Use of Lhasa Limited Products for the In Silico Prediction of Drug Toxicity

Overview

Journal Methods Mol Biol

Specialty Molecular Biology

Date 2022 Feb 21

PMID 35188642

Authors

David J Ponting

Michael J Burns

Robert S Foster

Rachel Hemingway

Grace Kocks

Donna S Macmillan

Andrew L Shannon-Little

Rachael E Tennant

Jessica R Tidmarsh

David J Yeo

Affiliations

Soon will be listed here.

Abstract

Lhasa Limited have had a role in the in silico prediction of drug and other chemical toxicity for over 30 years. This role has always been multifaceted, both as a provider of predictive software such as Derek Nexus, and as an honest broker for the sharing of proprietary chemical and toxicity data. A changing regulatory environment and the drive for the Replacement, Reduction and Refinement (the 3Rs) of animal testing have led both to increased acceptance of in silico predictions and a desire for the sharing of data to reduce duplicate testing. The combination of these factors has led to Lhasa Limited providing a suite of products and coordinating numerous data-sharing consortia that do indeed facilitate a significant reduction in the testing burden that companies would otherwise be laboring under. Many of these products and consortia can be organized into workflows for specific regulatory use cases, and it is these that will be used to frame the narrative in this chapter.

Citing Articles

Comprehensive chromatographic analysis of Belumosudil and its degradation products: Development, validation, and In silico toxicity assessment.

Ali A, Alanazi M, Attwa M, Darwish I, Darwish H Heliyon. 2024; 10(19):e38369.

PMID: 39391480 PMC: 11466582. DOI: 10.1016/j.heliyon.2024.e38369.

Selective Stability Indicating Liquid Chromatographic Method Based on Quality by Design Framework and In Silico Toxicity Assessment for Infigratinib and Its Degradation Products.

Ali A, Alanazi M, Attwa M, Darwish H Molecules. 2023; 28(22).

PMID: 38005198 PMC: 10673276. DOI: 10.3390/molecules28227476.

The VEGA Tool to Check the Applicability Domain Gives Greater Confidence in the Prediction of In Silico Models.

Danieli A, Colombo E, Raitano G, Lombardo A, Roncaglioni A, Manganaro A Int J Mol Sci. 2023; 24(12).

PMID: 37373049 PMC: 10298077. DOI: 10.3390/ijms24129894.

References

Sanderson D, Earnshaw C . Computer prediction of possible toxic action from chemical structure; the DEREK system. Hum Exp Toxicol. 1991; 10(4):261-73. DOI: 10.1177/096032719101000405. View

Ashby J, Tennant R . Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. Mutat Res. 1988; 204(1):17-115. DOI: 10.1016/0165-1218(88)90114-0. View

Barber C, Hanser T, Judson P, Williams R . Distinguishing between expert and statistical systems for application under ICH M7. Regul Toxicol Pharmacol. 2017; 84:124-130. DOI: 10.1016/j.yrtph.2016.12.012. View

Barber C, Amberg A, Custer L, Dobo K, Glowienke S, Van Gompel J . Establishing best practise in the application of expert review of mutagenicity under ICH M7. Regul Toxicol Pharmacol. 2015; 73(1):367-77. DOI: 10.1016/j.yrtph.2015.07.018. View

Mortelmans K, Zeiger E . The Ames Salmonella/microsome mutagenicity assay. Mutat Res. 2000; 455(1-2):29-60. DOI: 10.1016/s0027-5107(00)00064-6. View

Parenty A, Button W, Ott M . An expert system to predict the forced degradation of organic molecules. Mol Pharm. 2013; 10(8):2962-74. DOI: 10.1021/mp400083h. View

Weidolf L, Andersson T, Bercu J, Brink A, Glowienke S, Harvey J . Qualification of impurities based on metabolite data. Regul Toxicol Pharmacol. 2019; 110:104524. DOI: 10.1016/j.yrtph.2019.104524. View

Kroes R, Renwick A, Cheeseman M, Kleiner J, Mangelsdorf I, Piersma A . Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem Toxicol. 2003; 42(1):65-83. DOI: 10.1016/j.fct.2003.08.006. View

Cheeseman M, Machuga E, Bailey A . A tiered approach to threshold of regulation. Food Chem Toxicol. 1999; 37(4):387-412. DOI: 10.1016/s0278-6915(99)00024-1. View

10.

Kroes R, Kleiner J, Renwick A . The threshold of toxicological concern concept in risk assessment. Toxicol Sci. 2005; 86(2):226-30. DOI: 10.1093/toxsci/kfi169. View

11.

Thomas R, Thresher A, Ponting D . Utilisation of parametric methods to improve percentile-based estimates for the carcinogenic potency of nitrosamines. Regul Toxicol Pharmacol. 2021; 121:104875. DOI: 10.1016/j.yrtph.2021.104875. View

12.

Thresher A, Foster R, Ponting D, Stalford S, Tennant R, Thomas R . Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data. Regul Toxicol Pharmacol. 2020; 116:104749. DOI: 10.1016/j.yrtph.2020.104749. View

13.

Briggs K . Is preclinical data sharing the new norm?. Drug Discov Today. 2016; 23(3):499-502. DOI: 10.1016/j.drudis.2016.05.003. View

14.

Boetzel R, Ceszlak A, Day C, Drumm P, Gil Bejar J, Glennon J . An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug Product Risk Assessment. J Pharm Sci. 2018; 107(9):2335-2340. DOI: 10.1016/j.xphs.2018.04.009. View

15.

Drewe W, Dobo K, Sobol Z, Bercu J, Parris P, Nicolette J . Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop. Int J Toxicol. 2021; 40(3):285-298. DOI: 10.1177/1091581820982547. View

16.

Gold L, Sawyer C, Magaw R, Backman G, de Veciana M, Levinson R . A carcinogenic potency database of the standardized results of animal bioassays. Environ Health Perspect. 1984; 58:9-319. PMC: 1569423. DOI: 10.1289/ehp.84589. View

17.

Peto R, Pike M, Bernstein L, Gold L, Ames B . The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments. Environ Health Perspect. 1984; 58:1-8. PMC: 1569426. DOI: 10.1289/ehp.84581. View

18.

Judson P, Vessey J . A comprehensive approach to argumentation. J Chem Inf Comput Sci. 2003; 43(5):1356-63. DOI: 10.1021/ci020271o. View

19.

Judson P, Marchant C, Vessey J . Using argumentation for absolute reasoning about the potential toxicity of chemicals. J Chem Inf Comput Sci. 2003; 43(5):1364-70. DOI: 10.1021/ci020272g. View

20.

Foster R, Fowkes A, Cayley A, Thresher A, Werner A, Barber C . The importance of expert review to clarify ambiguous situations for (Q)SAR predictions under ICH M7. Genes Environ. 2020; 42:27. PMC: 7510098. DOI: 10.1186/s41021-020-00166-y. View