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dc.contributor.authorTseng, Yin-Chao
dc.contributor.authorGuth, Brian
dc.contributor.authorLinehan, Brian
dc.contributor.authorNg, Khing Jow
dc.contributor.authorSmith, Dustin M,
dc.identifier.citationTseng, Y.C. et al. 2016. Cardiovascular safety pharmacology studies in dogs enabled for a poorly soluble molecule using spray-dried dispersion: impact on lead selection. International journal of pharmaceutics, 512:137-146. []en_US
dc.identifier.issn1873-3476 (Online)
dc.description.abstractThe 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 24 h after a single oral dose (5, 10, and 50 mg/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 4 h. 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 4 h. In PK studies the Cmax of the BI-A-SDD formulation (25.4 μM; 77-fold the projected efficacious Cmax of 0.33 μM) was 7.5-fold higher than the Cmax observed using oral administration of a 10% hydroxypropyl-β-cyclodextrin formulation at 100 mg/kg in dogs (3.4 μM). 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 compoundsen_US
dc.subjectSpray-dried dispersionen_US
dc.subjectAmorphous solid dispersionen_US
dc.subjectSafety pharmacologyen_US
dc.subjectCardiovascular pharmacologyen_US
dc.titleCardiovascular safety pharmacology studies in dogs enabled for a poorly soluble molecule using spray-dried dispersion: impact on lead selectionen_US
dc.contributor.researchID26801124 - Guth, Brian Douglas

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