Survey of tumorigenic sensitivity in 6-month rasH2-Tg mice studies compared with 2-year rodent assays

Abstract

The pharmacokinetic endpoint of a 25-fold increase in human exposure is one of the specified criteria for highdose selection for 2-year carcinogenicity studies in rodents according to ICH S1C(R2). However, this criterion is not universally accepted for 6-month carcinogenicity tests in rasH2-Tg mice. To evaluate an appropriate multiple for rasH2-Tg mice, we evaluated data for 53 compounds across five categories of rasH2-Tg mouse-positive [(1) genotoxic and (2) non-genotoxic] carcinogens and rasH2-Tg mouse-negative [(3) non-genotoxic carcinogens with clear or uncertain human relevance; (4) non-genotoxic rodent-specific carcinogens; and (5) non-carcinogens], and surveyed their tumorigenic activities and high doses in rasH2-Tg mice and 2-year rodent models.Our survey indicated that Area Under the Curve (AUC) margins (AMs) or body surface area-adjusted dose ratios (DRs) of tumorigenesis in rasH2-Tg mice to the maximum recommended human dose (MRHD) were 0.05-to 5.2fold in 6 category (1) compounds with small differences between models and 0.2-to 47-fold in 7 category (2) including three 2-year rat study-negative compounds. Among all 53 compounds, including 40 compounds of the rasH2-Tg mouse-negative category (3), (4), and (5), no histopathologic risk factors for rodent neoplasia were induced only at doses above 50-fold AM or DR in rasH2-Tg mice except for two compounds, which induced hyperplasia and had no relationship with the tumors observed in the rasH2-Tg mouse or 2-year rodent studies.From the results of these surveys, we confirmed that exceeding a high dose level of 50-fold AM in rasH2-Tg mouse carcinogenicity studies does not appear to be of value.

EMA commentary on the ICH guideline for testing for carcinogenicity of pharmaceuticals

“…While a formal statement on the use of various genetically modified animal models for carcinogenicity assessment has been published nearly two decades ago, 32 the EU position has not been revisited since and neither has the role of these models following the ICH S1B addendum publication. During this ICH S1B process, the JPMA has provided scientific support for the exposure ratio that has been accepted as evidence for the ratio of 50 as the limit, 33 which is included in the addendum.…”

“…since and neither has the role of these models following the ICH S1B addendum publication. During this ICH S1B process, the JPMA has provided scientific support for the exposure ratio that has been accepted as evidence for the ratio of 50 as the limit, 33 which is included in the addendum.…”

Evaluation of the Carcinogenic Potential of Enarodustat (JTZ-951), a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor, in 26-Week Tg.rasH2 Mouse Study and 2-Year Sprague-Dawley Rat Study

“…9 Due to the low incidence of spontaneous tumors and lethal degenerative changes as commonly observed in long-term rodent studies, the Tg.rasH2 mouse has been used for most short-term carcinogenicity studies of pharmaceuticals in recent years. [11][12][13] Carcinogenicity assessments of other HIF-PH inhibitors, namely, roxadustat, daprodustat and vadadustat, have been already published. [14][15][16] Two-year traditional carcinogenicity studies were conducted in mice and rats for roxadustat and daprodustat, and a short-term carcinogenicity study using Tg.rasH2 mouse was conducted as an alternative model to the traditional 2-year mouse carcinogenicity assay for vadadustat, the same as enarodustat.…”

“…9 Due to the low incidence of spontaneous tumors and lethal degenerative changes as commonly observed in long-term rodent studies, the Tg.rasH2 mouse has been used for most short-term carcinogenicity studies of pharmaceuticals in recent years. 11-13…”

The potential of organoids in toxicologic pathology: Histopathological and immunohistochemical evaluation of a mouse normal tissue-derived organoid-based carcinogenesis model

“…In 1978, the National Toxicology Program was established, which examines chemical-induced carcinogenesis mostly in groups of male and female rats and mice exposed to a chemical for two years 1 . Since the 2000s, in addition to long-term studies focusing on continuous administration of test chemicals, several alternative medium-term models for examining carcinogenicity of chemicals established using genetically engineered mice (GEM), for example, rasH2 mice, have been introduced 2 , 3 , 4 , 5 . In addition, established animal carcinogenesis models treated with certain classes of chemical carcinogens have been frequently used not only for hazard assessment of chemicals, but also for preclinical evaluation of potential chemopreventive agents 6 , 7 .…”