title: Thyroid hormone beta receptor activation has additive cholesterol lowering activity in combination with atorvastatin in rabbits, dogs and monkeys.
abstract: OBJECTIVE
  Thyroid hormone receptor (TR) agonists are in clinical trials for the treatment of hypercholesterolaemia. As statins are the standard of clinical care, any new therapies must have adjunctive activity, when given in combination with statins. As already known for the statins, the cholesterol lowering effect of TR activation involves increased expression of the low-density lipoprotein receptor. Using animal models, we tested whether TR activation would have additive cholesterol lowering activity in the presence of effective doses of a statin.
  
  
  METHODS
  We evaluated the activity of a liver-targeted prodrug, MB07811, of a novel TH receptor beta agonist, MB07344, as monotherapy and in combination with atorvastatin in rabbits, dogs and monkeys.
  
  
  RESULTS
  In rabbits, MB07344 (i.v.) decreased total plasma cholesterol (TPC) comparable to that achieved with a maximally effective dose of atorvastatin (p.o.). The addition of MB07344 to atorvastatin resulted in a further decrease in TPC. Similarly, the addition of MB07811 (p.o.) to atorvastatin treatment decreased TPC beyond the level achieved with either agent as monotherapy. In dogs and monkeys, atorvastatin and MB07811 were administered as monotherapy or in combination. Consistent with the rabbit studies, the combination treatment caused a greater decrease in TPC than either MB07811 or atorvastatin administered as monotherapy.
  
  
  CONCLUSIONS
  We conclude that the effects of MB07811 and atorvastatin in lowering cholesterol are additive in animals. These results would encourage and support the demonstration of similarly improved efficacy of combination versus monotherapy with such agents in the clinic.
authors.affiliation: Department of Biological Sciences, Metabasis Therapeutics, Inc., La Jolla, CA, USA. ito@mbasis.com
authors.forename: B R
authors.initials: BR
authors.lastname: Ito
authors.forename: B-H
authors.initials: BH
authors.lastname: Zhang
authors.forename: E E
authors.initials: EE
authors.lastname: Cable
authors.forename: X
authors.initials: X
authors.lastname: Song
authors.forename: J M
authors.initials: JM
authors.lastname: Fujitaki
authors.forename: D A
authors.initials: DA
authors.lastname: MacKenna
authors.forename: C E
authors.initials: CE
authors.lastname: Wilker
authors.forename: B
authors.initials: B
authors.lastname: Chi
authors.forename: P D
authors.initials: PD
authors.lastname: van Poelje
authors.forename: D L
authors.initials: DL
authors.lastname: Linemeyer
authors.forename: M D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D008252:Macaca fascicularis; D008297:Male; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010636:Phenols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*
chemical_list: C539547:2-((3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl)-4-(3-chlorophenyl)-2-oxido(1,3,2)dioxaphosphonane; C540443:3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy methylphosphonic acid; D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D063065:Organophosphonates; D010636:Phenols; D011355:Prodrugs; D011758:Pyrroles; D037042:Thyroid Hormone Receptors beta; D002784:Cholesterol; D000069059:Atorvastatin