Pharmaceutical Outsourcing Q3 2023 - 18

ANALYTICAL TESTING
The Role and Challenges
of Plasma Protein Binding
in Oligonucleotide Drug
Development
Dr. Jie Wang
Principal Scientist, DMPK Services
WuXi AppTec
Plasma protein binding refers to the degree drugs bind to proteins
within the blood or plasma. In pharmacology, drugs exist in two forms:
unbound, or " free, " and the bound form. Unbound drug molecules are
pharmacologically active, can diffuse across cell membranes, reach
their site of action and be eliminated. In contrast, protein-bound
drugs largely remain within the vascular compartment, providing a
reservable pool of the drug that can be released into circulation as
free drug concentrations decline.
The balance between bound and unbound drugs plays a crucial role
in pharmacokinetics. These two types of drugs are in equilibrium
at steady-state conditions in vivo. Only unbound drugs are usually
available for pharmacological interactions, although some exceptions
exist. But the extent of protein binding directly influences a drug's
distribution volume and clearance rate, impacting its half-life and,
ultimately, the dosing regimen. Put simply, the degree of protein
binding can significantly impact a drug's efficacy.
Highly protein-bound drugs have a slower elimination rate,
potentially leading to prolonged drug action. Lower protein
binding, on the other hand, can result in rapid drug elimination,
necessitating more frequent dosing to achieve therapeutic levels.
Furthermore, alterations in protein binding due to drug-drug
interactions or pathophysiological changes can lead to variations
in free drug concentration, potentially resulting in sub-therapeutic
effects or toxicity.
Oligonucleotides and Plasma
Protein Binding
Oligonucleotides, or " oligos, " are a popular class of novel therapeutics
that present a unique challenge for protein binding. These short
Pharmaceutical Outsourcing | 18 | July/August/September 2023
DNA or RNA molecules are designed to modulate gene expression,
providing targeted treatments for various diseases, including genetic
disorders, cancers and viral infections. However, oligos' large size,
negative charge, and the presence of modifications increase their
complexity and propensity for nonspecific binding to plasma proteins.
Oligos' properties and anionic nature impede passive diffusion across
cell membranes, often a crucial step for reaching intracellular targets.
Their negative charge encourages binding to plasma proteins,
specifically to positively charged domains, thereby increasing their
plasma residence time and potentially limiting target accessibility.
Nonspecific binding represents another obstacle. Oligos can interact
with a range of plasma proteins in a nonspecific manner, not
dictated by the typical lock-and-key model of molecular interaction.
This diversity of binding partners complicates the quantification of
relevant, specific binding that directly impacts drug action.
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