Clinical Pharmacology II Flashcards
This deck contains the lectures 'TDM for biologicals' I and II and 'Immunosuppressive drug therapy in transplantation'
What is the definition of biologicals?
Any pharmaceutical drug product manufactured in, extracted from, or semi-synthesized from biological sources
Examples of biologicals (8)
- Vaccines
- Blood/blood components
- Allergenics
- Somatic cells
- Gene therapies
- Tissues
- Recombinant therapeutic proteins
- (Natural) antibiotics
Biologicals have a prominent positions in the treatment of …
- (haematological) malignancies
- transplant rejection
- auto-immune disease
- inflammatory disease
What are the three modes of action of biologicals?
- Cell surface molecule (cytokine receptor, co-stimulatory molecules)
- Soluble mediator (cytokines, growth factors)
- Receptor blocking
Target: cell surface molecule
- Cell elimination
- Receptor blocking
Target: soluble mediator
mediator neutralization
How does checkpoint inhibition by receptor block work? (7:30)
- PD-L1 binds to PD-1 and inhibits T cell killing of tumor cells
- Blocking PD-L1 or PD-1 allows T cell killing of tumor cell
Checkpoint inhibitors interfere with?
co-stimulation phase (signal 2) –> co-inhibitory molecules
Examples of biologicals used for transplant rejection + what are their targets?
T cells need to be controlled:
- Muromonab –> CD3
- Basiliximab –> CD25
Examples of biologicals used for haematological malignancies + what are their targets?
- Rituximab –> CD20
- Alemtuzumab –> CD25
Examples of biologicals used for auto-immune-/inflammatory disease + what are their targets?
- Infliximab –> TNF
- Adalimumab –> TNF
Where can the checkpoint inhibitors do their job?
- Priming phase (LN)
- Effector phase (solid malignancies)
Why is it convenient for a checkpoint inhibitors to act during the priming phase? + disadvantage of this?
If you give patients the CI, it can act in the LN (where T cell activation happens) , you can get rid of the co-inhibitory pathway
Why would they change the structural makeup from mouse to human?
Immunogenicity is lower if you use humanized monoclonals
Name the four structures of biologicals? + beschrijf hoe dat er uitziet in een volgende flashcard
- Mouse (-omab)
- Chimera (-ximab)
- Humanised (-zumab)
- Human (-umab)
What are the main issues/side effects of biologicals? (2)
- Anti-drug antibodies can cause clearance of biologicals –> loss of response
- Hypersensitivity reaction
Which cytokines are released during an hypersensitivity reaction?
TNF-a, IL-6, IL-1
Example of a loss-of-response reaction after administration of infliximab?
- Infliximab goes up, then crashes
- Anti-infliximab antibody goes up
- Disease severity increased
Therapeutic drug monitoring (TDM):
- Analysis of biologic (trough) level
- Analysis of ADA presence, when indicated
Bioavailability of the biologicals depends on.. (4)
- Distribution
- Recycling (FcRn)
- Degradation
- Neutralisation (ADA)
What do you have to change if a patient forms anti-biological antibodies??
Switch to other biological
How do we detect the in serum troph levels of infliximab and adalimumab?
- Sanquin Biologic Level ELISA
- Theradiag LISA TRACKER ELISA
How does the sanquin Biologic Level ELISA work?
- Anti-TNF mAb is bound to the plate
- TNF binds
- Serum of patient biologic binds to TNF
- Secondary antibody/anti-idiotype-biotin –> binds to variable region of any IgG
How does the theradiag LISA TRACKER ELISA work?
- TNF bound to plate
- Serum biologic binds to TNF (anti-TNF antibodies of patient)
- Secondary ab/anti-hu-IgG-biotin directed to IgG
