Keeping Toxicity to a Minimum

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Adverse drug reactions (ADRs) are reportedly the fourth to sixth highest cause of death in the United States and are estimated as being responsible for 5–10% of hospital admissions within Europe (1). Therefore, ADRs are considered to be a cause of considerable economic and clinical burden (2).

All pharmaceuticals have the potential to produce ADRs that can be related to the drug dose (i.e., dose-dependent), or can be dose-independent, which includes an allergic reaction to the API or other ingredient used in the formulation, or idiosyncratic reactions (3). As has been previously reported, the timely identification of ADRs can not only have a beneficial impact on the patient population but can also help to improve the efficiency and robustness of drug development pipelines (4).

Drug toxicity and drug development

According to research, drug toxicity is a significant causative factor of drug candidate attrition and, if unrecognized until late in the development cycle or during post-marketing, it can contribute to high costs (5). The potential impact of drug toxicity on drug development could be exacerbated as a result of the increasing frequency of more potent compounds entering the pipeline, such as cancer therapeutics.

Screening for a form of drug toxicity to the hematopoietic system (hematotoxicity) has been previously reported to have the potential to effectively improve drug development (6), particularly in light of the changing viewpoint that through using biological and physiological information while developing drugs toxicity can be minimized.

“Certain drug classes, such as tyrosine kinase inhibitors, antibody drug conjugates (ADCs), histone deacetylase (HDAC) inhibitors, and antivirals, are known to cause hematotoxicity, which includes neutropenia (reduction of white blood cells), thrombocytopenia (reduction in megakaryocytes that produce platelets), severe anemia (reduction in red blood cells), and lymphotoxicity (reduction in immune cells),” explains Dr. Emer Clarke, chief scientific officer, ReachBio. “Additionally, certain classes of drugs can also initiate cytokine storm events through hyperstimulation of the autoimmune system, causing damage to normal cells.”

In-vitro assays, such as colony-forming cell (CFC) assays, are useful tools for the detection of drug-induced toxicity to the hematopoietic system and have garnered significant support from the European Center for the Validation of Alternative Methods (ECVAM) (6). Using the platform of assays (CellPrism) available as an example, Clarke highlights that it is possible to determine whether compounds induce a cell lineage-specific or broader toxicity profile. “The assays involve culturing primary blood or bone marrow cells and testing these with drug compounds preclinically to evaluate read-outs that include the reduction of red blood cells, white blood cells, and platelets or the release of deleterious cytokines into cell cultures,” she says.

As safety is always a concern for industry, when advancing a new drug compound clinically, there is heightened interest from drug development agencies in drug assay platforms that can effectively predict unexpected “off-target” toxicities, explains Rob Chaney, chief operating officer, ReachBio. “Because some blood cells have very short half-lives, drugs that affect the cells could have a rapid and deleterious effect on patients,” he adds. “Some of the assays in the CellPrism platform, for example, have been validated by ECVAM, and drug development agencies (e.g., FDA) have recommended the use of these assays as part of a drug developers’ toxicology strategy.”

Off-target effects

ADCs are an innovative class of drugs that are expected to witness significant growth over the next few years (7). These therapies comprise an antibody that is chemically linked to a cytotoxic drug, and although they have desired targeting ability to kill tumor cells, some ADCs also cause off-target effects (8).

“Concerning ADCs in the hematopoietic system, the two most common side effects are neutropenia and thrombocytopenia,” reveals Clarke. “The reason for these side effects is that the linker, which binds the antibody to the toxic payload, becomes vulnerable to enzymatic cleavage of the patient’s own neutrophils via enzyme release.”

Clarke continues to explain that the cleavage of the linker is believed to be a consequence of natural neutrophil degradation systemically, whereby enzymes in circulation indiscriminately cleave these linkers. “This [cleavage] results in a toxic payload that normally would be targeting certain cancer cells (via the antibody) but instead damages healthy circulating blood cells,” she says.

Two assay platforms, specifically designed for ADCs, have been developed by ReachBio as a result of increasing demand by industry for ways to assess the potential toxicity of these innovative therapies, Clarke reports. “The first one looks at off-target effects on white blood cells, red blood cells, and platelets. The second assay platform involves the incubation of the ADC drug with cultured neutrophils that release enzymes and cleave the ADC linker, thus causing systemic toxicity by virtue of unbound toxic payload in circulation,” she adds. “These assays have helped stratify the potency of the ADC and the stability of various linker constructs.”

Streamlining selection

Predicting toxicity based on a drug’s chemical structure can prove a difficult task; as a result of the difficulties encountered, drug developers aim to eliminate certain compounds early in the drug screening process using a series of assays, Chaney specifies. “As drug development companies streamline compound selection throughout the drug development process and towards clinical trials, the assays implemented for toxicity testing are better defined and provide more clinical relevance,” he summarizes.

References

1. C. Giardina, et al., Front. Pharmacol., April 11, 2018. DOI: 10.3389/fphar.2018.00350.
2. J. Sultana, P. Cutroneo, and G. Trifirò, J. Pharmacol. Pharmacother., 4 (5) 73–77 (2013).
3. D.E. Smith Marsh, “Adverse Drug Reactions,” MSD Manual (Professional Version) [accessed Feb. 3, 2020].
4. E. Muñoz, V. Nováček, and P.-Y. Vandenbussche, Brief. Bioinform., 20 (1) 190–202 (2019).
5. F.P. Guengerich, Drug Metab. Pharmacolinet., 26 (1) 3–14 (2011).
6. I.N. Rich, Curr. Opin. Drug Disc., 6 (1) 100–109 (2003).
7. Grand View Research, “Antibody Drug Conjugates Market Size, Share and Trends Analysis Report by Application (Brain Tumor, Blood, Breast, Ovarian, Lung Cancer), by Technology (Cleavable, Non-Cleavable Linker), and Segment Forecasts, 2019–2025,” grandviewresearch.com, Market Report (January 2019).
8. H. Zhao, et al., Mol. Cancer Ther., 16 (9) 1866–1876 (2017). PT

Article Details

Pharmaceutical Technology
Vol. 44, No. 3
March 2020
Pages: 26–29

Citation 

When referring to this article, please cite it as F. Thomas, “Keeping Toxicity to a Minimum,” Pharmaceutical Technology 44 (3) 2020.