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• W2564907584 abstract "AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA5746 Background: Nab technology when applied to hydrophobic molecules, such as paclitaxel, leads to improved drug safety and efficacy as well as enhanced drug delivery compared to surfactant-based drug formulations. Nab-17AAG is a nanoparticle albumin-bound, injectable form of the hydrophobic Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG), a geldanamycin analogue that showed some clinical anti-tumor activity with MTD at 450 mg/m2 for weekly dosing and 650 mg/m2 for every 3-week dosing. Due to previously reported cardiovascular toxicities with alternative formulations of 17AAG, we evaluated the in vivo cardiovascular and respiratory effects of nab-17AAG in monkeys. Methods: Based on a Latin Square design, telemetry-implanted, male cynomolgus monkeys (n = 4) were administered placebo (HSA, 600 mg/kg) or nab-17AAG IV at doses of 20, 40 and 55 mg/kg on day (d) 1, 8, 15 and 22. A range of hemodynamic and lead II-ECG variables were recorded from telemetry-data capture (Open A.R.T./PONEHMAH Physiological Platform) 2 hrs before (predose; PD) and 1, 2, 4, 8 and 14 hrs after administration of nab-17AAG. Blood gas samples were taken PD, 5 hrs after each scheduled dose, in addition to d7 and 21. Blood samples for hematology and serum chemistry were taken PD and d24. Treatment-related effects with telemetric and blood gas data were evaluated using statistical tests, rANOVA and ANCOVA respectively. Results: Following IV administration of nab-17AAG at doses of 20, 40, and 55 mg/kg, there were no test article-related effects observed on hemodynamics (SBP, DBP, MAP), mean HR, respiration rate, lead II-ECG variables (PR interval, QRS duration, RR interval and QT interval), or HR-corrected QTcB interval. No test article-related changes were observed in arterial blood gas parameters (PO2, PCO2, oxyhemoglobin, and HbO2 saturation) or body weights. Treatment-related emesis was observed both during administration and post-dosing. However, emesis was more frequently associated with the mid- and high-dose cohorts. Therefore, using a Latin Square, multiple-dosage regimen, the no-observed-adverse-effect level (NOAEL) for the telemetry parameters, (including lead II QT interval and HR-corrected QTcB interval) for nab-17AAG in conscious male cynomolgus monkeys was 55 mg/kg. Conclusions: The NOAEL for the telemetry parameters in conscious, male cynomolgus monkeys using a multiple-dosing, Latin Square-based regimen for nab-17AAG was 55 mg/kg. This value corresponds to a weekly nab-17AAG dose of 660 mg/m2 which is 44% higher than the reported MTD of 17-AAG (450 mg/m2). These data are strongly indicative of the cardiovascular and respiratory safety of nab-17AAG." @default.
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• W2564907584 date "2008-05-01" @default.
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• W2564907584 title "Cardiovascular and respiratory assessment following IV administration of nanoparticle albumin-bound 17AAG (nab-17AAG) in conscious cynomolgus monkeys" @default.
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