Safety and Toxicity Assessment

The development of a new drug requires the assessment of three major areas in drug design namely: efficacy, bioavailability, and safety. 30% of failures in the development of drugs are related to toxicity and safety issues. Among these, hepatotoxicity is one of the major issues. Toxicity is a complex biological property that cannot be accurately estimated purely based on dose-response relationships without a sound scientific understanding of the effects. There are two complementary systems to address drug safety. Before a drug is approved, clinical trials ensure that this drug is safe and effective for its intended use.

Fig.1 Artificial intelligence (AI) and machine learning (ML) present an opportunity for improving drug safety. (Basile, 2019)

In Vitro Toxicity Assays

Most toxicity models have varying degrees of accuracy with the correlation between human and animal toxicities being best for cardiovascular, hematological, and gastrointestinal diseases and the poorest correlation for adverse drug reactions (ADRs) such as hypersensitivity, cutaneous reactions, and hepatotoxicity. In drug discovery, the best strategy to uncover drug candidate toxicity liabilities is to use a panel of well-characterized toxicity screens around a particular type of toxicity in parallel with efficacy and ADME/PK optimization to identify drug candidates with the best overall profile.

• Reactive Intermediates

In vitro screening and identification of reactive metabolites are normally conducted using liver microsomes that contain both Phase I drug metabolizing enzymes such as cytochrome P450s (CYPs), flavin monooxygenase (FMO), dehydrogenases and oxidases, and Phase II enzymes.

• DNA Binding

The covalent binding of the drug candidate or reactive metabolites to DNA can be assessed in microsomal incubations in the presence of DNA. To increase the resolution and detection limit of DNA adducts, HPLC on-lined with a radioisotope detector can be used.

• Mutagens and Carcinogens Assays

Ames tests for mutagens are some of the most commonly performed toxicity assays in the pharmaceutical industry. The various mutagenicity assays detect different genetic alterations and therefore, drug candidates can give uniformly positive and negative results in the various tests.

• Reactive Oxygen Species (ROS)

ROS are by-products primarily from mitochondria cellular metabolism processes. If the antioxidant defense system cannot remove these free radicals for some reason, then they can potentially react with cellular macromolecules such as lipids, proteins, and DNA and either cause damage or cell death. There is a variety of fluorometric assays with medium-throughput screening capability that can be used to detect oxidative stress.

• Hepatotoxicity Assays

Drug-induced liver injury has been the most common reason for the withdrawal of approved drugs. Therefore, evaluation of hepatotoxicity is very critical in drug discovery. Recently, a robust hepatotoxicity screen using a series of immortalized cell lines and primary hepatocytes cultures have been described.

• Final Selection

Once the selection criteria for efficacy/potency, ADME, PK, and toxicity have been defined and accomplished in the lead optimization stage, drug candidates are promoted to the final selection stage. These compounds will receive more extensive in vivo efficacy, PK, and toxicity testing.

Fig.2 Preclinical drug discovery assays for toxicity endpoints. (Caldwell, 2009)

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References

1. Basile, A.O.; et al. Artificial intelligence for drug toxicity and safety. Trends in pharmacological sciences. 2019, 40(9): 624-635.
2. Caldwell, G.W.; et al. ADME optimization and toxicity assessment in early- and late-phase drug discovery. Curr Top Med Chem. 2009;9(11):965-80.