title: Pulmonary bioavailability of a phosphorothioate oligonucleotide (CGP 64128A): comparison with other delivery routes.
abstract: OBJECTIVE
  Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents.
  
  
  METHODS
  The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses.
  
  
  RESULTS
  Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intraperitoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (< 2%). Intra-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, respectively.
  
  
  CONCLUSIONS
  Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.
authors.affiliation: Novartis Horsham Research Centre, Horsham, West Sussex, UK. paul.nicklin@pharma.novartis.com
authors.forename: P L
authors.initials: PL
authors.lastname: Nicklin
authors.forename: D
authors.initials: D
authors.lastname: Bayley
authors.forename: J
authors.initials: J
authors.lastname: Giddings
authors.forename: S J
authors.initials: SJ
authors.lastname: Craig
authors.forename: L L
authors.initials: LL
authors.lastname: Cummins
authors.forename: J G
authors.initials: JG
authors.lastname: Hastewell
authors.forename: J A
authors.initials: JA
authors.lastname: Phillips
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007408:Intestinal Absorption; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013873:Thionucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014132:Trachea / Q000378:metabolism* / Q000473:pathology; D014316:Tritium
chemical_list: D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D014316:Tritium; C108494:ISIS 3521