Podcast
Questions and Answers
What role does the neonatal Fc receptor (FcRn) play in the pharmacokinetics of monoclonal antibodies (MAbs)?
What role does the neonatal Fc receptor (FcRn) play in the pharmacokinetics of monoclonal antibodies (MAbs)?
FcRn recycling increases the half-life (t1/2) of MAbs by protecting them from degradation.
How do monoclonal antibodies accumulate in diseased tissues, and what implications does this have for therapy?
How do monoclonal antibodies accumulate in diseased tissues, and what implications does this have for therapy?
MAbs can exhibit accumulation in diseased tissues through mechanisms like enhanced permeability, which can improve therapeutic efficacy.
Explain the concept of target-mediated drug disposition as it relates to MAbs.
Explain the concept of target-mediated drug disposition as it relates to MAbs.
Target-mediated drug disposition refers to the saturation of drug clearance due to specific binding of MAbs to their targets, affecting their pharmacokinetics.
What is the significance of renal filtration in the elimination of monoclonal antibody fragments?
What is the significance of renal filtration in the elimination of monoclonal antibody fragments?
Signup and view all the answers
Identify two patient-related parameters that can affect the absorption, distribution, metabolism, and excretion (ADME) of MAbs.
Identify two patient-related parameters that can affect the absorption, distribution, metabolism, and excretion (ADME) of MAbs.
Signup and view all the answers
What are the two principal routes of administration for monoclonal antibodies (mAbs)?
What are the two principal routes of administration for monoclonal antibodies (mAbs)?
Signup and view all the answers
Why do functional proteins like mAbs rarely survive the gastrointestinal (GI) tract?
Why do functional proteins like mAbs rarely survive the gastrointestinal (GI) tract?
Signup and view all the answers
What is a significant advantage of administering mAbs intravenously?
What is a significant advantage of administering mAbs intravenously?
Signup and view all the answers
What does subcutaneous administration require and what are its limitations?
What does subcutaneous administration require and what are its limitations?
Signup and view all the answers
How does the extracellular matrix affect the absorption of negatively charged mAbs?
How does the extracellular matrix affect the absorption of negatively charged mAbs?
Signup and view all the answers
What is the molecular weight of IgG approximately, and why is it relevant?
What is the molecular weight of IgG approximately, and why is it relevant?
Signup and view all the answers
What are the mechanisms through which mAbs distribute from blood vessels to interstitial space?
What are the mechanisms through which mAbs distribute from blood vessels to interstitial space?
Signup and view all the answers
What factors can affect the absorption of mAbs administered subcutaneously?
What factors can affect the absorption of mAbs administered subcutaneously?
Signup and view all the answers
Study Notes
Biologics 2 - ADME of MAbs
- MAbs (monoclonal antibodies) often don't survive the GI tract due to acidification and proteases.
- Two main administration routes are intravenous (IV) and subcutaneous (SC).
ADME of MAbs - Absorption - Intravenous
- IV administration provides rapid exposure and effect, directly entering the circulatory system.
- Administered in a controlled manner in clinical settings.
ADME of MAbs - Absorption - Subcutaneous
- SC administration requires injection into the skin.
- Limited to small volumes due to potential side effects.
- Self-administration is possible.
- Absorption happens in the subcutaneous connective tissue, which has a negatively charged extracellular matrix.
- This matrix is less permeable to negatively charged IgG.
ADME of MAbs - Absorption - Subcutaneous, site of absorption
- Absorption happens in the subcutaneous connective tissue.
- Tissue characteristics (e.g., elastic fibers, lymphocytes, mast cells, fibroblasts, collagenous fibers) affect the absorption process.
ADME of MAbs - Absorption - Subcutaneous, Effect of MW on route of absorption
- Proteins larger than 40 kDa are mostly absorbed via the lymphatic system.
- Smaller molecules diffuse directly into blood vessels.
- IgG has a molecular weight of approximately 150 kDa.
ADME of MAbs - Absorption - Subcutaneous, Factors that affect absorption
- Factors like protein size, formulation, injection volume, excipients, and degradation can affect absorption.
- Other factors include species, age, skin type, anesthesia, skin temperature, and blood flow.
- Uptake of less than 16 kDa molecules occurs into capillaries and travels to the central lymphatic ducts.
ADME of MAbs - Absorption - Subcutaneous, Factors that affect absorption - Plasma data
- Plasma absorption rate from SC administration is slower than IV.
- Absorption half-life (T1/2) of a Mab varies depending on its molecular weight.
ADME of MAbs - Distribution - From blood vessels to interstitial space
- MAbs typically enter interstitial space via transmembrane (passive diffusion) and transcytotic vesicles pathways.
- Paracellular diffusion through junctions is also possible.
ADME of MAbs - Distribution - Paracellular diffusion
- Distribution depends on the type of vasculature (continuous, fenestrated, discontinuous/sinusoidal).
- The central nervous system (CNS) is typically impermeable to most MAbs.
- Certain tissues like the liver, bone marrow, and spleen have discontinuous/sinusoidal vasculature and have a higher distribution of MAbs.
ADME of MAbs - Distribution - Accumulation in diseased tissue
- Antibodies can accumulate in inflamed tissues.
- For example, anti-TNF IgGs accumulate.
- PEG-Fab' (PEGylated antibody fragment) in inflamed tissue has a longer half-life than full-sized IgG.
ADME of MAbs - Recycling - The neonatal Fc receptor (FcRn)
- FcRn mediates receptor-mediated transcytosis, particularly in rodents (postnatal).
- In humans, it is important during the fetal stage.
- FcRn is crucial for IgG recycling and can be involved in the kidney excretion or recycling of MAbs.
ADME of MAbs - Recycling - The neonatal Fc receptor (FcRn) - Pinocytosis
- FcRn recycles approximately two-thirds of IgG molecules through pinocytosis.
- The recycling capacity is limited by plasma IgG levels.
ADME of MAbs - FcRn recycling
- FcRn recycling increases the half-life of MAbs.
- Mutant mice lacking FcRn receptors cannot recycle MAbs as effectively.
ADME of MAbs - IgG trapped in kidneys
- MAb fragments in the glomerulus are excreted or recycled via FcRn-mediated transcytosis.
ADME of MAbs - Elimination by pinocytosis
- MAbs not bound to FcRn are degraded in the lysosomes within endosomes.
- This pathway is a non-specific method for Mab degradation.
ADME of MAbs - Elimination by receptor-mediated endocytosis
- Leucocytes and endothelial cells use receptor-mediated endocytosis to eliminate MAbs.
- This process includes the involvement of the Golgi, early endosomes, and late endosomes.
ADME of MAbs - Clearance
- Rituximab has a biphasic pharmacokinetics profile.
- Clearance is primarily through specific binding to target (CD20) during the initial phase.
- Later, non-specific catabolism plays a role, particularly when target saturation is reached.
- Clearance can be saturable.
ADME of MAbs - Target-mediated drug deposition
- Certain MAbs, such as efalizumab, exert their effects through receptor downregulation (e.g., CD11).
- Higher doses tend to saturate the receptor, leading to non-specific clearance mechanisms and prolonged half-lives.
- Lower doses show quicker clearance from plasma due to receptor binding.
ADME of MAbs - Renal Excretion
- MAb fragments of smaller molecular weights (e.g., less than 50 kDa) can be filtered from the blood by the kidneys.
- Factors like different fragment structures and sizes (IgG, scFv-Fc, etc.) influence renal clearance rates.
ADME of MAbs - PEGylation
- PEGylation (polyethylene glycol) increases the half-life of Fab (antibody fragment) fragments.
- This is achieved by increasing the molecular weight which slows clearance.
ADME of MAbs - Conformational effect on PK profile
- The conformation and structures of different MAbs influence clearance rates in the body.
- Those that lack Fc regions have impaired FcRn recycling and renal excretion, leading to shorter half-lives compared to those with Fc domains.
Therapeutic Antibodies – Immunogenicity
- Therapeutic MAbs (foreign proteins) can trigger an immune response in patients resulting in anti-drug antibodies (ADAs).
- MAb aggregates are particularly immunogenic due to their higher propensity to induce immune responses by being more efficiently digested.
Studying That Suits You
Use AI to generate personalized quizzes and flashcards to suit your learning preferences.
Related Documents
Description
Explore the pharmacokinetics of monoclonal antibodies (MAbs) focusing on their absorption through various administration routes. Learn about the differences between intravenous (IV) and subcutaneous (SC) administration, including their mechanisms, effects, and challenges. This quiz delves into the specific characteristics of subcutaneous absorption and its implications for therapy.
