Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Biotherapeutics species selectivity and target

A

High species selectivity (affinity/potency)

Multifunctional- target binding, Fc effector function, FcRn binding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Biotherapeutics PK and PD

A

Target can affect PK behavior, mostly has linear PK

PD related immunogenicity sometimes observed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

New chemical entity PK and PD

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Chemical structure of biotherapeutics affects on PK

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

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

A

Affects distribution and clearance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Immunogenicity of biotherapeutics affects on PK

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

When B cells recognize antigens they differentiate into

A

Plasma cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Plasma cells produce and secrete________ which bind to _________

A

antibodies, specific antigen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

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

A

Neutralization, opsonization, complement activation, ADCC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Basic antibody structure

A

Y shaped molecule having 2 antigen binding sites

The stalk is known as the Fc region

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
How are neutralized microbes eliminated from the body?
Phagocytosis
26
Opsonization
Enhances phagocytosis. Antibodies coat antigen and recognized by phagocytes. The phagocytes bind to the antibody covered microbe by binding to the Fc region
27
Complement activation
Cytolysis, inflammation, or opsonization occurs after activation of the classical pathway.
28
Antibody-dependent cell-mediated cytotoxicity (ADCC)
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
29
PD of monoclonal antibodies
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
30
Antibodies are immune system related proteins called
immunoglobulins
31
Antibodies are comprised of
4 polypeptides- 2 heavy chains and 2 light chains to form a Y shape
32
Explain the variable region
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
33
What does treating an antibody with a protease do?
Cleave the variable region, producing Fab (fragmented antigen binding) that includes the variable ends of an antibody
34
What does the constant region of the antigen do?
Determines the mechanism used to destroy the antigen
35
What are the 5 classes of antibodies?
IgM, IgG, IgA, IgD, IgE | Divided based on their constant region structure and immune function
36
Key experiments revealing antibody structure
Proteolytic treatment of immunoglobulin with enzymes papain and pepsin Chemical treatment of immunoglobulin with mercaptoethanol
37
Papain
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
38
Mercaptoethanol
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
Pepsin
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
Polyclonal vs monoclonal antibodies
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
How do you collect antibodies from rabbits?
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
How to make mABs
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
T/F Generating humanized mAbs has nothing to do with human cells
True
44
Fully human monoclonal antibody steps
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
Humanized monoclonal antibody steps
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
Oral bioavailability of mAbs
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
SubQ absorption of mAbs
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
mAbs distribtion
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
Convective Transport
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
Elimination mechanisms of therapeutic monoclonal antibodies
Clearance by reticuloendothelial system (linear, non specific) Clearance via target mediated disposition (non-linear, saturable) Total clearance: Res-target
51
What factors relate to rate of antibody elimination
``` 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
Elimination/clearance of mAbs
Primarily eliminated by catabolism Rarely eliminated through the kidneys Biliary excretion accounts for very small amount of elimination of IgG antibodies
53
IgG elimination
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
The neonatal Fc receptor mediated recycling of antibodies
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
Murine antibody | Monoclonal antibodies
0% human (no human Fc region) | omab
56
Chimeric antibody
65% human Fc region substituted from human antibody -ximab
57
Humanized antibody
>90% human Protein sequence of Fc region is identical to that of a human variant) -zumab
58
Human antibody
100% human | -umab
59
Antibody drug conjugates
Have a drug conjugated with the Fc region of the antibody | Name of the antibody followed by name of the drug
60
Fragments of an antibody are used when:
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
PK of pembrolizumab
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
Anti- PDL1
Stop PD1 from switching off cytotoxic T cells
63
Anti-CDLA4
Drives dentritic cells to have anti tumor responses
64
PDL1 and CDLA4 blockade can have benefit when given together T/F
True
65
CRISPR/Cas9
enables geneticists and medical researchers to edit parts of the genome by removing, adding or altering sections of the DNA sequence.
66
________ medicine is what a great physician practices
Personalized
67
Precision medicine states
A disease can be precisely understood, diagnosed, and treated at an individual bases
68
Personalized medicine practices _________
Precision medicine
69
Predictive medicine
To predict the probability if an individual will develop a particular disease
70
Preventative medicine
To prevent a disease from happening
71
Therapeutic medicine
To treat a disease, typically by pharmacotherapy
72
What is the essence of precision medicine?
Integrate molecular information into practice, including preventative and therapeutic
73
Why are we ready for precision medicine?
``` Informatics computer institute malolos NGS Big data summit Liquid biopsy Microbiota Metabolomics society ```
74
Where do we get the most money for precision medicine?
``` 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
NIH blueprint
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
China plans
China has announced plans to initiate research and development into the technology of precision medicine
77
Basic promises of precision medicine for an individual
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
Oseltamivir example
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
Aspirin/clopidogrel hyporesponsiveness example
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
Essential premise for pharmacotherapy
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
Secondary premise for pharmacotherapy
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
Dose vs Dosage
Dose- a specified amount of medication at one time | Dosage- a composite term including the amount, the period of time, and the frequency
83
Goal of personalized dosage
To optimize a dosage that maximizes the efficacy and minimizes toxicity
84
Starting dose for personalized dosing
Standard dose | Alter based on PK/PD factors
85
PBPK modeling
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
``` PKPD parameters Mathematical modeling Drug concentrations Therapeutic efficacy Clinical relevance Level of difficulty ```
``` Mathematical modeling-yes Drug concentrations-yes Therapeutic efficacy- yea Clinical relevance- more Level of difficulty - more ```
87
``` PBPK parameters Mathematical modeling Drug concentrations Therapeutic efficacy Clinical relevance Level of difficulty ```
``` Mathematical modeling- Yes Drug concentrations- Yes Therapeutic efficacy- No Clinical relevance- Less Level of difficulty -Less ```
88
COVID-19 vaccine
Sinovac Biotech- inactivated SARS-CoV-2 Sanofi- SARS-CoV-2 protein AstraZeneca- Adenoviruses vector Pfizer and Moderna- DNA/RNA
89
What is the measure of systemic exposure?
AUC- how much drug is absorbed and what happens to the drug
90
T/F Absorption rate constant is typically greater than K10
True | Shorter Tmax= absorbed faster= higher Ka
91
What would the typical volume of distribution be for most small molecules?
Greater than 60L
92
What does half life impact?
Frequency of drug administration, extent of drug accumulation, wash out between study periods
93
What is the primary cause of low/poor oral bioavailability of biologics?
1st pass metabolism

Drug Delivery (2 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions