title: Toxicokinetics and toxicity of atorvastatin in dogs.
abstract: HMG-CoA reductase inhibitors (e.g., statins) are an important clinical option to lower cholesterol and treat co-morbidities. Atorvastatin is the most prescribed statin and has obtained generic status. We recently had a clinical development program evaluating a combination of atorvastatin with a GPR119 agonist as a treatment for dyslipidemia, where toxicological evaluations in dogs were completed. There were several challenges related to selecting doses for atorvastatin, including understanding the dose-exposure relationship from different drug forms used by the innovator in their general toxicology studies, bioanalytical assays that did not separate and quantify parent from metabolites, and high variability in the systemic exposures following oral dosing. The studies in this report characterized the toxicokinetics and toxicity of atorvastatin in the dog for up to 13-weeks. Overall, there were no notable differences in the toxicokinetics of atorvastatin or the two active hydroxylated metabolites between the sexes at Week 13. However, systemic exposures were markedly lower at Week 13 compared to that observed at Week 4, suggesting induction of metabolism or reduced absorption from the gastrointestinal tract following oral dosing. Changes in laboratory chemistries included increased liver enzyme levels and lower cholesterol levels. Histopathologic evaluation revealed multifocal minimal to slight hemorrhages in the submucosa of the gallbladder; all findings were reversible. The information from these studies along with the existing clinical experience with atorvastatin can be used to design robust toxicology studies in dogs and reduce animal use.
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Herron
authors.affiliation: Scinovo, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Brueckner
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Chism
authors.affiliation: Safety Assessment, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Kemp
authors.affiliation: Safety Assessment, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Prescott
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Smith
authors.affiliation: Safety Assessment, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Melich
authors.affiliation: Charles River Laboratories, Preclinical Services Montreal, 22022 Transcanadienne, Senneville, QC, Canada, H9X 3R3.
authors.forename: N
authors.initials: N
authors.lastname: Oleas
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Electronic address: joseph.w.polli@gsk.com.
authors.forename: J W
authors.initials: JW
authors.lastname: Polli
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics / Q000633:toxicity; D000069059:Atorvastatin / Q000493:pharmacokinetics* / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D018675:Toxicity Tests
chemical_list: D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069059:Atorvastatin
keywords: Cholesterol; Drug interaction; Dyslipdemia; GPR119; NC3Rs; Statin