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Drug Delivery > Exam 4 > Flashcards

Exam 4 Flashcards

1
Q

Biotherapeutics

A

Large molecules derived from living cells and used for the treatment, diagnosis, or prevention of disease

Composed of sugars, proteins, or nucleic acids or complex combinations of the substances, may be living.

Examples- vaccines, blood and blood components, monoclonal antibodies, somatic cell therapy, gene therapy, tissues, recombinant therapeutic proteins

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2
Q

Human insulin structure

A

Composed of 51 amino acids and has a molecular mass of 5808Da.
It is a dimer of an A-chain and a B-chain, which are linked together by disulfide bonds.

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3
Q

Rapid/immediate onset insulin

A

Regular human insulin (SQ, IV, IM), insulin aspart, insulin glulisine, and insulin lispro (all SQ)
All are soluble in crystalline zinc

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4
Q

Intermediate acting insulin

A

Neutral protamine Hagedorn (NPH) insulin, also known as Isophane Insulin
Effect in 90 minutes and lasts for 16 hours
Made by mixing regular insulin and protamine in exact proportions with zinc and phenol such that a neutral pH is maintained and crystals are formed.

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5
Q

Insulin detemir

A

Long acting insulin
Differs from human insulin in that the amino acid threonine in position B30 has been omitted, and a C14 fatty acid chain has been attached to the amino acid B29

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6
Q

Insulin glargine

What does arginine and glycine do?

A

Long acting insulin
Differs from human insulin by replacing asparagine with glycine in position 21 of the A-chain and by carboxyterminal extension of B-chain by 2 arginine residues.

The arginine amino acids shift the isoelectric pH of 5.4 to 6.7, making the molecule more soluble at physiologic pH. The isoelectric shift allows for injection of a clear solution.

The glycine substitution prevents deamination of the acid-sensitive asparagine at acidic pH.

In the neutral subQ space, higher-order aggregates form, resulting in a slow, peakless dissolution and absorption of insulin from the site of injection. It can achieve a peakless level for at least 24 hours.

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7
Q

Insulin time of onset, shortest to longest

A

Rapid (lispro, aspart, glulisine), short (regular), intermediate (NPH), Long (detemir), longest (glargine), longest acting insulin (degludec)

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8
Q

Biotherapeutics vs new chemical entities

A 
Biotherapeutics have: 
Larger MW
High selectivity (potency)
Multifunctional target binding
Slow clearance, long half life
Linear PK

New chemical entities have less species selectivity and a single target

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9
Q

Biotherapeutics species selectivity and target

A

High species selectivity (affinity/potency)

Multifunctional- target binding, Fc effector function, FcRn binding

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10
Q

Biotherapeutics toxicity, clearance, half life, dosing

A

Toxicity- largely target mediated “exaggerated pharmacology”
Slow clearance
Long half-life (days)
Infrequent dosing (weekly/monthly)

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11
Q

New chemical entity toxicity, clearance, half life, dosing

A

Toxicity - often “off-target” mediated
clearance- slow
short half life (hours)
Frequent dosing (daily)

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12
Q

Biotherapeutics PK and PD

A

Target can affect PK behavior, mostly has linear PK

PD related immunogenicity sometimes observed

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13
Q

New chemical entity PK and PD

A

Non-linearity from saturation of metabolic pathways (PK)
DDI mostly PD related
Immunogenicity rarely observed

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14
Q

MW of biotherapeutics affects on PK

A

High molecular weight leads to slower distribution and high mean residence time in the central compartment

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15
Q

Chemical structure of biotherapeutics affects on PK

A

Usually proteins in nature: Leads to higher target specificity and affects distribution

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16
Q

Metabolic pathways of biotherapeutics affects on PK

A

Generally not metabolized by the CYP450 or UGT enzymes, metabolism includes FcRn mediated recycling: reason for long clearance

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17
Q

Target-mediated drug disposition (TMDD) of biotherapeutics affects on PK

A

Affects distribution and clearance

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18
Q

Immunogenicity of biotherapeutics affects on PK

A

Can lead to faster clearance of biologics due to anti-drug antibody (ADA) generation

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19
Q

When B cells recognize antigens they differentiate into

A

Plasma cells

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20
Q

Plasma cells produce and secrete________ which bind to _________

A

antibodies, specific antigen

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21
Q

what are the mechanisms in which antibodies provide protection for the body?

A

Neutralization, opsonization, complement activation, ADCC

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22
Q

Basic antibody structure

A

Y shaped molecule having 2 antigen binding sites

The stalk is known as the Fc region

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23
Q

Once antibodies bind to their antigen they have 2 main strategies of blocking the pathogen, what are they?

A
  1. ) Block the pathogen from entering the host cell (neutralization)
  2. ) Recruiting the effector cells and molecules to kill the pathogens (opsonization, complement activation, ADCC)
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24
Q

Neutralization

A

The antibodies bind to their specific microbes or microbial toxins.
In doing this they block pathogen entry into the cells and neutralize their infectivity
Neutralization discourages or prevents a pathogen from initiating an infection
Viruses, bacterial toxins, snake venom, etc.

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25
Q

How are neutralized microbes eliminated from the body?

A

Phagocytosis

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26
Q

Opsonization

A

Enhances phagocytosis.
Antibodies coat antigen and recognized by phagocytes. The phagocytes bind to the antibody covered microbe by binding to the Fc region

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27
Q

Complement activation

A

Cytolysis, inflammation, or opsonization occurs after activation of the classical pathway.

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28
Q

Antibody-dependent cell-mediated cytotoxicity (ADCC)

A

When there is an intracellular infection or parasitic infection where phagocytosis cannot eliminate the ADCC is used.
Antibodies coat target cell by binding to foreign antigens. The Fc region of these antibodies is targeted by leukocytes (NK cells). Degranulation occurs due to the cytotoxins released and results in the lysis of the pathogen
Antibody dependent

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29
Q

PD of monoclonal antibodies

A

Receptor blockage (can block a receptor like IL6 directly)
Ligand blockage (VEGF antibody prevents receptor activation by ligand)
Inhibition of signal induction
Depletion
Receptor downregulation
Direct binding/delivery- Targeted drug therapy, prodrug activated at site where enzyme is targeted

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30
Q

Antibodies are immune system related proteins called

A

immunoglobulins

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31
Q

Antibodies are comprised of

A

4 polypeptides- 2 heavy chains and 2 light chains to form a Y shape

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32
Q

Explain the variable region

A

The variable region includes the ends of the light and heavy chains and is composed of 110-130 amino acids. It gives the antibody its specificity for binding antigen

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33
Q

What does treating an antibody with a protease do?

A

Cleave the variable region, producing Fab (fragmented antigen binding) that includes the variable ends of an antibody

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34
Q

What does the constant region of the antigen do?

A

Determines the mechanism used to destroy the antigen

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35
Q

What are the 5 classes of antibodies?

A

IgM, IgG, IgA, IgD, IgE

Divided based on their constant region structure and immune function

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36
Q

Key experiments revealing antibody structure

A

Proteolytic treatment of immunoglobulin with enzymes papain and pepsin
Chemical treatment of immunoglobulin with mercaptoethanol

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37
Q

Papain

A

A proteolytic enzyme that cleaves proteins
Splits antibodies into 3 fragments and 2 are identical.
Each identical fragment consists of light and heavy chain and have antigen binding capacity. These are called the Fab (fragments of antigen binding) sites. The third fragment consists of constant regions of heavy chains and crystallize during cold storage (Fc). Plays role in opsonization and complement fixation

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38
Q

Mercaptoethanol

A

Reducing agent that breaks disulphide bonds. Leads to the formation of 2 53 kDa chains and two 22kDa chains
The larger molecules are H (heavy chains) and the smaller are l (light chains)

39
Q

Pepsin

A

A proteolytic enzyme
Cleaves at the disulfide bonds that link heavy chains
2 antibody arms remain linked, called F(ab’)2
Same antigen binding capacity
Other part is cleaved into smaller fragments

40
Q

Polyclonal vs monoclonal antibodies

A

Polyclonal antibodies are antibodies that are secreted by different B cell lineages within the body and monoclonal antibodies are antibodies that come from a single cell lineage

41
Q

How do you collect antibodies from rabbits?

A
  1. ) Inject antigen into rabbit
  2. ) Antigen activates B cells
  3. ) Plasma B cells produce polyclonal antibodies
  4. ) Obtain antiserum from rabbit containing polyclonal antibodies
42
Q

How to make mABs

A

Inject antigen into mouse
Take spleen cells from mouse and mix them with myeloma cells from cell culture.
Select and grow the hybrid cells and allow them to proliferate into clones (hybridomas). The chosen hybridoma is then grown to produce large batches of desired mAB

43
Q

T/F Generating humanized mAbs has nothing to do with human cells

A

True

44
Q

Fully human monoclonal antibody steps

A

1.) Mouse injected with human therapeutic agent
2.) Target-specific antibody DNA extracted
3.) Antibody genes clones, and mAb expressed from CHO (chinese hamster ovary) cells
Human recombinant antibody made

45
Q

Humanized monoclonal antibody steps

A

1.) Mouse injected with human therapeutic target
2.) Target- specific antibody DNA extracted
3.) CDR engineered for high affinity and grafted into human framework, clones, and mAb expressed from CHO (chinese hamster ovary) cells
Humanized recombinant antibody made

46
Q

Oral bioavailability of mAbs

A

They do not have an appreciable oral bioavailability due to their large size, limited membrane permeability, and limited stability toward gastrointestinal protease activity
This is why IV infusion is most common, followed by SC and IM injections

47
Q

SubQ absorption of mAbs

A

Involves an absorption process from the site of injection that relies significantly on the convective transport of the mAb through the interstitial space in to the lymphatic system, draining into the systemic circulation.
Because the flow of the lymph fluid in the lymphatic vessels is very slow compared to the blood flow in the capillary vessels, the resulting absorption process of mAbs into the systemic circulation after

48
Q

mAbs distribtion

A

No passive diffusion due to large size
Main mechanism is through convective transport
After extravasation, antibody distribution through the interstitial space relies upon diffusion, convection, and affinity to target antigens within the interstitial space or on cell surfaces in the tissues

49
Q

Convective Transport

A

Convection is determined by the flux of fluid from the vascular space to the tissue, which is driven by the blood tissue hydrostatic gradient, as well as by the sleving effect of the paracellular pores.

50
Q

Elimination mechanisms of therapeutic monoclonal antibodies

A

Clearance by reticuloendothelial system (linear, non specific)
Clearance via target mediated disposition (non-linear, saturable)
Total clearance: Res-target

51
Q

What factors relate to rate of antibody elimination

A 
mAb structure, affinity, engineering
Antigen distribution (soluble versus membrane associated)
Antigen concentration, expression, turnover rate
Host factors (blood flow, concurrent medications)
Tissue heterogeneity, structure, porosity

Due to very large size (150kDa) very little intact antibody or antibody target complex is filtered by the kidney.

52
Q

Elimination/clearance of mAbs

A

Primarily eliminated by catabolism
Rarely eliminated through the kidneys
Biliary excretion accounts for very small amount of elimination of IgG antibodies

53
Q

IgG elimination

A

Occurs mostly through intracellular catabolism by lysosomal degradation to amino acids after uptake by either pinocytosis (an unspecified fluid phase endocytosis) or by receptor-mediated endocytosis process

54
Q

The neonatal Fc receptor mediated recycling of antibodies

A

Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (neonatal Fc receptors) which explains their long elimination half life ( up to 4 weeks)
Mainly applies to IgG antibodies

55
Q

Murine antibody

Monoclonal antibodies

A

0% human (no human Fc region)

omab

56
Q

Chimeric antibody

A

65% human
Fc region substituted from human antibody
-ximab

57
Q

Humanized antibody

A

> 90% human
Protein sequence of Fc region is identical to that of a human variant)
-zumab

58
Q

Human antibody

A

100% human

-umab

59
Q

Antibody drug conjugates

A

Have a drug conjugated with the Fc region of the antibody

Name of the antibody followed by name of the drug

60
Q

Fragments of an antibody are used when:

A

You want to decrease PD parameters
It is used in drugs that have a narrow therapeutic index like Digoxin. Digifab binds to digoxin in a short amount of time to clear it from the body.
The penetration of the fragment is larger, there is a shorter half life, and it is cleared by the kidneys.

61
Q

PK of pembrolizumab

A

IV administered, immediately bioavailable without protein binding
Small Vd at steady state
Undergoes catabolism to form small peptides and single AA
Does not rely on metabolism for clearance
Clearance increases with increasing BW (0.2L/day)
Half life is 27 days
Dosing q 3 weeks, steady state reached by 19 weeks

62
Q

Anti- PDL1

A

Stop PD1 from switching off cytotoxic T cells

63
Q

Anti-CDLA4

A

Drives dentritic cells to have anti tumor responses

64
Q

PDL1 and CDLA4 blockade can have benefit when given together T/F

A

True

65
Q

CRISPR/Cas9

A

enables geneticists and medical researchers to edit parts of the genome by removing, adding or altering sections of the DNA sequence.

66
Q

________ medicine is what a great physician practices

A

Personalized

67
Q

Precision medicine states

A

A disease can be precisely understood, diagnosed, and treated at an individual bases

68
Q

Personalized medicine practices _________

A

Precision medicine

69
Q

Predictive medicine

A

To predict the probability if an individual will develop a particular disease

70
Q

Preventative medicine

A

To prevent a disease from happening

71
Q

Therapeutic medicine

A

To treat a disease, typically by pharmacotherapy

72
Q

What is the essence of precision medicine?

A

Integrate molecular information into practice, including preventative and therapeutic

73
Q

Why are we ready for precision medicine?

A 
Informatics computer institute malolos
NGS
Big data summit
Liquid biopsy
Microbiota
Metabolomics society
74
Q

Where do we get the most money for precision medicine?

A 
Obamas precision medicine- 215 mill
National research cohort- 130mill
National cancer institute- 70 mill
Food and drug administration- 10 mill
ONC-HIT- 5 mill
75
Q

NIH blueprint

A

Individuals risk for developing disease
Individuals response to common medications
Biological signals known as biomarkers
Genome: Genotyping
Environment: Lifestyle, chemical exposure, electronic device and others

76
Q

China plans

A

China has announced plans to initiate research and development into the technology of precision medicine

77
Q

Basic promises of precision medicine for an individual

A

The risk for developing a particular disease can be predicted, and thus minimized
A particular disease can be treated based on his/her integrated molecular information

78
Q

Oseltamivir example

A

Tamiflu gets metabolized by CES1 (hydrolysis) into carboxylate which is toxic. Carboxylate needs to get metabolized by MRP4 for excretion
If a patient does not have CES1, metabolism will not happen and if they do not have MRP4, the drug will be toxic.

79
Q

Aspirin/clopidogrel hyporesponsiveness example

A

Hydrolysis of aspirin by CES2 leads to deactivation into salicylate.
Aspirin resistance: Increased hydrolysis and COX variation/expression
Clopidogrel is hydrolyzed into active the inactive metabolite by CES1 and oxidized into active metabolite (prodrug) by CYP enzymes
Clopidogrel resistance- decreased oxidation, increased hydrolysis, P2Y12 mutations
hyporesponders- increased hydrolysis, large CYP inhibition
Hyperresponders- decreased hydrolysis, little CYP inhibition

80
Q

Essential premise for pharmacotherapy

A

Majority of medicines work but the efficacy and/or toxicity very depending on a dose and patient
Medicines that do not work for a patient are largely related to genetic incompatibility
Example- CES1 mutation causes impairment for oseltamivir.

81
Q

Secondary premise for pharmacotherapy

A

The optimum therapeutic efficacy for a patient can be achieved by adjusting dosage regimens
Dose adjustments is individual-based and referred to as personalized dosing

82
Q

Dose vs Dosage

A

Dose- a specified amount of medication at one time

Dosage- a composite term including the amount, the period of time, and the frequency

83
Q

Goal of personalized dosage

A

To optimize a dosage that maximizes the efficacy and minimizes toxicity

84
Q

Starting dose for personalized dosing

A

Standard dose

Alter based on PK/PD factors

85
Q

PBPK modeling

A

Physiological system- age, sex, blood flow, organ volumes, enzyme and transporter expression, plasma protein concentrations, genetics
Drug- clearances, distribution, solubility, tissue partitioning, protein binding affinity, and membrane permeability

86
Q 
PKPD parameters
Mathematical modeling
Drug concentrations
Therapeutic efficacy
Clinical relevance
Level of difficulty
A 
Mathematical modeling-yes
Drug concentrations-yes
Therapeutic efficacy- yea
Clinical relevance- more
Level of difficulty - more
87
Q 
PBPK parameters
Mathematical modeling
Drug concentrations
Therapeutic efficacy
Clinical relevance
Level of difficulty
A 
Mathematical modeling- Yes 
Drug concentrations- Yes
Therapeutic efficacy- No
Clinical relevance- Less
Level of difficulty -Less
88
Q

COVID-19 vaccine

A

Sinovac Biotech- inactivated SARS-CoV-2
Sanofi- SARS-CoV-2 protein
AstraZeneca- Adenoviruses vector
Pfizer and Moderna- DNA/RNA

89
Q

What is the measure of systemic exposure?

A

AUC- how much drug is absorbed and what happens to the drug

90
Q

T/F Absorption rate constant is typically greater than K10

A

True

Shorter Tmax= absorbed faster= higher Ka

91
Q

What would the typical volume of distribution be for most small molecules?

A

Greater than 60L

92
Q

What does half life impact?

A

Frequency of drug administration, extent of drug accumulation, wash out between study periods

93
Q

What is the primary cause of low/poor oral bioavailability of biologics?

A

1st pass metabolism

Drug Delivery (2 decks)

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