Bioanalysis
Accurate Quantification of ASOs in Mouse Serum Using Microsampling LC-MS/MS
Design and Validation of a Bioanalytical Method to Support a Clinical Pharmacokinetic Study Involving the Use of Multiple Lots of the Biological Therapeutic Drug
Top 5 Ways Integrated Drug Development Solutions Save You Time and Money
Since 2004, the average cost of bringing a new drug to market has increased from $800 million to about $2.6 billion, without, for the most part, shorter development time
Application of Mitra Microsampling for the Quantitative Bioanalysis of Antisense Oligonucleotides
Current Strategies for Using Commercial LBA Kit in Regulated Bioanalysis
ISSUE NO. 33 — End-to-End CNS Drug Development Solutions
In Issue 33 of The Altascientist, we explore how a comprehensive, end-to-end integrated approach to drug development for central nervous system (CNS) therapeutics can take you seamlessly from lead candidate selection to market.
Engaging at the outset with a fully integrated and experienced drug development partner can ensure safety, with timely data sharing at every step of the drug development plan, and facilitate agile, flexible decision-making and planning.
With detailed case studies, study considerations, and more, this Issue covers:
- preclinical safety and toxicity testing,
- formulation and manufacturing,
- early-phase clinical trials, and
- bioanalysis.
the cns drug development landscape
The different parts of the nervous system, including the brain and spinal cord (i.e., central nervous system – CNS) and the peripheral nervous system, are important drug targets for many serious diseases affecting human health. As the body’s processing center, the CNS is responsible for all functions of our bodies, including thoughts, emotions, memories, and behaviors.
According to Fortune Business Insights, the global CNS market is projected to grow from $89.02 billion in 2021 to $166.53 billion in 2028, at a compound annual growth rate (CAGR) of 9.4%. This growth is driven primarily by the rising demand for age-related neurodegenerative treatments due to the increasing global population over the age of 65, the growing potential of psychedelic therapies in treating conditions like PTSD and psychosis, and CNS-active drugs proving increasingly effective across various areas, such as acute and chronic pain, brain diseases, and autoimmune disorders.
“The successful delivery of drugs targeting the treatment of CNS conditions is challenged by the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BSCFB), which protect the CNS from intrusion by harmful substances. Large molecules are less able to penetrate the blood/brain barrier to deliver therapeutic results and thus most CNS-active drugs are small molecules.” — The Altascientist, Issue 33, pg. 2.
SPECIALIZED ASSESSMENTS AND STUDIES
Unsurprisingly, drugs working on the CNS are subject to stringent regulatory requirements, and specialized safety assessments are often mandated. To confirm CNS activity without safety concerns, dedicated nonclinical and early-phase clinical studies, with relevant endpoints and biomarkers and supporting bioanalysis, are needed, and drug manufacturing must be carefully managed via rigorous handling and production processes.
“Specialized assessments in nerve conduction are sometimes performed in CNS drug development, depending on the specifics of the new molecular entities. These key assays, performed in NHPs, can be included in preclinical safety and toxicology programs to assess the peripheral neuropathy (PN) liability of a new drug.” — The Altascientist, Issue 33 pg. 5.
The many advancements in developing CNS-active drugs have been hampered by higher failure rates compared to drug discovery in most other therapeutic domains. Identifying CNS experts with a well-established record of conducting rigorous, high-quality research can assure the effective management of challenges and reduce the risks of delaying or failing to advance promising drug candidates.
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Four Key Steps to Optimizing a Large Molecule Bioanalytical Program
Biologics are large, complex molecules that can undergo structural changes during the manufacturing process, storage, or administration to patients. This means bioanalysis of biologics is a critical aspect of the drug development process, and one that requires sensitivity, specificity, and selectivity.
Hybridization LC-MS/MS Workflow to Quantify an siRNA Drug Candidate in Plasma, CSF, and Tissues
Dr. Keyhani Reflects on International Day of Women and Girls in Science
Opinion | A Day to Celebrate, and a Call to Action
Dr.
ISSUE NO. 30 — The Evolution and Advancement of Liquid Chromatography-Mass Spectrometry in Drug Development
The drug development landscape is constantly evolving, with science and technology advancing hand-in-hand to improve the essential steps of determining drug concentration profiles and the characterization of drug transformation products. The ultimate goal is to better understand drug distribution, metabolism, and pharmacokinetic characteristics, and to present regulatory bodies with a complete and comprehensive submission package driven by current guidelines.
To this end, liquid chromatography (LC) coupled with mass spectrometry (MS) via an atmospheric pressure ionization (API) interface is a well-established analytical approach to support each phase of drug development, from early discovery through to clinical studies.
In Issue 30 of The Altascientist, we explore the numerous benefits of incorporating a stable isotope labelled internal standard for quantitative LC-MS, and detail recent advances in MS technology, including:
• stable isotope labelled internal standards (SLIS) for LC-MS quantitation
• Dried blood microsampling
• anti-epileptic drug panel
• COVID-19 neutralizing monoclonal antibodies
• differential mobility spectrometry
• bioequivalence
• large molecule bioanalysis
• oligonucleotides
Also included are several case studies, which exemplify novel bioanalytical workflows that are required to meet the challenges faced in both nonclinical and clinical development, across a variety of drug classes.
What is Liquid Chromatography-Mass Spectrometry?
The mainstream adoption of the LC-MS approach for the support of drug development initiatives originated in the early 1990s, pioneered by the triple-stage quadrupole (QqQ) platform. To this day, the QqQ architecture remains the gold standard for drug quantitation in biological fluids due to the unique nature by which MS/MS is performed.
Specifically, ionized precursor ions with a targeted mass-to-charge ratio (m/z) are transmitted through the first resolving quadrupole (Q1) and axially accelerated into a collision cell (q) containing an inert gas (N2 or Ar). The resulting collision-induced fragmentation leads to the production of progeny ions whose profile represents a fingerprint unique to that of the selected precursor. Progeny ions of a specific m/z can then be transmitted from the collision cell through the third resolving quadrupole (Q3) for detection. The scan function representing precursor ion selection with subsequent collision-induced dissociation and detection of a specific progeny ion is often referred to as multiple (or selected) reaction monitoring (MRM or SRM, respectively), and is single-handedly responsible for the mainstream adoption of the QqQ platform for quantitative mass spectrometry.
Over the years, advancements in LC-MS technology have been required to meet the ever-increasing complexities of assay demands. And the ubiquitous leveraging of LC-MS may largely be attributed to the following characteristics:
• high sensitivity with broad dynamic range and selectivity from interferences, particularly when incorporating a tandem mass spectrometric (i.e., MS/MS) approach;
• a near-universal and thermodynamically favorable electrospray ionization process that facilitates the transport of analyte ions from the condensed state of LC into the gas phase for MS detection; and
• the ability to support multiplexing capabilities due to rapid MS/MS scanning and chromatographic separation.
Explore all issues of The Altascientist in our Resource Center. And don’t forget to subscribe to “The Altascientist: Audiobooks” on Spotify, Apple Podcasts, or wherever you get your audio content.