Drug Discovery and Development

  • Home Drug Discovery and Development
  • Drug Discovery
  • Women in Pharma and Biotech
  • Oncology
  • Neurological Disease
  • Infectious Disease
  • Resources
    • Video features
    • Podcast
    • Voices
    • Webinars
  • Pharma 50
    • 2025 Pharma 50
    • 2024 Pharma 50
    • 2023 Pharma 50
    • 2022 Pharma 50
    • 2021 Pharma 50
  • Advertise
  • SUBSCRIBE

Turning Tox Screening toward Biologics

By Drug Discovery Trends Editor | November 7, 2008

Technology Advances

As pharmaceuticals turn more toward biologics, companies face challenges in finding ways to screen these new products for toxicokinetics. In preclinical safety studies of small molecules, pharmaceutical companies typically used liquid chromatography (LC) followed by mass spectrometry (MS) to measure a compound’s toxicokinetic profile and check for reactive metabolites. Biologics and their metabolites, however, pose a different challenge because the current analytical techniques are primarily based on ligand-binding assays. “This requires a different approach to toxicokinetic profiling. For example, serum-binding profiles are often carrier-protein specific for biologics compared to small molecules, which tend to ubiquitously bind to serum albumin,” says Rohan Thakur, PhD, director of small molecule solutions at Thermo Fisher Scientific in Waltham, Mass. “Proteins are different because these are rarely chemically-synthesized, but rather biologically-produced.” He adds, “Heterogeneity and hence purity is always in question.”

Part of the problem in assessing the potential toxicokinetics of a biologic is that it often depends on its heterogeneity. “Glycosylation and phosphorylation types of heterogeneity may change target-receptor kinetics, affecting toxicokinetics,” says Thakur. “For example, dephosphorylation of the native protein due to a change in the partition coefficient can make it active again, thereby influencing the toxicokinetic profile.” Such complexities of biologics are pushing toxicity testing from ligand-binding assays to LC/MS. But even here, technology faces some new challenges. For instance, proteins usually require a higher mass-to-charge range than small molecules, because proteins tend to have multiple charges, whereas small molecules usually have a mass-to-charge ratio of one. In addition, the endogenous nature of biologics often means that chemical background becomes an issue. Consequently, LC-MS for testing biological must be more specific. (See “Seeing More in HPLC.”)

“We recently launched our TSQ Vantage,” says Thakur, “and the whole idea behind the TSQ Vantage was S-Lens technology coupled to the HyperQuads, which leads to an increase in signal but reduced the transmission of chemical noise, thereby enhancing the signal-to-noise ratio, a vital factor in quantitative analysis.” Thakur adds that the TSQ series of triple-stage quadrupoles provides highly-selective, reaction monitoring (H-SRM). “This gives far better specificity compared to basic SRM methodology for the quantitative analysis of peptides,” says Thakur.

Seeing more in HPLC

Testing a new compound’s properties, including toxicity, often requires high-performance liquid chromatography (HPLC). Phenomenex in Torrance, Calif., recently released several products that turn up the potential of HPLC for stability and toxicology studies. As Terrell Mathews, product manager at Phenomenex, says, “In degradation studies, for instance, you need to detect peaks that are 0.1 percent of the parent peaks. That requires sensitivity and a way to compress the main peak, which takes high surface area materials.” That’s why Phenomenex introduced a 2.5 micrometer particle in their Synergi HPLC line that provides 475 square meters of surface area per gram.

In addition, during very early in vitro and in vivo toxicology studies, pharmaceutical companies require fast and accurate testing of low-concentration compounds in cellular and plasma matrices. “The goal at this early stage is to not do any sample preparation, but just put it right on an LC/MS system,” says Mathews. Such raw samples, though, can clog some columns. Phenomenex’s new two millimeter internal diameter Onyx, however, is a high throughput monolithic column for HPLC. “It’s very highly permeable,” says Mathews, “so it does not clog with dirty samples and produces no carry-over.” In short, says Mathews, “The Onyx provides consistent results with little clean up ahead of time.”

About the Author
Mike May, PhD, is a publishing consultant for science and technology based in Minnesota.

This article was published in Drug Discovery & Development magazine: Vol. 11, No. 11, November, 2008, pp. 14.


Filed Under: Drug Discovery

 

Related Articles Read More >

EVEREST lead investigator on why Dupixent sets a new bar for treating coexisting CRSwNP and asthma
Sanders, King target DTC pharma ads but the industry worries more about threats to its $2B R&D model
Zoliflodacin wins FDA nod for treatment of gonorrhea
FDA approved ENFLONSIA for the prevention of RSV in Infants
“ddd
EXPAND YOUR KNOWLEDGE AND STAY CONNECTED
Get the latest news and trends happening now in the drug discovery and development industry.

MEDTECH 100 INDEX

Medtech 100 logo
Market Summary > Current Price
The MedTech 100 is a financial index calculated using the BIG100 companies covered in Medical Design and Outsourcing.
Drug Discovery and Development
  • MassDevice
  • DeviceTalks
  • Medtech100 Index
  • Medical Design Sourcing
  • Medical Design & Outsourcing
  • Medical Tubing + Extrusion
  • Subscribe to our E-Newsletter
  • Contact Us
  • About Us
  • R&D World
  • Drug Delivery Business News
  • Pharmaceutical Processing World

Copyright © 2025 WTWH Media LLC. All Rights Reserved. The material on this site may not be reproduced, distributed, transmitted, cached or otherwise used, except with the prior written permission of WTWH Media
Privacy Policy | Advertising | About Us

Search Drug Discovery & Development

  • Home Drug Discovery and Development
  • Drug Discovery
  • Women in Pharma and Biotech
  • Oncology
  • Neurological Disease
  • Infectious Disease
  • Resources
    • Video features
    • Podcast
    • Voices
    • Webinars
  • Pharma 50
    • 2025 Pharma 50
    • 2024 Pharma 50
    • 2023 Pharma 50
    • 2022 Pharma 50
    • 2021 Pharma 50
  • Advertise
  • SUBSCRIBE