Tg.rasH2 mouse model for Assessing Carcinogenic Potential of Pharmaceuticals: Industry Survey and Recommendations

The Tg.rasH2 mouse was developed as a model for the alternative carcinogenicity testing. As an alternative to traditional 2-year mouse bioassay, this model has found extensive use in support of biopharmaceutical drug development over the last few decades. It has the potential of improving quality, timeliness, reduction of animal numbers, and in some instances allow expedient decision making regarding the potential for human carcinogenicity. Despite the increased use of the Tg.rasH2 model, there has been no systematic survey of current practices in the design, interpretation of results from the bioassay, and global health authority perspectives. Therefore, the aim of this work was to poll the pharmaceutical industry on study design practices used in the dose range finding and definitive 6-month Tg.rasH2 study, and on results relative to the ongoing revisions to ICH S1. Participants in the survey are member companies of IQ DruSafe. The survey results provide very useful insights in study design and interpretation. Importantly, the results identified several key opportunities for reducing animal use and increasing the value of testing for potential human carcinogenicity using this model

Hyperglycemic Zucker diabetic fatty rats are resistant to the adverse effects of a potent glucokinase activator

Glucokinase, which catalyzes the initial step in glycolysis (glucose-6-phosphate formation), is a key regulator of glucose homeostasis. As a result, glucokinase activators have been in development for the treatment of type 2 diabetes. Daily administration of a Bristol-Myers Squibb glucokinase activator (BMS-GKa) to healthy euglycemic Sprague Dawley (SD) rats and beagle dogs in 1-month studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures that were comparable to those expected at therapeutic clinical exposures. A subsequent study was conducted in markedly hyperglycemic, insulin-resistant Zucker diabetic fatty (ZDF) rats. Daily oral administration of BMS-GKa to male ZDF rats for 1 month did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1-month SD rat study at exposures that exceeded those observed in SD rats. This confirmed that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GKa activation and would not occur in diabetics where baseline glucose levels would be much higher providing a compelling justification to proceed to early clinical studies in diabetic patients

Tg.rasH2 Mouse Model for Assessing Carcinogenic Potential of Pharmaceuticals: Industry Survey of Current Practices

The Tg.rasH2 mouse was developed as an alternative model to the traditional 2-year mouse bioassay for pharmaceutical carcinogenicity testing. This model has found extensive use in support of pharmaceutical drug development over the last few decades. It has the potential to improve quality and timeliness, reduce animal usage, and in some instances allow expedient decision-making regarding the human carcinogenicity potential of a drug candidate. Despite the increased use of the Tg.rasH2 model, there has been no systematic survey of current practices in the design, interpretation of results from the bioassay, and global health authority perspectives. Therefore, the aim of this work was to poll the pharmaceutical industry on study design practices used in the dose range finding and definitive 6-month studies and on results relative to the ongoing negotiations to revise The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S1 Guidance. Twenty-two member companies of International Consortium for Innovation and Quality in Pharmaceutical Development DruSafe Leadership Group participated in the survey, sharing experiences from studies conducted with 55 test compounds between 2010 and 2018. The survey results provide very useful insights into study design and interpretation. Importantly, the results identified several key opportunities for reducing animal use and increasing the value of testing for potential human carcinogenicity using this model. Recommended changes to study designs that would reduce animal usage include eliminating the requirement to include positive control groups in every study, use of nontransgenic wild-type littermates in the dose range finding study, and use of microsampling to reduce or eliminate satellite groups for toxicokinetics