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Parenteral therapy 2 > Biologics > Flashcards

Biologics Flashcards

1
Q

Biologics

A

Class of drugs produced by a living system

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2
Q

Biosimilar

A

A biological product that is approved based on demonstrating that it is highly similar to an FDA approved product
No clinically meaningful differences in safety and efficacy from reference product

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3
Q

Traditional v. biologic formulations

A

R&D: test new chemical entities v. replace or supplement natural proteins
Clinical intervention: chemical v. biological
Type: Oral v. larger complex proteins
Stability: room T v. refrigerated
Assay: standard drug testing v. minute amounts in vivo (challenge monitoring therapeutic levels)

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4
Q

Amino acids

A

20 different amino acids

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5
Q

Native state of proteins

A

properly folded and/or assembled and is bioactive

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6
Q

Types of folded proteins

A

primary structure
secondary structure (b pleated sheet and alpha helix)-H bond
tertiary structure
quaternary structure

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7
Q

Peptide and protein stability

A

Chemical stability
Physical stability

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8
Q

Chemical stability

A

deamidation
racemization (D to L or vice versa)
hydrolysis
oxidation
disulfide exchange reaction

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9
Q

Physical stability

A

denaturation
aggregation
precipitation
adsorption

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10
Q

Monoclonal antibody (IgG)

A

Fab–antigen binding in the top y portions
Fc–effector functions, does the attacking

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11
Q

Physico-chemical characteristics of monoclonal antibodies

A

N-terminal heterogeneity
AA modifications
fragmentation
oligosaccharides
disulfide bonds
C-terminal heterogeneity

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12
Q

deamidation AA

A

Asn, Gln

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13
Q

Racemization AAa

A

Asp

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14
Q

Hydrolysis AA

A

Asp-X

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15
Q

Oxidation AA

A

Met, Cys, His, Try, Tyr

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16
Q

Disulfide exchange AA

A

Cys

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17
Q

Denaturation

A

protein unfolding from the natural state to a more disordered arrangement
partial or complete
reversible or irreversible
loss of biological activity
–>aggregation
–>precipitation

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18
Q

Things that cause denaturation

A

heat
pH
ionic strength
surface
surfactant
organic solvent
filtration
freezing/freeze-drying
moisture
shear forces

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19
Q

pH and denaturation

A

pH below isoelectric point: net positive charge –> repelling of AA and denaturation
pH below isoelectric point: net negative charge –> repelling of AA and denaturation

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20
Q

Protein adsorption

A

Preferential accumulation of protein at surface
reduces surface tension
Quantity is a few mg/m^2
Minimal at pI–> pH and ionic strength is important
Partly reversible on hydrophilic surfaces
Often irreversible on hydrophobic surfaces
Increases with hydrophobicity of protein/surface
Adsorbed proteins may denature to optimize surface interaction

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21
Q

Aggregation

A

Formation of abnormal soluble aggregates or peptide or protein
Chemical and/or physical interaction
Reversible or irreversible
high concentration
loss of biological activity

22
Q

Preciptation

A

macroscopic equivalent of aggregation

23
Q

Practical issues handling biologics

A

Require refrigeration
Extreme temperatures/thawing can denature proteins
Sterility–usuallly no preservative
Excessive agitation can denature proteins
Proper diluent is critical
Proteins may adsorb to plastic/glass
Dosing is based on units of activity v. chemical weight
Proteins usually administered SC or IV
Home admin: transport, storage and patient education

24
Q

To prevent adsorption

A

apply a surfactant

25
PH modifier
Buffering agents
26
Toxicity agents
Tonicity modifiers
27
Bulking agent
Sugars and polyols Amino acids Polymers and proteins
28
Wetting and/or solubilization agent
Surfactants
29
Antioxidant
Antioxidant Preservatives
30
Antimicrobial preservatives
Antimicrobial preservatives
31
Chelating or complexing agent
Chelator preservatives
32
Stability of recombinant TNF under refrigeration
Over a year protein purity is 99% but potency is 50%
33
Measured activity of TNF
Is low with just D5W but at expected amounts with D5W + 0.25% human serum albumin
34
Measured activity of IL-2
Should not be administered with an in-line filter because activity decreases drastically
35
Expiration dates before v. After reconstitution
Years before reconstitution 30 days after reconstitution (8 hours if no preservative)
36
Factors for parenteral administration of biologics
Concentration of protein drug Choice of diluent and additives Contact surfaces (proteins like to adsorb to plastics)
37
Immunogenicity
Creation of anti drug antibodies against the biologic Could also create a cytokine storm Could cause anaphylaxis
38
To avoid immunogenicity
Human v. Animal Contaminants Formulation (storage of freeze-dried material at room temp Level of glycosylation Route of application Dose Aggregates (instability or improper reconstitution)
39
IV administration for biologics
Most common for monoclonal antibodies
40
Advantages of IV
Large volume can be injected Control rate of infusion 100% bioavailability High Cmax Relatively low patient variability
41
Disadvantages of IV
Specialized equipment with trained personnel Longer clinic/office stays Less patient convenience
42
SC route advantages
Self-administration Less invasive Better patient compliance Lower cost
43
SC route disadvantages
Limited injection volume; hyaluronidase Injection site irritation Inter patient variability Injection site differences Bioavailability <100%
44
Hylauronidase
Degrades the matrix at the extracellular site to increase the effective volume of SC route
45
Capillary permeability
Decreases with increasing MW
46
SC injection routes
Abdomen is higher than the thigh
47
SC absorption and peak concentration time
The lower the MW the faster the time to perks concentration
48
Renal clearance and proteins
The larger the molecule, the less clearance (esp if charged) With renal disease, renal clearance decreases
49
SC injection results for monoclonal antibodies
Not complete bioavailability Time to peak is about a week Terminal half life is about 3 weeks
50
New delivery systems for biologics
Transdermal Transnasal Ophthalmic (eye drops/lenses) Implantable (depots or pumps) New oral (CR) Pulmonary
51
Targeted biologics delivery
Monoclonal antibodies Liposomes Modified cells containing active genes
52
Antibody-drug conjugates for cancer targeting
ADC binds tumor associated antigen Enters the cell Lysosome breaks up ADC in cell Drug is released in cell and reaches target site

Parenteral therapy 2 (6 decks)

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