Engwall Michael J, Everds Nancy, Turk James R, Vargas Hugo M
Translational Safety and Bioanalytical Sciences, Amgen Inc., Thousand Oaks, CA, United States.
Non-clinical Sciences, Seattle Genetics, Inc., Seattle, WA, United States.
Front Cardiovasc Med. 2021 Feb 23;8:587149. doi: 10.3389/fcvm.2021.587149. eCollection 2021.
Doxorubicin-related heart failure has been recognized as a serious complication of cancer chemotherapy. This paper describes a cardiovascular safety pharmacology study with chronic dosing of doxorubicin in a non-human primate model designed to characterize the onset and magnitude of left ventricular dysfunction (LVD) using invasive and non-invasive methods. Cynomolgus monkeys ( = 12) were given repeated intravenous injections of doxorubicin over 135 days (19 weeks) with dosing holidays when there was evidence of significantly decreased hematopoiesis; a separate group ( = 12) received vehicle. Arterial and left ventricular pressure telemetry and cardiac imaging by echocardiography allowed regular hemodynamic assessments and determination of LVD. Blood samples were collected for hematology, clinical chemistry, and assessment of cardiac troponin (cTnI) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Myocardial histopathology was a terminal endpoint. There was variable sensitivity to the onset of treatment effects, for example 25% of doxorubicin-treated animals exhibited LVD (e.g., decreases in ejection fraction) following 50-63 days (cumulative dose: 8-9 mg/kg) on study. All animals deteriorated into heart failure with additional dosing 135 days (total cumulative dose: 11-17 mg/kg). Reductions in arterial pressure and cardiac contractility, as well as QTc interval prolongation, was evident following doxorubicin-treatment. Both cTnI and NT-proBNP were inconsistently higher at the end of the study in animals with LVD. Measurements collected from control animals were consistent and stable over the same time frame. Minimal to mild, multifocal, vacuolar degeneration of cardiomyocytes was observed in 7 of 12 animals receiving doxorubicin and 0 of 12 animals receiving vehicle. This repeat-dose study of doxorubicin treatment in the cynomolgus monkey demonstrated a clinically relevant pattern of progressive heart failure. Importantly, the study revealed how both telemetry and non-invasive echocardiography measurements could track the gradual onset of LVD.
多柔比星相关的心力衰竭已被公认为癌症化疗的一种严重并发症。本文描述了一项在非人类灵长类动物模型中进行的心血管安全药理学研究，该研究通过长期给予多柔比星，旨在使用侵入性和非侵入性方法来表征左心室功能障碍（LVD）的发生和严重程度。将12只食蟹猴在135天（19周）内反复静脉注射多柔比星，当有证据表明造血功能显著下降时给予给药假期；另一组12只接受赋形剂。通过动脉和左心室压力遥测以及超声心动图进行心脏成像，以便定期进行血流动力学评估并确定LVD。采集血样进行血液学、临床化学检查，并评估心肌肌钙蛋白（cTnI）和N末端B型利钠肽原（NT-proBNP）。心肌组织病理学是终末指标。对治疗效果的发生存在不同的敏感性，例如，25%接受多柔比星治疗的动物在研究进行50 - 63天（累积剂量：8 - 9 mg/kg）后出现LVD（如射血分数降低）。所有动物在额外给药135天（总累积剂量：11 - 17 mg/kg）后均恶化为心力衰竭。多柔比星治疗后，动脉压和心脏收缩力降低以及QTc间期延长明显。在研究结束时，LVD动物的cTnI和NT-proBNP均不一致地升高。在相同时间范围内，从对照动物收集的测量数据一致且稳定。在接受多柔比星的12只动物中有7只观察到心肌细胞有轻度至中度、多灶性、空泡变性，而接受赋形剂的12只动物中未观察到。这项在食蟹猴中进行的多柔比星重复给药研究证明了一种与临床相关的进行性心力衰竭模式。重要的是，该研究揭示了遥测和非侵入性超声心动图测量如何能够追踪LVD的逐渐发生。
