title: Cardiovascular safety pharmacology studies in dogs enabled for a poorly soluble molecule using spray-dried dispersion: Impact on lead selection.
abstract: The aim of this study was to identify an adequate formulation for a poorly soluble lead molecule (BI-A) that would achieve sufficiently high plasma concentrations after oral administration in dogs to enable a robust cardiovascular safety pharmacology assessment in telemetry-instrumented conscious dogs during lead optimization in drug discovery. A spray-dried dispersion of BI-A (BI-A-SDD) containing a 1:2 ratio of BI-A and hydroxypropyl methylcellulose acetate succinate-LF was prepared using a Büchi spray dryer B-90 (B-90). Physical form characterization, an in vitro dissolution test and a preliminary pharmacokinetic (PK) study following oral administration of BI-A-SDD were performed. Thereafter, effects on cardiovascular parameters in conscious, chronically-instrumented dogs were investigated for 24h after a single oral dose (5, 10, and 50mg/kg) using a modified Latin square cross-over study design. The BI-A-SDD powder was confirmed to be amorphous and was stable as an aqueous suspension for at least 4h. The BI-A-SDD suspension provided a greater rate and extent of dissolution than the crystalline BI-A suspension and the supersaturation was maintained for at least 4h. In PK studies the Cmax of the BI-A-SDD formulation (25.4μM; 77-fold the projected efficacious Cmax of 0.33μM) was 7.5-fold higher than the Cmax observed using oral administration of a 10% hydroxypropyl-β-cyclodextrin formulation at 100mg/kg in dogs (3.4μM). In conscious, chronically-instrumented dogs, the doses tested and plasma concentrations achieved were sufficient to enable a robust safety pharmacology evaluation. Multiple off-target hemodynamic effects were detected including acute elevations in aortic blood pressure (up to 22% elevation in systolic and diastolic blood pressure) and tachycardia (68% elevation in heart rate), results that were confirmed in other in vivo models. These results led to a deprioritization of BI-A. The study demonstrated that a spray-dried dispersion, prepared using the B-90 in drug discovery, enhanced the oral exposure of a poorly water-soluble molecule, BI-A, and thereby enabled its evaluation in safety pharmacology studies that ultimately resulted in deprioritization of BI-A from a pool of lead compounds.
authors.affiliation: Department of Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States. Electronic address: yin-chao.tseng@boehringer-ingelheim.com.
authors.forename: Yin-Chao
authors.initials: YC
authors.lastname: Tseng
authors.affiliation: Department of Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Linehan
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States.
authors.forename: Khing Jow
authors.initials: KJ
authors.lastname: Ng
authors.affiliation: Department of Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States.
authors.forename: Dustin M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Inc., Biberach and der Riss, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Markert
authors.affiliation: Department of Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States.
authors.forename: Mita
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Inc., Biberach and der Riss, Germany; Pre-Clinical Drug Development Platform (PCDDP), North-West University, Potchefstroom, South Africa.
authors.forename: Brian
authors.initials: B
authors.lastname: Guth
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D065546:Drug Liberation; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D023421:Models, Animal; D010316:Particle Size; D011208:Powders / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D058998:Remote Sensing Technology; D012995:Solubility; D013535:Suspensions / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D011208:Powders; D013535:Suspensions; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose
keywords: Amorphous solid dispersion; Cardiovascular pharmacology; Hemodynamics; Safety pharmacology; Spray-dried dispersion; Telemetry