Abstract
Abstract Background: ABI-013 is an albumin-bound 70-nm nanoparticle form of a novel docetaxel analog with improved activity in vivo as a tumor-targeting chemotherapeutic agent. Because docetaxel-induced microtubule stabilization has the potential to cause contractile dysfunction in cardiac hypertrophy, the effects of ABI-013 on the cardiovascular (CV), respiratory, and central nervous system (CNS) were examined. Methods: In the cardiopulmonary safety study, male conscious telemetered cynomolgus monkeys (n = 4/group) were administered ABI-013 intravenously (IV) over 30 min at 0, 2, 5 and 10 mg/kg weekly for 4 weeks following a 4×4 Latin Square dosage regimen. Parameters recorded by telemetry included arterial blood pressure, heart rate, respiratory rate, intra-abdominal body temperature, electrocardiogram (ECG, lead II: PR, QRS, RR, QT, and QTcB), and motor activity for up to 24 h postdose. Blood cardiac Troponin I and creatine kinase (CK) isoenzyme levels and arterial blood gas parameters (pH, pO2, pCO2, O2Hb, sO2, HCO3) were also evaluated. In the CNS safety study, male and female Sprague-Dawley rats (n = 4 animals/sex/group) were given single IV doses of ABI-013 (3.5 or 5 mg/kg) or docetaxel (Taxotere®, 3.5 mg/kg). Functional observation battery, locomotor activity, and motor coordination were evaluated for 5 days to assess changes in behavioral parameters. In addition, ABI-013 and Taxotere® were evaluated in an in vitro human ether-a-go-go (HERG) potassium channel patch-clamp assay using hERG-transfected HEK293 cells. Results: In the cardiopulmonary safety studies in monkeys, there were no statistically significant difference in ECG data (PR, QRS, RR, QT, and QTcB), arterial BP (systolic, diastolic, and mAP), respiratory rate, intra-abdominal body temperature, motor activity, and arterial blood gas parameters (pH, pO2, pCO2, O2Hb, sO2, HCO3) between the ABI-013 dose groups and the control group. The levels of cardiac Troponin I and cardiac-specific CK-MB levels remained within normal limits. In the CNS safety study, ABI-013 had no adverse effects on motor activity, behavioral changes, coordination, and sensory/motor reflex responses in the conscious rat at both dose levels. In the whole cell patch-clamp assay, the inhibitory effect of ABI-013 on hERG currents was 70-fold less potent than that of docetaxel. Conclusions: ABI-013 infusion once weekly for 4 wks was well-tolerated at all dose levels. All ECG and pulmonary evaluations were normal with no indication of conduction abnormalities or cardiac muscle toxicity with a no-observed-adverse-effect level (NOAEL) determined at 10 mg/kg. The results of these preclinical studies in monkeys and rats provide evidence that ABI-013 is a safe antitumor agent without cardiovascular or CNS effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2617.
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