Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
A repeated dose toxicity study in monkeys was conducted with ophthalmic solution A prepared from the drug substance for nonclinical studies (hereafter GLP-DS). Some animals showed signs of conjunctivitis from Week 11 of treatment. From the symptoms and time of onset, the conjunctivitis were thought to be an allergic. To identify the allergen, contact allergenicity was assessed in guinea pigs for GLP-DS and a new drug substance batch for a clinical trial with less impurity contents (Clinical-DS). The result for GLP-DS was positive, whereas Clinical-DS was negative. The animals showed positive for GLP-DS were challenged with several impurities. Positive reactions were found for two of the impurities (Related Substance 1 and 2, RS1 and RS2). The positive reaction induced by RS1 was obviously stronger than RS2. It was speculated that the allergen is RS1, but the involvement of RS2 could not be denied. In the study with monkeys, the test formulations were switched to what were prepared with Clinical-DS. The conjunctivitis did not worsen and disappeared within 8 weeks of the switching. Thus, the active ingredient was not considered to be the cause of conjunctivitis. For RS1, the content thoroughly be controlled. RS2 will continuously be monitored as an important degradation product. We have learned that when there was a potential risk for the impurity, it is important for toxicologists to cooperate with other functions and establish measures to prevent actualization.
