title: Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate.
abstract: In vivo study was performed to determine the tolerability and pharmacokinetics of ISIS 104838, a phosphorothioate antisense oligonucleotide targetting human tumour necrosis factor alpha (TNF-alpha) mRNA, following multi-dose administration via intravenous and oral routes. Oral tablet formulations of ISIS 104838 were pre-formulated with the permeation enhancer, sodium caprate, in an enteric-coated solid dosage form. The average plasma bioavailability of ISIS 104838 was 1.4% relative to IV. The tissue distribution profile was similar following both routes of administration, with highest concentrations observed in the kidney followed by the liver, lymph nodes and spleen. Plasma bioavailability underestimated the tissue accumulation of ISIS 104838 observed 1 day after the last dose. Mean systemic tissue bioavailability ranged from 2.0 to 4.3%, relative to IV tissues, and was dependent on tissue type. No marked differences were noted in the pharmacokinetic parameters following multi-dosing either via intravenous or oral routes. All formulations administered were well tolerated. This paper reports the first evaluation of solid oral dosage forms comprising sodium caprate and an antisense oligonucleotide. Furthermore, this study demonstrates the oral delivery of ISIS 104838 from solid oral dose formulations, with the achievement of comparable tissue concentrations of the oligonucleotide to that of the intravenous treatment.
authors.affiliation: Elan Drug Delivery, Trinity College, Dublin 2, Ireland. araoof@prdbe.jnj.com
authors.forename: Araz A
authors.initials: AA
authors.lastname: Raoof
authors.forename: Peter
authors.initials: P
authors.lastname: Chiu
authors.forename: Zeibun
authors.initials: Z
authors.lastname: Ramtoola
authors.forename: Iain K
authors.initials: IK
authors.lastname: Cumming
authors.forename: Chingleou
authors.initials: C
authors.lastname: Teng
authors.forename: Susan P
authors.initials: SP
authors.lastname: Weinbach
authors.forename: Greg E
authors.initials: GE
authors.lastname: Hardee
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Levin
authors.forename: R S
authors.initials: RS
authors.lastname: Geary
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003652:Decanoic Acids / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D013608:Tablets, Enteric-Coated; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D003652:Decanoic Acids; D016376:Oligonucleotides, Antisense; D013608:Tablets, Enteric-Coated; C031071:decanoic acid