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
What is the fundamental assay difference between the Sanquin-ELISA and the Theradiag ELISA?
- Position of serum-biological in the chain. (SQ -Sandwich ELISA - more specific)
- Different secondary antibody (which the LT one binds to all the IgG and the SQ binds to only the variable region of certain ab’s) –> specificity build in
What is a bio-similar? What is the big difference with the biological originator?
Structurally related molecule with the same target. Much cheaper.
What are the three steps from the psoriasis treatment ladder?
Topical, photo, systemic
Drug targets in psoriasis (5)
- IL-12
- IL-17
- IL-22
- IL-23
- TNF-a
What is the aim of ‘Therapeutic Drug Monitoring (TDM)’?
Promoting optimum (personalized) drug treatment by maintaining drug concentration within a ‘therapeutic range’
What is the main immunosuppressive drug?
Tacrolimus
Advantages tacrolimus (3)
- Low incidence of rejection
- Transplantation of other organs is possible
Disadvantages tacrolimus (3)
- precious kidney function lost
What do CART-T cells work?
Manipulate T cells to recognize or repress specific antigen
Describe the effect of betalacept
Blocks both CD80/86 (polyclonal) -> costimulation
In what situations can belatacept be used?
Name three new forms of immunosuppression
- Anti-IL-6
- Imlifidase
- CAR-T cells
What is -omab?
Mouse derived mAb
What is -ximab
Chimeric mAb
What is -zumab
Humanized mAb
What is -umab?
Human mAb
