Biology subjects

Weaver, R.

Publications and source records attributed to Weaver, R..

3 recordsLinked to original sources

bioRxiv2026

From TD50 to Benchmark Dose in Nitrosamine Risk Assessment: Evidence from N-Nitrosotrimetazidine Carcinogenicity and TGR Mutation Data.

The presence of N-nitrosamine drug substance-related impurities (NDSRIs) in pharmaceuticals represents a significant regulatory and safety challenge due to their classification as "cohort of concern" compounds. This paper describes the toxicological evaluation of N-Nitrosotrimetazidine (NTMZ), performed to refine the initial default acceptable intake (AI) limits of 18 to 26.5 ng/day established by regulatory authorities. The evaluation followed a tiered approach: NTMZ was first confirmed as mutagenic in vitro via the standard Ames test. To further investigate its genotoxic potential, two in vivo studies were conducted in Wistar and transgenic rats. Detection of DNA strand breaks in the liver and duodenum (comet assay) together with positive results in the cII mutation assay confirmed an in vivo mutagenic mode of action. Benchmark Dose (BMD) analysis of the transgenic rat data yielded a BMDL50 of 7 mg/kg/day in the male liver. To characterize long-term carcinogenic risk, a GLP-compliant 2-year carcinogenicity study was conducted in Wistar rats. Chronic exposure induced dose-dependent increases in liver tumors (hemangiosarcomas, hepatocellular carcinomas and adenomas) and intestinal tumors (adenomas and adenocarcinomas), leading to a Tumor Dose 50 (TD50) of 23 mg/kg/day in male rats. Benchmark dose analysis of tumor incidence identified a lowest BMDL10 of 2.6 mg/kg/day in females, which served as the basis for deriving an AI of 13 microg/day. This assessment demonstrates a strong predictive correlation between the BMD derived from the in vivo transgenic model, the BMDL10 and the final TD50 values obtained in the 2-year carcinogenicity study. These findings provided the scientific basis for establishing a conservative AI of 13 microg/person/day based on the BMDL10 and further support the regulatory acceptance and use of BMD-derived approaches for the evaluation of nitrosamine impurities.

pharmacology and toxicology↗

bioRxiv2026

Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance

Computational protein engineering provides a powerful approach to address longstanding clinical challenges. Severe insulin resistance syndromes caused by mutations in the insulin receptor (IR) are life-threatening disorders for which effective long-term therapies remain lacking. Here, we define the in vivo activity and therapeutic potential of RF-409, a de novo-designed IR agonist that activates the receptor through a mechanism distinct from insulin. RF-409 exhibits markedly prolonged circulation compared to insulin and produces sustained improvements in glucose homeostasis without detectable adverse effects on body composition or liver function. In a patient-derived IR D707A mouse model of severe insulin resistance, RF-409--but not insulin--activates the mutant receptor, restoring glucose regulation and ameliorating hyperglycemia, hyperinsulinemia, lipoatrophy, and pancreatic atrophy. Mechanistically, RF-409 engages the IR through a noncanonical binding geometry while stabilizing an active conformation resembling that induced by insulin. Phosphoproteomic profiling shows that RF-409 elicits broadly insulin-like signaling with distinct temporal features in receptor-proximal regulation. Together, these findings establish a framework for reactivating dysfunctional receptors and suggest broader applications beyond rare receptoropathies, including diabetes and liver disease.

pharmacology and toxicology↗

bioRxiv2022

Rats exhibit higher hepatic stress response pathway capacities compared with mice and humans

To minimise unexpected toxicities in early phase clinical studies of new drugs, it is vital to understand fundamental similarities and differences between preclinical test species and humans. We have used physiologically-based pharmacokinetic modelling to identify doses of the model hepatotoxin acetaminophen yielding similar hepatic burdens of the reactive metabolite N-acetyl-p-benzoquinoneimine in mice and rats, to enable comparison of tissue adaptive responses under conditions of equivalent chemical insult. Mice exhibited a greater degree of liver injury than rats, despite the equivalent hepatic NAPQI burden. Transcriptomic and proteomic analyses highlighted the stronger activation of stress response pathways (including the Nrf2 oxidative stress response and autophagy) in the livers of rats. Components of these pathways were also found to be expressed at a higher basal level in the livers of rats compared with both mice and humans. Our findings exemplify a systems approach to understanding differential species sensitivity to hepatotoxicity, and have important implications for species selection and human translation in the safety testing of new drug candidates.

pharmacology and toxicology↗