Nonclinical and In Vivo Toxicology (Tox) Studies: Primary Safety and Toxicity Evaluation for your IND Submission
Toxicological or Toxicology (tox) Studies help determine drug safety by evaluating adverse effect profiles, organ and tissue exposures, and margins of efficacy vs. toxicity. Indeed, these toxicology studies in drug development often range doses encompassing the therapeutic index, defining the window between minimum efficacious and maximum tolerated (or feasible) doses. Typically, test articles selected for nonclinical toxicology assessment are optimized drug discovery leads evaluated previously for pharmacokinetics, potency, and efficacy in preclinical disease models. This preliminary data collection is often essential for designing initial toxicology studies, especially for selecting dose levels, routes, and regimens. Tox studies usually begin with dose range-finding (DRF), maximum tolerated dose (MTD), and single ascending dose or short-term (7-day) repeat dose nonclinical toxicology studies. The purpose of these toxicity studies is to ascertain an appropriate dosing regimen for the long term (≥28-day) repeat dose GLP toxicity study. Generally, the repeat dose studies encompass the drug effects on the entire body utilizing various toxicology services such as gross pathology, histology, and microscopy. Furthermore, additional focused studies are performed to evaluate safety on particular organ systems or anticipated risk factors.
Tox Studies: From Nonclinical Toxicology to Clinical Toxicological Analysis
Regulatory authorities mandate toxicological studies for all novel drug entities, their active metabolites, or metabolites demonstrating significant systemic exposure following drug administration. Before performing regulated repeated dose toxicity studies, pharmaceutical and biochemical researchers often perform single dose toxicity study, maximum tolerated dose (MTD) study, and dose range finding (DRF) study to establish appropriate dosing margins. A short term (typically 7 to 14 days) repeated dose toxicity study is often performed to evaluate any acute toxicity and determine whether dose accumulation occurs by performing toxicokinetic (TK) analysis on the first and last days of dosing. These results are then used to design definitive GLP repeat dose toxicology studies, typically dosing for at least 28 days, depending on the drug’s intended clinical administration. Afterward, TK analysis data are generated during these studies to interpret the dose-exposure relationships, whether saturable metabolism occurs with increasing doses or accumulation occurs with multiple doses, and to empirically demonstrate steady-state exposures. Additional evaluations and studies are performed to assess cardiac, pulmonary, or reproductive health effects and the drug’s potential for carcinogenicity or genetic mutations. Assuming the drug of interest demonstrates adequate safety for first in human (FIH) testing, results from the toxicological studies in drug development may be used to aid in the designs for initial single ascending dose (SAD) and subsequent multiple ascending dose (MAD) PK studies in clinical trials.