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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
Q

PH modifier

A

Buffering agents

26
Q

Toxicity agents

A

Tonicity modifiers

27
Q

Bulking agent

A

Sugars and polyols
Amino acids
Polymers and proteins

28
Q

Wetting and/or solubilization agent

A

Surfactants

29
Q

Antioxidant

A

Antioxidant
Preservatives

30
Q

Antimicrobial preservatives

A

Antimicrobial preservatives

31
Q

Chelating or complexing agent

A

Chelator preservatives

32
Q

Stability of recombinant TNF under refrigeration

A

Over a year protein purity is 99% but potency is 50%

33
Q

Measured activity of TNF

A

Is low with just D5W but at expected amounts with D5W + 0.25% human serum albumin

34
Q

Measured activity of IL-2

A

Should not be administered with an in-line filter because activity decreases drastically

35
Q

Expiration dates before v. After reconstitution

A

Years before reconstitution
30 days after reconstitution (8 hours if no preservative)

36
Q

Factors for parenteral administration of biologics

A

Concentration of protein drug
Choice of diluent and additives
Contact surfaces (proteins like to adsorb to plastics)

37
Q

Immunogenicity

A

Creation of anti drug antibodies against the biologic
Could also create a cytokine storm
Could cause anaphylaxis

38
Q

To avoid immunogenicity

A

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
Q

IV administration for biologics

A

Most common for monoclonal antibodies

40
Q

Advantages of IV

A

Large volume can be injected
Control rate of infusion
100% bioavailability
High Cmax
Relatively low patient variability

41
Q

Disadvantages of IV

A

Specialized equipment with trained personnel
Longer clinic/office stays
Less patient convenience

42
Q

SC route advantages

A

Self-administration
Less invasive
Better patient compliance
Lower cost

43
Q

SC route disadvantages

A

Limited injection volume; hyaluronidase
Injection site irritation
Inter patient variability
Injection site differences
Bioavailability <100%

44
Q

Hylauronidase

A

Degrades the matrix at the extracellular site to increase the effective volume of SC route

45
Q

Capillary permeability

A

Decreases with increasing MW

46
Q

SC injection routes

A

Abdomen is higher than the thigh

47
Q

SC absorption and peak concentration time

A

The lower the MW the faster the time to perks concentration

48
Q

Renal clearance and proteins

A

The larger the molecule, the less clearance (esp if charged)
With renal disease, renal clearance decreases

49
Q

SC injection results for monoclonal antibodies

A

Not complete bioavailability
Time to peak is about a week
Terminal half life is about 3 weeks

50
Q

New delivery systems for biologics

A

Transdermal
Transnasal
Ophthalmic (eye drops/lenses)
Implantable (depots or pumps)
New oral (CR)
Pulmonary

51
Q

Targeted biologics delivery

A

Monoclonal antibodies
Liposomes
Modified cells containing active genes

52
Q

Antibody-drug conjugates for cancer targeting

A

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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