Biologics PK handout Flashcards
Biologics
- generally derived from ___ material
- ___ in structure
- living
- complex
Examples of biologics
- monoclonal antibodies
- cytokines
- growth factors
- enzymes
- immunodulators/immunotherapies
- proteins
- vaccines
- blood producrs
- gene therapy
Monoclonal antibodies
* target specific
* their side-effects are mostly related to exaggerated ___ effects
pharmacological
Small molecule drugs
* more prone to induce
___ effects
harmful non-target
- Antibodies used as drugs belong to ___ class
- accounts for ___ of naturally occurring antibodies
- IgG
- 75-80%
IgG action
- ADCP
- CDC
- ADCC
- antibody dependent cellular phagocytosis
- complement depenent cytotoxicity
- antibody dependent cellular cytotoxicity
mAb: Absorption
- Cannot be taken ___ due to instability in GI tract and difficulty in permeating the intestinal epithelium
- Must be given ___
- Reach systemic circulation by ___ flow of the interstitial fluids into ___ capillaries into ___ channels
- orally
- parenterally
- convective, lymphatic
major pathway for mAb: ___
minor pathway for mAb: ___
- convective
- diffusion
Lymphatic system
- ___ transport system, for fluid and proteins by collecting them from ___ space and returning them to ___ circulation
- lymph flow rate is 100-500 times ___ than blood
- the protein composition of lymph is nearly equivalent to ___
- major transport route for ___ cells and macromolecules
- one way, interstitial, blood
- slower
- interstitial fluid
- immune
Lymph drains into blood circulation
* right lymph duct → right ___ vein
* ___ duct → left subclavian veins
- subclavian
- thoracic
mAb: Distribution
Volume of distribution of mAB lies between that of ___ (0.04 L/kg) and extracellular ___ (0.23 L/kg)
- plasma
- water
mAb: Elimination
- Renal elimination of mAb is ___
- mAbs are mainly eliminated through ___, resulting in smaller peptides and amino acid
- Pinocytosis by endothelial cells involving ___ extends IgG ___ (IgG recycling)
- Clearance from circulation is via ___ or ___ pathway
- insignificant
- proteolytic degradation
- FcRn, half life
- nonspecific, specific
Fc receptors
- FcγR
- FcRn (neonatal FcR)
Nonspecific clearance pathway
Proteolysis by ___ (RES):
* Dose-___ as therapeutic mAb concentration is below endogenous ___ level (10 mg/ml)
- reticuloendothelial system
- independent, IgG
Specific clearance pathway
Target-mediated clearance
* Dose-___ as antibody binding to the target antigen can be ___
- dependent
- saturated
mAb elimination: IgG salvage by FcRn
- ___ Fc receptor
- expressed in ___ syncytiotrophoblast and
___ endothelium - FcRn in endothelial cells protects ___ from catabolism
- The cells internalize IgG which binds to ___ in an acidic endosomal
compartment. FcRn then recycles IgG back into circulation, extending its serum ___
- neonatal
- placenta and vascular
- IgG
- FcRn, half life
T or F: The absence of FcRn leads to faster mAb elimination
true
FcRn binding delays mAb ___
and extends mAb half-life
elimination
mAb elimination: Reticuloendothelial system (RES)
- ___ phagocyte system
- part of the ___ that consists of the phagocytic cells located in reticular connective tissue (liver, bone marrow, and lymphoid)
- immune cells binding to ___ region of antibody, followed by receptor-mediated endocytosis and degradation in lysosome
- mononuclear
- immune system
- Fc
Specific clearance pathway: Target mediated disposition
- After mAbs bind to a specific antigen, they may be ___ or ___
- Most prominent for ___ antigen
- at high doses of mAb, pathway is ___
- internalized or catabolized
- membrane bound
- saturated
mAb: Immunogenecity
- mAbs may trigger an immune response, formation of ___ (ADA), in patients
- increased fraction of ___ sequence in the protein molecule leads to more immune response.
- antidrug antibodies
- nonhuman
mAb: Immunogenecity
- Both ___and ___ ADA form circulating ADA-mAb immune complex that is cleared by ___
- ___ route has higher likelihood for ___ at the injection site
- as duration of treatment lengthens, the chances to elicit an immune response ___
- ADA-mAb complex formation may increase mAb ___
- neutralizing, non-neutralizing, RES
- aggregate formation
- increases
- clearance
T or F: Cytochrome P450 enzymes in the liver play critical roles in elimination of
monoclonal antibodies
False
T or F: Oral route is the preferred route of administering biologics
False
T or F: Genetic engineering of Fc portion of mAb for better binding affinity to FcRn is expected to increase mAb half-life
True
T or F: Ranibizumab is Fab fragment of antibody targeting VEGF (vascular endothelial growth factor) while bevacizumab is a full-sized antibody. Clearance of ranibizumab is expected to be faster than that of bevacizumab.
True
T or F: After months of infliximab (mAb against TNFa) treatment for a patient with inflammatory bowel disease, anti-infliximab antibodies are detected. The elimination rate of infliximab is expected to increase as compared to the beginning of therapy.
True
T or F: Antidrug antibodies (ADA) against mAb typically increase both the elimination rate and the efficacy of mAb.
False
T or F: mAb engineering for increased binding to FcRn can increase the mAb half-life
True
T or F: mAb engineering for enhanced binding to FcγR can improve potency
True
