Brott David A, Andersson Håkan A S, Stewart Jane, Ewart Lorna, Christoph Greg, Harleman Johannes, Armstrong Duncan, Kinter Lewis B
Drug Safety & Metabolism, AstraZeneca Pharmaceuticals, R&D, Wilmington, DE, USA.
Drug Safety & Metabolism, AstraZeneca, R&D, Södertälje, Sweden.
Toxicol Rep. 2014 Nov 20;1:1202-1212. doi: 10.1016/j.toxrep.2014.11.010. eCollection 2014.
Ticagrelor is an orally available, direct acting and reversible P2Y receptor antagonist approved for treatment of acute coronary syndrome. The objectives of these studies were to (1) evaluate the Ticagrelor 2-year rat carcinogenicity bioassay data; (2) investigate potential mode of action (MOA) and (3) interpret human relevance.
The following studies were done (1) rat two-year carcinogenicity study in male and female rats, (2) and genotoxicity assays, (3) quantitative whole body autoradiography (QWBA; male and female rats), (4) pharmacological profiling for more than 300 assays, and (5) ovariectomized rat assay.
The carcinogenicity study indicated Ticagrelor increased uterine tumor incidence while decreasing mammary and pituitary tumors/hyperplasia incidences in only high dose female rats. However, this altered tumor incidences were not P2Y target related since marketed non-reversible P2Y receptor antagonists were not associated with alter tumor incidences. MOA studies determined Ticagrelor exposure in the anterior pituitary and Ticagrelor was (1) non-genotoxic, (2) peripherally-restricted, (3) a dopamine transport (DAT) inhibitor with an IC lower than systemic free exposure in the rat carcinogenic study and more than a log higher than the free systemic exposure seen in clinical trials and (4) an inhibitor of estradiol-induced prolactin secretion.
Similar to Ticagrelor, centrally active dopamine agonists induce the same altered tumor incidence patterns that according to literature do not translate into the clinical setting, with a MOA involving decreased prolactin secretion. The Ticagrelor MOA data and literature suggest that altered dopamine levels in the hypophyseal part of the hypothalamus-hypophyseal axis (by Ticagrelor) will result in similar altered tumor incidences in rat that do not translate into the clinical setting, based on qualitative species differences. In conclusion Ticagrelor increased uterine tumors in the rat carcinogenesis study by a MOA consistent with reduced dopamine inhibition of prolactin, which is not a patient safety risk.
替格瑞洛是一种口服可用的、直接作用且可逆的P2Y受体拮抗剂，已被批准用于治疗急性冠状动脉综合征。这些研究的目的是：（1）评估替格瑞洛的两年大鼠致癌性生物测定数据；（2）研究潜在的作用机制（MOA）；（3）解释与人类的相关性。
进行了以下研究：（1）对雄性和雌性大鼠进行两年致癌性研究；（2）进行遗传毒性试验；（3）定量全身放射自显影（QWBA；雄性和雌性大鼠）；（4）进行300多项试验的药理学分析；（5）进行去卵巢大鼠试验。
致癌性研究表明，替格瑞洛仅在高剂量雌性大鼠中增加了子宫肿瘤的发生率，同时降低了乳腺和垂体肿瘤/增生的发生率。然而，这种肿瘤发生率的改变与P2Y靶点无关，因为已上市的不可逆P2Y受体拮抗剂与肿瘤发生率的改变无关。作用机制研究确定替格瑞洛在前垂体中的暴露情况，且替格瑞洛：（1）无遗传毒性；（2）外周受限；（3）是一种多巴胺转运体（DAT）抑制剂，其IC在大鼠致癌研究中低于全身游离暴露水平，比临床试验中观察到的游离全身暴露水平高一个对数以上；（4）是雌二醇诱导的催乳素分泌的抑制剂。
与替格瑞洛类似，中枢活性多巴胺激动剂会诱导相同的肿瘤发生率改变模式，根据文献，这种模式不会转化为临床情况，其作用机制涉及催乳素分泌减少。替格瑞洛的作用机制数据和文献表明，下丘脑-垂体轴垂体部分的多巴胺水平改变（由替格瑞洛引起）将导致大鼠出现类似的肿瘤发生率改变，但基于定性的种属差异，这种改变不会转化为临床情况。总之，在大鼠致癌研究中，替格瑞洛通过一种与多巴胺对催乳素抑制作用降低相一致的作用机制增加了子宫肿瘤的发生，这对患者安全并无风险。
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