title: Remofovir mesylate: a prodrug of PMEA with improved liver-targeting and safety in rats and monkeys.
abstract: Adefovir dipivoxil (Hepsera), a first-line therapy for chronic hepatitis B, is an esterase-activated prodrug of PMEA. Dose-limiting nephrotoxicity necessitates suboptimal dosing at 10 mg/day. Remofovir mesylate (MB06866Q) (Hepavir B) is a CYP3A4-activated prodrug of PMEA based on the HepDirect technology that targets PMEA to the liver. In a whole body autoradiography study in rats after oral dosing (30 mg/kg) of [14C]adefovir dipivoxil or [14C]remofovir mesylate, remofovir yielded 15 times higher concentrations of radioactivity in the liver than adefovir dipivoxil, but only one-third of the concentrations in the kidney. After oral dosing (4 mg/kg) of the same radiolabelled agents in cynomolgus monkeys, remofovir mesylate yielded 60 times higher levels of total radioactivity in the liver, but only two-thirds of total radioactivity levels in the kidney. Thus, remofovir mesylate may provide better efficacy and reduced nephrotoxicity. In portal vein-cannulated rats (30 mg/kg) after a single oral dose of [14C]adefovir dipivoxil or [14C]remofovir mesylate, no PMEA was detectable in rat portal plasma early after dosing, indicating that intestinal CYP3A4 does not play a role in conversion of remofovir mesylate to PMEA. The portal/systemic extraction ratio was quite high in both models, suggesting good liver-targeting properties. Portal and systemic remofovir/PMEA ratio indicates that the liver is the site of conversion of remofovir to PMEA. 28-Day toxicity studies demonstrated renal toxicity in rats at doses of 100 mg/kg or higher with no safety concerns at 30 mg/kg and acceptable safety in monkeys at doses up to 60 mg/kg. Thus, in rats and non-human primates, remofovir mesylate has liver-targeting properties and is safer than adefovir dipivoxil.
authors.affiliation: Valeant Pharmaceuticals International, Costa Mesa, Calif., USA. cclin@valeant.com
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Li-Tain
authors.initials: LT
authors.lastname: Yeh
authors.forename: Domenico
authors.initials: D
authors.lastname: Vitarella
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000225:Adenine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D001345:Autoradiography; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D000882:Haplorhini; D019694:Hepatitis B, Chronic / Q000188:drug therapy; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008698:Mesylates / Q000737:chemistry*; D063065:Organophosphonates / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: C120290:9-(2-(phosphonomethoxy)ethyl)adenine diphosphate; D000998:Antiviral Agents; D002250:Carbon Radioisotopes; D008698:Mesylates; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C497721:pradefovir; D000225:Adenine; C106812:adefovir dipivoxil