less than 100% of the nominal dose. This is due largely to complex biophysical factors associated with filtration mechanisms of the respiratory system (Byron ct al., Pharm. Res., 3 (1989) 225-229) and patient factors. The incomplete absorption of pharmaceutical aerosols in the lung may be due in part to mechanical losses of drug during drug administration. For example, some drug is retained usually on the mouth adapter (actuator) of the inhaler during use, and often there is significant loss in the throat as a result of inertial impaction (Ganderton and Jones, Drug Delivery to the Respiratory Tract, Ellis Horwood, 1987; Byron et al., Pharm. Res., 3 (1989) 225-229). Inefficient delivery of drugs to the airways may be the single largest cause for low drug absorption via lung. For peptides, physicochemical characteristics of the drug, stability to metabolizing enzymes, molecular weight, permeability to lung mucosa, and stimulation of the alveolar macrophage clearance mechanism (Forrest, In Moren et al. (Eds), Aerosols in Medicine, Principles, Diagnostics and Therapy, Elsevier, 1985) may be more significant in decreasing the efficiency of absorption from the airways. In a previous study (Adjei et al., Int. J. Pharm., 61 (1990) 135-144), male and female beagle dogs were administered an inhalation solution aerosol formulation of leuprolide acetate at daily dosages of 0, 0.5, 1, and 2 mg for 14 consecutive days. The results demonstrated: (a) significant plasma levels following administration of leuprolide to the lung compared to a placebo aerosol formulation as control, (b) a linear dose-dependent increase in pulmonary bioavailability of leuprolide in the dose range of 0.5-2.0 mg/dog per day; (c) no significant differences in pulmonary absorption between male and female dogs; (d) a corresponding decrease in plasma gonadotropins with sequential increases in plasma leuprolide concentrations; and (e) approx. 50% lower bioavailability on day 14 compared with day 1 of the study. The present study clarifies phenomenologic and pharmacokinetic issues associated with lung delivery of leuprolide acetate. For this study, male and female beagle dogs were administered leuprolide using a suspension aerosol formulation instead of a cosolvent based solution aerosol formulation of the drug (Adjei et al., Int. J. Pharm., 61 (1990) 135-144). The results demonstrated: (a) linear dose-dependent increases in plasma AUC of leuprolide in the dose range of 1.5-9mg/dog per day; (b) no change in bioavailability with multiple dosage of the aerosol up to 14 days; (c) no toxicologic findings over the 14 day dosing period; and (d) the no-toxic effect level of leuprolide was 9 mg/dog per day. This paper also attempts to explain differences between in vivo performance of the alcohol-based solution aerosol (Adjei et al., Int. J. Pharm., 61 (1990) 135-144) compared with a suspension aerosol formulation of the drug.