Methods to evaluate and improve the injection site tolerability of intravenous formulations prior to first-in-human testing

Abstract Introduction Evaluation of infusion site tolerability is required for the development of intravenous formulations of New Molecular Entities and is of particular importance for investigational drugs that have the potential to precipitate on contact with the blood stream. Based on a comprehensive set of in vitro and in vivo studies conducted with JNJ-X, a development stage small molecule investigational drug, with a pH-dependent solubility that showed potential to cause infusion site irritation at high concentrations, we have developed a systematic approach for evaluating and selecting suitable intravenous formulations for compounds that show potential to precipitate at the infusion site. Methods Aqueous formulations containing a range of concentrations of JNJ-X with different excipients, and buffering agents at different pHs (3.9–7.4) were evaluated in an in vitro solubility assay, a modified hen's egg test-chorioallantoic membrane assay (HET-CAM VT ) and in vivo in rabbit, rat, and dog intravenous infusion toxicity studies. Results The data obtained with JNJ-X in the different in vitro and in vivo studies were compared and used to support the development of an in silico model and to create a systematic approach to screen and identify candidate intravenous formulations with improved tolerability. Discussion/conclusion This approach provides a framework that can be used to assess the risk for infusion site irritation and identify better tolerated formulations with a reduced need for in vivo testing.