PULMONARY BIOAVAILABILITY OF A PHOSPHOROTHIOATE OLIGONUCLEOTIDE (CGP 64128A) - COMPARISON WITH OTHER DELIVERY ROUTES

Purpose. Phosphorothioate antisense oligodeoxynucleotides are promisin g therapeutic candidates. When given systemically in clinical trials t hey are administered via slow intravenous infusion to avoid their puta tive plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral ad ministration routes which have the potential to enhance the therapeuti c and commercial potential of these agents. Methods. The delivery of C GP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and int ra-tracheal (pulmonary) routes was investigated in rats using radiolab elled compound and supported by more specific capillary gel electropho retic analyses. Results. Intravenously administered CGP 64128A exhibit ed the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intraperitoneal administration resulted in significant bioavailabi lities (30.9% and 28.1% over 360 min, respectively) and reduced peak p lasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (<2%). Int ra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, r espectively. Conclusions. Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-trach eal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-depende nt increase in pulmonary bioavailability suggests that low doses may b e retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.