title: A pharmacokinetic evaluation of 14C-labeled afovirsen sodium in patients with genital warts.
abstract: Afovirsen sodium is a 20-mer phosphorothioate oligonucleotide designed to be complementary to the messenger ribonucleic acid sequence for the translation initiation codon of the E2 protein vital to replication of human papillomaviruses types 6 and 11. 14C-Labeled afovirsen was given as a single-dose intradermal injection in each of four warts of five patients to determine the time-dependent changes in concentration of intact afovirsen in genital warts and to determine the systemic absorption and elimination of radiolabeled compound. Intact afovirsen in genital warts was determined by high pressure liquid chromatography analysis of protease K digested extracts. Intact afovirsen was present in wart tissue for at least 72 hours at concentrations several times in excess of the estimated minimal inhibitory concentration of 1 mumol/L. Absorption of radiolabeled afovirsen from the injection site was rapid, with a peak plasma concentration achieved within 1 hour. Clearance of afovirsen was primarily attributable to slow metabolism, with about 30% of the radiolabel eliminated as 14C-CO2 in expired air over a 6-day period after dosing. Radioactivity eliminated in urine represented metabolites of afovirsen. From the clinical pharmacokinetic data presented here and from previously published pharmacokinetic data in rats, the disposition of afovirsen in humans appears to be relatively similar to that in rats. These data suggest that once or twice weekly dosing regimen in the clinic may be appropriate.
authors.affiliation: Isis Pharmaceuticals, Carlsbad Research Center, CA 92008.
authors.forename: S T
authors.initials: ST
authors.lastname: Crooke
authors.forename: L R
authors.initials: LR
authors.lastname: Grillone
authors.forename: A
authors.initials: A
authors.lastname: Tendolkar
authors.forename: A
authors.initials: A
authors.lastname: Garrett
authors.forename: M J
authors.initials: MJ
authors.lastname: Fratkin
authors.forename: J
authors.initials: J
authors.lastname: Leeds
authors.forename: W H
authors.initials: WH
authors.lastname: Barr
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001483:Base Sequence; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D003218:Condylomata Acuminata / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D013873:Thionucleotides / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D002250:Carbon Radioisotopes; D013873:Thionucleotides; C084960:afovirsen sodium