title: Strategic integration of in vivo cardiovascular models during lead optimization:  predictive value of 4 models independent of species, route of administration, and influence of anesthesia.
abstract: The strategic integration of in vivo cardiovascular models is important during lead optimization to enable a wide therapeutic index for cardiovascular safety. However, under what conditions (eg, species, route of administration, anesthesia) studies should be performed to drive go/no-go is open to interpretation. Two compounds, torcetrapib and a novel steroid hormone mimetic (SHM-1121X), both with off-target cardiovascular liabilities, were profiled in 4 in vivo cardiovascular models. Overlapping plasma concentrations of torcetrapib were achieved in all models tested; values ranged from therapeutic to supratherapeutic. In anesthetized rats, intravenous torcetrapib elicited dose-dependent increases in mean arterial pressure (MAP; 2-18 mm Hg above vehicle during the low- and high-dose infusion), and in anesthetized dogs, torcetrapib increased MAP from 4 to 22 mm Hg. In conscious rats, a single oral dose of torcetrapib increased MAP from 10 to 18 mm Hg in the low-dose and high-dose groups, respectively, whereas in conscious dogs, MAP increased from 3 to 12 mm Hg. SHM-1121X produced marked hypotension in the same models. Pharmacokinetic-pharmacodynamic analysis demonstrated strong correlation across the models tested for both compounds. Results suggest that equivalency across models allows for flexibility to address key issues and enable go/no-go during lead optimization without concern for discordant results. The predictive value of each model was validated with torcetrapib and, when put into practice, led to a decisive no-go for SHM-1121X.
authors.affiliation: Department of Cardiometabolic Diseases, Boehringer-Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Rd, Ridgefield, CT 06877-0368, USA. ryan.fryer@boehringer-ingelheim.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Paul C
authors.initials: PC
authors.lastname: Harrison
authors.forename: Akalushi
authors.initials: A
authors.lastname: Muthukumarana
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Nodop Mazurek
authors.forename: Khing Jow
authors.initials: KJ
authors.lastname: Ng
authors.forename: Rong Rhonda
authors.initials: RR
authors.lastname: Chen
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Harrington
authors.forename: Roger M
authors.initials: RM
authors.lastname: Dinallo
authors.forename: Liguo
authors.initials: L
authors.lastname: Chi
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
mesh_terms: D000284:Administration, Oral; D000758:Anesthesia / Q000379:methods*; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008297:Male; D023421:Models, Animal; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D000924:Anticholesteremic Agents; D011804:Quinolines; C483909:torcetrapib