Immunomodulatory drugs are at the forefront for the treatment of various types of cancer, infectious diseases, and numerous autoimmune diseases, including rheumatoid arthritis, type I diabetes, lupus, and multiple sclerosis. As the complexity of these therapeutics increases, so must the sophistication of the bioanalytical assays designed to either quantify them or measure their impact on the patient.

In Issue 41 of The Altascientist, we explore common classes of immunomodulators, bioanalytical methods used to quantify them, and their associated biomarkers. Featuring two scenarios that explore the complexities of bioanalysis for immunomodulators, The Altascientist offers practical considerations for ensuring accurate bioanalysis, as well as pharmacokinetic, pharmacodynamic, and safety data in clinical trials.

This issue also covers: 
•    classes of immunomodulators, including monoclonal antibodies, CAR-T cells, and vaccines;
•    immunotherapy trials, focusing on complex study designs and diverse patient populations; and
•    bioanalytical methods and assays, including pharmacokinetics and anti-drug antibodies (ADA).

Immunomodulation Assessments for Clinical Trials

Immunomodulators can be broadly defined as immunostimulants and immunosuppressants, with many types of modalities. The growing understanding of the immune system's role in various diseases, along with advancements in drug development, have led to a natural evolution from traditional vaccines, small molecules, and cytokines, to increased targeted biologics and innovative approaches in gene therapy and vaccines. 
 

“Each class of immunomodulator has a defined complexity and mechanism of action. Thus, the appropriate bioanalytical program will need to be carefully designed for the drug type and the intended purpose of the clinical study." –The Altascientist, Issue 41 pg. 2.

This includes careful consideration of pharmacokinetic and pharmacodynamic endpoints, as well as regulatory and bioanalytical requirements.

Particular attention is needed for monoclonal antibodies, CAR-T cells, antibody-drug conjugates (ADCs), and vaccines, as each class requires tailored strategies to support clinical studies and ensure accurate data collection.

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In Issue 40 of The Altascientist, different analytical testing techniques to support drug product development specific to bioavailability are explored, including a case study on the manufacturing of a nanosuspension. 

During the early stages of drug development, fully characterizing the active pharmaceutical ingredients (APIs) is crucial for optimizing the drug product formulation. Specifically, understanding your API’s particle size, crystalline structure (including different polymorph forms), and dissolution profile to inform downstream formulation dosing decisions for clinical trials.

 In this issue of The Altascientist, you will discover: 

• methods for identifying and characterizing your API;
• common techniques to determine particle size distribution (PSD);
• formulation approaches to maximize bioavailability; and
• a nanosuspension case study.

CHARACTERIZATION OF YOUR API

The analytical testing of APIs is a multi-faceted approach involving various techniques and methodologies to ensure that the API is adequately absorbed in the body to exert its therapeutic effect. 

“By rigorously evaluating and optimizing the chemical, physical, and biological properties of the API, pharmaceutical scientists can enhance bioavailability, leading to more effective and reliable medications.” —The Altascientist, Issue 40 pg. 1

Dissolution testing, in which liquid is used to simulate conditions within the human body; particle size analysis (PSA), in which the drug’s API, or formulation, is measured; and X-ray diffraction (XRD), used to determine crystalline structures, are just some of the methods used to determine key API properties.

Formulation Approaches to Maximize Bioavailability

When an API has been fully characterized and determined to be a good candidate for development, formulation decisions are made. Some of the most common approaches to maximize the bioavailability of the API are discussed in-depth in Issue 41, including nanomilling, liquid-filled hard-shell capsules (LFHCs), and spray-dried dispersion. 

Nanomilling can be applied to nearly any insoluble API, making it a valuable first step in the solubilization process:

“Nanomilling’s universal applicability is a major advantage over other formulation approaches for poorly water-soluble APIs[; it] can be applied to just about any insoluble API fairly easily, making it an appealing first-line approach to solubilization.” —The Altascientist, Issue 40 pg. 6.

Additionally, since many APIs have high melting points and poor aqueous solubility, which directly affect their dissolution and bioavailability, LFHCs are valuable for effectively metabolizing lipid-based solutions. These solutions can then be used as liquid carriers, optimizing API absorption. 

As explained in the issue, the advantages of LFHCs are “pre-made dosage form, in that the shell itself does not require formulation, and are ideal for low doses. Small quantities of LFHCs can be filled in-house, with lab-scale equipment and just a few grams of formulation for preclinical or early-phase clinical trials.” (pg. 7)

There are many important considerations to make during drug product formulation development. Thorough characterization of the API and a comprehensive testing regimen will identify the critical attributes needed to support a successful program. Mastery of manufacturing techniques to achieve the appropriate particle size is crucial for ensuring targeted bioavailability, and robust analytical testing crucial. Selecting the right methods and documenting results with precision is paramount.

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.