In silico models for repeated-Dose Toxicity (RDT): Prediction of the No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) for drugs

The preclinical stage in drug development requires the determination of repeated-dose toxicity (RDT) in animal models. The main outcome of RDT studies is the determination of the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL). NOAEL is important since it serves to calculate the maximum recommended starting dose (MRSD) which is the safe starting dose for clinical studies in human beings. Since in vivo RDT studies are expensive and time-consuming, in silico approaches could offer a valuable alternative. However, NOAEL and LOAEL modeling suffer some limitations since they do not refer to a single end point but to several different effects and the doses used in experimental studies strongly influence the final results. Few attempts to model NOAEL and LOAEL have been reported. The available database and models for the prediction of NOAEL and LOAEL are reviewed here.