The QNOAEL vs. BMD for Point of Departure

Abstract

AbstractQuantile bootstrap (QB) methods can be applied to the problem of estimating the No Observed Adverse Effect Level (NOAEL) of a New Molecular Entity (NME) to anticipate a safe starting dose for beginning clinical trials. An estimate of the NOAEL from the extended QB method (called the QNOAEL) can be calculated using multiple disparate studies in the literature and/or from laboratory experiments. The QNOAEL is similar in some ways to the Benchmark Dose (BMD) and is superior to the BMD in others. The Benchmark Dose method is currently widely used in toxicological research.Results are used in a simulation based on nonparametric cluster analysis methods to calculate confidence levels on the difference between the Effect and the No Effect studies. The QNOAEL simulation generates an intuitive curve that is comparable to the dose-response curve.The QNOAEL of ellagic acid (EA) will be calculated for clinical trials of its use as a component therapeutic agent (in BSN476) for treating Chikungunya infections. This will be the first application of QB to the problem of NOAEL estimation for a drug. The specific aims of the proposed study are to evaluate the accuracy and precision of the QB Simulation and QNOAEL compared to the Benchmark Dose Method, and to calculate the QNOAEL of EA for BSN476 Drug Development.