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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.
摘要：
HMG-CoA还原酶抑制剂(例如，他汀类药物）是降低胆固醇和治疗合并症的重要临床选择。阿托伐他汀是最常用的他汀类药物，已获得通用状态。我们最近有一个临床开发计划，评估阿托伐他汀与GPR119激动剂联合治疗血脂异常。在那里完成了狗的毒理学评估。选择阿托伐他汀的剂量有几个挑战，包括了解的剂量暴露关系从不同的药物形式使用的创新者在他们的一般毒理学研究，没有将母体与代谢物分离和定量的生物分析测定，口服给药后全身暴露的高变异性。本报告中的研究表征了阿托伐他汀在狗中长达13周的毒物动力学和毒性。总的来说,在第13周时,性别间阿托伐他汀或两种活性羟基化代谢物的毒代动力学没有显著差异.然而,与第4周时观察到的相比,第13周时的全身暴露显著降低,提示口服给药后胃肠道代谢诱导或吸收减少.实验室化学的变化包括肝酶水平升高和胆固醇水平降低。组织病理学评估显示胆囊粘膜下层多灶性出血至轻度出血；所有发现均为可逆的。来自这些研究的信息以及阿托伐他汀的现有临床经验可用于设计狗的强大毒理学研究并减少动物使用。
