Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2018 and 2019

Barrow, Paul; Clemann, Nicole

doi:10.1016/j.reprotox.2020.06.013

Cited by 11 publications

(4 citation statements)

References 16 publications

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“…33,34 Barrow and Clemann reported that fetal toxicity was observed in all of the 18 marketed small molecule oncology drugs with embryo-fetal development toxicology studies that they examined and the fetal toxicity occurred even at nonmaternally toxic exposure in two-thirds of the drugs. 69 Malformation and fetal lethality were observed in 12 and 13 of the 18 drugs, respectively. While cases of pregnancy in patients with cancer treated with small molecule anticancer therapeutics are very sporadic, the effects of treatment with small molecule kinase inhibitors on fetuses including skeletal malformations, soft tissue abnormalities involving abnormal vessel and organ formation, and low birth weights have been also reported in humans.…”

Section: Discussionmentioning

confidence: 99%

Nonclinical Safety Profile of Sotorasib, a KRAS^G12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer

et al. 2021

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Sotorasib is a first-in-class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. A comprehensive nonclinical safety assessment package, including secondary/safety pharmacology and toxicology studies, was conducted to support the marketing application for sotorasib. Sotorasib was negative in a battery of genotoxicity assays and negative in an in vitro phototoxicity assay. Based on in vitro assays, sotorasib had no off-target effects against various receptors, enzymes (including numerous kinases), ion channels, or transporters. Consistent with the tumor-specific target distribution (ie, KRASG12C), there were no primary pharmacology-related on-target effects identified. The kidney was identified as a target organ in the rat but not the dog. Renal toxicity in the rat was characterized by tubular degeneration and necrosis restricted to a specific region suggesting that the toxicity was attributed to the local formation of a putative toxic reactive metabolite. In the 3-month dog study, adaptive changes of hepatocellular hypertrophy due to drug metabolizing enzyme induction were observed in the liver that was associated with secondary effects in the pituitary and thyroid gland. Sotorasib was not teratogenic and had no direct effect on embryo-fetal development in the rat or rabbit. Human, dog, and rat circulating metabolites, M24, M10, and M18, raised no clinically relevant safety concerns based on the general toxicology studies, primary/secondary pharmacology screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity assessment. Overall, the results of the nonclinical safety program support a high benefit/risk ratio of sotorasib for the treatment of patients with KRAS p.G12C-mutated tumors.

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Section: Discussionmentioning

confidence: 99%

Nonclinical Safety Profile of Sotorasib, a KRAS^G12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer

et al. 2021

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“…Synthetic drugs generally have precise structural formulas and definite drug target information but are often accompanied by specific toxic and side effects (Adderley et al, 2021; Barrow & Clemann, 2021). Therefore, early assessment of drug toxicity and screening for drug‐derived organ damage should be emphasized.…”

Section: Applications Of Msi In the Toxicological Analysis And Safety...mentioning

confidence: 99%

Advances in mass spectrometry imaging for toxicological analysis and safety evaluation of pharmaceuticals

Chen

Xie

et al. 2022

Mass Spectrometry Reviews

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Safety issues caused by pharmaceuticals have frequently occurred worldwide, posing a tremendous threat to human health. As an essential part of drug development, the toxicological analysis and safety evaluation is of great significance. In addition, the risk of pharmaceuticals accumulation in the environment and the monitoring of the toxicity from natural medicines have also received ongoing concerns. Due to a lack of spatial distribution information provided by common analytical methods, analyses that provide spatial dimensions could serve as complementary safety evaluation methods for better prediction and evaluation of drug toxicity. With advances in technical solutions and software algorithms, mass spectrometry imaging (MSI) has received increasing attention as a popular analytical tool that enables the simultaneous implementation of qualitative, quantitative, and localization without complex sample pretreatment and labeling steps. In recent years, MSI has become more attractive, powerful, and sensitive and has been applied in several scientific fields that can meet the safety assessment requirements. This review aims to cover a detailed summary of the various MSI technologies utilized in the biomedical and pharmaceutical area, including technical principles, advantages, current status, and future trends. Representative applications and developments in the safety‐related issues of different pharmaceuticals and natural medicines are also described to provide a reference for pharmaceutical research, improve rational clinical medicine use, and ensure public safety.

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“…Malaria being particularly severe in young children and pregnant women, juvenile and embryo fetal toxicity risk assessment will need to be conducted. 15 Malaria treatments are based on 3-day dosing and ideally aim at full efficacy as a single-dose cure, which is the preferred treatment regimen in most clinical trials. 16 It is therefore important to consider the difference in toxicity risks between the treatment of acute disease (which can be very brief) and the long-term treatment required for chronic disease (e.g., cancer, metabolic disorders), since the latter necessitate a repeated and sustained treatment that may lead to cumulative exposures and hence higher toxicity risk.…”

Section: Human Toxicity Potential Of Hdt and De-risking Strategiesmentioning

confidence: 99%

Host-directed therapy, an untapped opportunity for antimalarial intervention

Wei¹,

Adderley

Leroy

et al. 2021

Cell Reports Medicine

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Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2018 and 2019

Cited by 11 publications

References 16 publications

Nonclinical Safety Profile of Sotorasib, a KRAS^G12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer

Nonclinical Safety Profile of Sotorasib, a KRAS^G12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer

Advances in mass spectrometry imaging for toxicological analysis and safety evaluation of pharmaceuticals

Host-directed therapy, an untapped opportunity for antimalarial intervention

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Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2018 and 2019

Cited by 11 publications

References 16 publications

Nonclinical Safety Profile of Sotorasib, a KRASG12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer

Nonclinical Safety Profile of Sotorasib, a KRASG12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer

Advances in mass spectrometry imaging for toxicological analysis and safety evaluation of pharmaceuticals

Host-directed therapy, an untapped opportunity for antimalarial intervention

Contact Info

Product

Resources

About

Nonclinical Safety Profile of Sotorasib, a KRAS^G12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer

Nonclinical Safety Profile of Sotorasib, a KRAS^G12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer