Combined 514 Final Exam
new drugs are typically tested on:
"normal" cells • Cells engineered in the lab to mimic disease • Small animal models created to mimic aspects of human disease
Testing potency is testing the
"relevant biological function"
Afrezza
(insulin human) inhalation powder
Diffusion systems
- Drug release mechanism involves primarily diffusion (with some dissolution) - Usual method employed = microencapsulation - Release can be modified with Fick's first law21
Expandable systems disadvantages
- Failure in unfolding of arms. -Premature degradation of polymers during storage
Benefits of PEG
- Improves drug solubility - Enhanced protection from proteolytic degradation - Increased circulation time with IV injection - Can reduce uptake by macrophages (non-proteins)
Why formulate drugs into liposomes/nanoparticles?
- Increase solubility of poorly soluble drugs - Increase the circulation half-life of drugs (decreased frequency of injections, enhanced patient compliance) - Decreases overall toxicity of drugs - Enhances delivery to disease sites, such as tumors due to EPR effect
Benefits of extended-release
- Increases efficacy by maintaining a constant plasma drug level in the therapeutic window range for an extended period of time - Reduces dosing frequency - Eliminates drug accumulation in the body - Minimizes toxicity of the drug - Can increase patient compliance - Can reduce cost of patient treatment
What factors affect phase transition temperature of lipids?
- Length of acyl chain in the lipid - The degree of saturation of the hydrocarbon chains in lipid - The type of polar head group
Drawbacks of PEG
- Non-degradable (must be MW < 5000 to clear kidneys) - Can have toxicity concerns related to accumulation and long circulation times - Can result in strong anti-PEG responses (when attached to tetrameric proteins) - Used ubiquitously in commercial products - Anti-PEG antibodies - Hypersensitivies
Characteristics of PEG
- Not biodegradable - Very hydrophilic - Highly miscible in most solvents and water - Low toxicity
Drug release mechanisms of hydrogels
- Passive diffusion from the hydrogel - Diffusion due to external stimulus - Release due to degradation of the hydrogel
Drawbacks of extended-release:
- Poor formulations can lead to dose dumping - The drug often cannot be removed from the system
Dissolution systems
- Release rate controlled by dissolution - Decrease the dissolution rate by coating or mixing with slowly dissolving polymer - Drug release rate is controlled by varying thickness and release rate of the polymer
How can endotoxin be minimized in compounded preparations?
- Remember where they originate: dead bacterial cell walls - Use endotoxin-free glassware and implements in your compounding - Use sterile water that has been tested to have less than 0.25 endotoxin units/mL - Use drugs and excipients from a reputable source
Characteristics of Nanocrystal technology
- Small particles coated with surfactant - High surface area - Can be given orally or by injection
Characteristics of Nanocrystal technology
- Small particles coated with surfactant - High surface area - Can be given orally or by injection
mAbs are a:
- a versatile platform to treat many diseases
Gastroretentive dosage forms with controlled drug release are important for drugs which are:
-Acting locally in the stomach -Absorbed incompletely due to a narrow window of absorption in the GIT -Unstable in the intestinal or colonic environment -Exhibit low solubility at high pH values
-At site of action, the drug concentration is roughly the _____ as ______ in unaffected tissue, which can lead to _____
-At site of action, the drug concentration is roughly the same as elsewhere in unaffected tissue, which can lead to toxicity concerns
Vascular barriers/challenges to systemic delivery
-Blood constituents oSerum proteins oBlood cells -Blood flow oAccess to diseased organs/tissues/cells
Nucleic acid modes of therapy
-DNA- or mRNA mediated gene therapy: Introduction of a gene of interest -Gene editing - CRISPR -Antisense therapy or RNA interference therapy: sequence is complementary to mRNA of interest
Which of the components in Onpratto® can induce an immune response?
-Double stranded RNA -Cationic/ionizable lipid DLin-MC3-DMA -PEG (in a small population)
what are some Drawbacks of some polymeric therapies?
-Expensive -Difficult to administer -Added toxicity issues
503B exemptions:
-FDA approval requirements prior to marketing -labeling products with adequate directions for use
What are some examples of targeted Oral Drug Delivery?
-Gastro-retentive Devices -Enteric Coating -Colon Targeting Devices
why do we formulate drugs into liposomes/nanoparticles?
-Increase solubility of poorly soluble drugs -Increase the circulation of half-life of drugs -decrease overall toxicity of drugs -Enhance delivery to disease sites, such as tumors due to EPR effect
Parts on an Antibody
-Large Y-shaped protein -immunoglobin family -Produced by B-cells of the body -Each tip contains a region that specifically binds ligands in a "lock & key" configuration
Microbial targeted drug delivery to colon
-Once the tablet arrives in the colon, the bacteria enzymatically degrade the lactulose into organic acid. -This lowers the pH of the area surrounding the system -Acid coating dissolves -Drug is released
Insulin protein was originally isolated from animals and resulted in
-Rash, anaphylaxis, weight gain, hypoglycemia •Serious problems arose with blood contaminants -AIDS contamination in Factor VIII preparations •Presence of residual animal proteins induced serious side effects in patients
How can endotoxins be minimized in compounded preparations?
-Remember where they originate: from dead bacterial cell walls. • Use endotoxin-free glassware and implements in your compounding • Use sterile water that has been tested to have less than 0.25 Endotoxin Units/mL • Use drugs and excipients from a reputable source
Why use colon targeted delivery?
-Site specific delivery: -Local treatment of inflammatory bowel diseases -Suitable for drugs that are susceptible to degradation by the upper GI-tract -Preventing gastric irritation (orally administered NSAIDS) -Lower enzymatic activity compared to upper GI-tract
Requirements of expandable systems
-System should be biodegradable to avoid permanent retention in the stomach. -System should be sufficiently stable to withstand mechanical contractions in the stomach.
High Density Drug Delivery Systems
-Weight is used as a retention mechanism. Density of the system > gastric juice
-Density can be increased by incorporating heavy inert material into the system like:
-Zinc oxide -Titanium oxide -Iron powder -Barium sulphate
Drug release in osmotic controlled drug delivery system
-a function of osmotic pressure —is independent of GI environment -dictated by properties of semipermeable membrane and the osmotic agent
Intracellular barriers in nucleic acid delivery (cellular entry and intracellular trafficking)
-cellular entry -endosomal trapping -endocytic recycling -lysosomal degradation -crossing the nuclear membrane
Extracellular barriers in nucleic acid delivery (administration and circulation)
-clearance by liver or kidney -phagocytic uptake -immune recognition -aggregation w/ serum proteins -degradation by endonucleases
Factors that affect pMDIs and Liquid Aerosol Formulation
-drug solubility (solutions, stable suspension) -vapor pressure (droplet size, velocity--> deposition -surface tension -Hygroscopicity -density
An outsourcing facility is
-engaged in compounding sterile drugs -has elected to register as an outsourcing facility -complies with all sections of 503B
Cremophor and ETOH Induce Serious Problems like
-hypersensitivity reactions from formulation (not drug) •Leads to axonal degeneration and demyelination-Results in peripheral neuropathy
Murine suffix
-momab
Extracellular barriers in nucleic acid delivery (distribution and diffusion)
-obstruction by a dense network of extracellular matrix proteins -phagocytic uptake
Luxturna
-one-time gene therapy for individuals with an inherited retinal disease (slows vision loss) -uses the adeno-associated viral vector serotype 2 (AAV2) to carry a functional copy of the RPE65 gene into the retinal pigment epithelial (RPE) cells to compensate for the RPE65 mutation
Membrane controlled systems-reservoir device
-rate controlling membrane has constant thickness -drug diffuses out from the core through the membrane according to Fick's law -follows zero order kinetics
Safety in cell therapy
-safety testing is key Must be manufactured entirely under aseptic conditions •However, often have short half-lives which means they are administered to patients before all current sterility results are available
Activatable systems: Osmotic controlled drug delivery systems
-semipermeable membrane that surrounds core tablet -core tablet contains drug and osmotic agent -membrane only allows water to enter tablet -influx of water helps dissolve/suspend the drug -presence of osmotic agent in the core creates osmotic pressure
Nanoparticle crystals for drug delivery:
-small particles coated w/ surfactant -high surface area -oral or injection
Drug release in osmotic controlled drug delivery systems can be altered by changing:
-the surface area of the tablet -thickness or composition of the membrane -size of the orifice
Fully human suffix
-umab
Chimeric suffix
-ximab
Humanized suffix
-zumab
Hypotonic osmolarity
0-249 mOsmol/L
half life equation
0.693/lambda
What is the size of a small particle drug?
1 nanometer
Nano
1 to 100 nm
Stomach pH/surface area
1-3, 3.5
Development of Antibody Therapies
1. Immunize mouse with antigen 2. B cells produce antibodies 3. Isolate splenic B-cells and fuse them with tumor cells to immortalize B-cells (hybridoma) 4. generation of large amounts of antibodies
What are 3 modified release dosage forms?
1. Membrane controlled systems (reservoir) 2. Activatable systems 3. Matrix-based systems
Delivery vehicle/vector
1. Non-viral vectors: with toll-like receptors and induce an immune response 2. Viral vectors like the adeno-associated virus (AAV) have immunogenicity issues
Phase transition temperature of lipids-examples
1. The length of the acyl chain in the lipid 2. degree of saturation of hydrocarbon chains in lipid 3. type of polar head group
Kymriah Manufacturing process
1. extract cells from a patient 2. modifications to make cells therapeutic 3. expand modified cells to reach a clinical dose 4. deliver back into same patient for personalized cell therapy
CAR T-cell therapy
1. isolate T cells 2.engineer with CAR 3. re-infuse back into patient
Toxic Effects of Oligonucleotides
1.Liver and kidney toxicity -clearance mainly by kidney and live 2.Injection site reactions 3.Immune and interferon-like responses -Interactions with toll-like receptors 4.Off target effects -non-specific binding to other targets
How many times do we blink a minute?
10-20 x per min
How many patient volunteers in phase 2?
100-300
The mean time from synthesis of a new compound to marketing approval in the United States is ______ years
14.2 years.
What is the maximum volume of a subcutaneous injection?
2 mL
Potency is not assessed until phase _____ and validated in phase ____
2, 3
Gravitational sedimentation occurs with drugs between __ to __ microns
2-5
Injection volume for IM
2-5 mL, but it depends on the site Max adult deltoid injection = 2 mL Max adult injection for other sites = 5 mL *different for children
How many people have to be affected nationwide to be an orphan disease?
200,000 or less
Which of the following is a not therapeutic radionuclide? 223Ra 211At 201Tl
201Tl
Slightly hypotonic osmolarity
250-269 mOsmol/L
Isotonic osmolarity
270-328 mOsmol/L
How many types of glass in parenteral products?
3 They have potential drug-solution interactions with glass surfaces
What is the max number of >0.5 um particles in ISO 8?
3,520,000
Citric acid/citrate pka
3.1, 4.8, 6.4
A minimum of _____ days must pass between the time an IND is submitted and a Phase 1 study can begin
30
How long after submitting an IND do you have to wait before beginning a clinical trial?
30 days
The blinking eye can accommodate a volume of up to:
30 microliters
Slightly hypertonic osmolarity
329-350 mOsmol/L
What is the max number of >0.5 um particles in ISO 7?
352,000
What is the max number of >0.5 um particles in ISO 5?
3520
What is a hydrogel?
3D, mostly hydrophilic polymeric network that can absorb up to thousands of times its weight in water of biological fluid
Acetic acid/acetate pKa
4.8
How many types of injectable products are there?
5
duodenum pH/surface area
5-7, 2
What is the pH of the nasal mucus?
5.5-6.5
For every 5,000 compounds discovered, how many will advance through the clinical trial phases and how many will ultimately be approved by the FDA?
5/1
For every 5000 compounds discovered, how many will advance through the clinical trial phases and how many will ultimately be approved by the FDA?
5/1
Compliance with cGMP
501(a)(2)(B)
Labeling with adequate directions for use
502(f)(1)
ileum pH/surface area
6-8, 280
Sodium bicarbonate pKa
6.3, 10.3
jejunum pH/surface area
6.5, 180
Intertial impact ion of drugs larger than __ microns will not get past the trachea
60
colon pH/surface area
7-8, 1.3
Phosphoric acid/phosphate pKa
7.2
Glutamic acid/glutamate pKa
9.7
Hypertonic osmolarity
>350 mOsmol/L
How efficient is a HEPA filter?
>99.97% efficient in removing particles as small as 0.3 microns
The purification process of antibodies involves Protein ___
A
Relationship between radioactivity and time
A = Ao e^ (lamba x t)
Recombinant DNA
A DNA molecule made in vitro with segments from different sources.
What is a passive DPI?
A breath-powered device used to deliver solid aerosols
What is a passive dry powder inhaler?
A breath-powered device used to deliver solid aerosols
Primary engineering controls (PECs)
A device or room that provides an ISO 5 environment for compounding CSPs
What is a PEC?
A device or room that provides an ISO Class 5 environment for compounding Compounded Sterile Preparations (CSPs)
Targeted-release
A dosage form that releases drug at or near the intended physiologic site of action
alpha particle
A helium nucleus produced in radioactive decay Therapeutic
when low levels of a highly potent drug are needed at site of action
A little of a highly potent drug at site of action means a little of a highly potent drug off-site
When high levels of drugs are needed to be transported to site of action...
A lot of drug at site of action means a lot of drug off-site
What is an orphan drug?
A pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease
Valve holding chamber:
A spacer with a one-way valve to contain the aerosol until inhaled and direct exhalation away from the aerosol in the chamber
The ideal concentration for liquid protein formulations to prevent absorption is a "medium" concentration of: A. 1-10 mg/ml B. 20-50 mg/ml C. 50-100 mg/ml D. 100-200 mg/ml
A. 1-10 mg/ml
What is a dry powder inhaler? A. A device used to aerosolize and deliver a solid drug product B. A device used to aerosolize and deliver a pharmaceutical suspension C. A device used to aerosolize and deliver a pharmaceutical solution
A. A device used to aerosolize and deliver a solid drug product
Which of the following is correct: A. Biologics are complex molecules produced using biological systems. B. A biosimilar has identical clinical properties to the original biologic. C. A biosimilar has identical physicochemical properties to the original biologic. D. Biologics can include chemically synthesized small molecules
A. Biologics are complex molecules produced using biological systems.
Which of the following is a mechanism used to accelerate a new drug application? A. Breakthrough Therapy B. Fast Pass C. Priority Mail
A. Breakthrough Therapy
Protein drugs are comprised of: A. Chains of amino acids B. Cells of the immune system C. DNA and RNA D. Chemically linked small molecule compounds
A. Chains of amino acids
Which is NOT a use of stem cells for therapy? A. Cloning B. Regenerative medicine C. Patient-specific drug screening D. Organ development for transplant
A. Cloning
Which type of stem cell CANNOT be generated in a patient-specific manner? A. Embryonic stem cell B. Induced pluripotent stem cell C. Adult/Somatic stem cell
A. Embryonic stem cell
Which is NOT a consequence of reduced stability of protein therapies? A. Increased therapeutic efficacy B. Decreased therapeutic efficacy C. Altered function D. Altered biodistribution
A. Increased therapeutic efficacy
Cell- and virus-based delivery systems improve protein therapies by: A. Providing sustained production of therapeutic proteins in the body B. Reducing protein aggregation C. Improving stabilization D. Reducing protein fragmentation
A. Providing sustained production of therapeutic proteins in the body
Which of the following is the primary advantage of local pulmonary drug delivery compared to oral drug delivery? A. Reduces systemic drug exposure B. Rapid absorption into systemic circulation C. Increases bioavailability by avoiding first-pass metabolism
A. Reduces systemic drug exposure
What is the biggest limitation of using iPS cells for transplant therapy? A. Safety, as iPS cells can form tumors when implanted in vivo B. They can be generated in a patient-specific manner C. Their generation does not require destruction of an embryo
A. Safety, as iPS cells can form tumors when implanted in vivo
When a company files an ANDA for a generic product, it must have: A. The same route of administration as the "brand name" drug B. The same coloring agents as the "brand name" drug C. Evidence of a separate patent
A. The same route of administration as the "brand name" drug
What is a disadvantage of adult stem cells over embryonic stem cells? A. They are restricted in their differentiation potential. B. They require destruction of an embryo. C. They grow too fast.
A. They are restricted in their differentiation potential.
Why are viscosifying agents added to intranasal dosage forms? A. To increase the drug residence time at the site of absorption B. To increase the permeability of the nasal epithelium C. To ensure sterility of multidose dosage forms
A. To increase the drug residence time at the site of absorption
What is the "dead volume" in a nebulizer? A. volume of residual drug solution that could not be nebulized during administration B. volume of drug solution that is collected on the baffle during administration C. minimum volume of drug solution required to prevent drug-induced cytotoxicity of the respiratory epithelium D. minimum volume of drug solution required to kill bacteria in the respiratory tract
A. volume of residual drug solution that could not be nebulized during administration
Which of the components in Luxturna® can induce an immune response?
AAV
What must drug companies submit for approval to market a generic product?
ANDA
Hatch-Waxman Act involved submission of:
ANDAs
The Hatch-Waxman Act involved submission of...
ANDAs (Abbreviated new drug applications). -regulates generic drugs
Albumin-bound Paclitaxel is called
Abraxane
Sterility
Absence of viable microorganisms
More rapid approval of a drug for which therapy provides meaningful advantage over available therapies and surrogate endpoint is likely to predict clinical benefit?
Accelerated approval
GIVLAARI treats
Acute hepatic porphyria (AHP)
Modified release dosage forms help patients:
Adhere to therapy by reducing dosing frequency
Umbilical cord as stem cell source
Advantages - Large number of stem cells - Less imunogeneic - Decreased risk of GVHD Disadvantages - Weight limit (recipient must be <60 kg) - Delayed engraftment - Engraftment failure
advantages and disadvantages of "naked" nucleic acids" (non-viral vectors)
Advantages: have no viral genes, so don't cause diseases Disadvantages: insufficient at nucleic acid/ gene transfer, unstable in the body (needs chemical modifications)
advantages and disadvantages of adeno-associated vircus
Advantages: integrate genes into host chromosomes, cause no known human disease Disadvantages: small capacity foreign genes
Small-volume nebulizers:
Aerosol devices that convert liquid drug solutions or suspensions into aerosol and is powered by compressed air, oxygen, a compressor, or electricity
Abraxane is a nanoparticle formulation that contains:
Albumin nanoparticles with paclitaxel adsorbed to the protein surface
What is the optimal site of drug absorption for systemic delivery via the pulmonary route?
Alveoli
Fate of 1-micron drug
Alveoli or breathed out (<2)
Actual gas exchange happens in a structure known as an _________
Alveolus (alveolar-capillary membrane)
Delivery to anterior eye
Anterior Eye: Blood-aqueous barrier • Endothelium of iris/ciliary blood vessels and ciliary epithelium • Intercellular permeation restricted by tight junction complexes
What is an Antibody Therapy?
Antibodies can be created to target virtually any extracellular target on the surface of cells
Asorbic acid, sodium metabisulfite, and alpha tocopherol are common...
Antioxidants
Are immune therapies (vaccines) systemic or local?
Applied locally, but activate cells throughout the entire body
The term "nano" describes materials with dimensions of:
Approximately 1 to 100 nanometers
Onset of action for IM
Aq and emulsion: 15-30 mins Suspensions: 2-4 hrs Oily solutions: 1-2 days
Onset of action for subcutaneous
Aq: 15-60 mins Suspensions and implants: 1-4 hrs
Onset of action for IV
Aq=immediant Emulsions = 10-20 mins
Phase II Clinical Trials
Assess a drug's effectiveness in treating a particular disease or medical condition Usually evaluate more than 1 dose (dose-ranging) Establish safety profile with longer-term dosing 100-300 patient volunteers Duration: ~2 years End of phase II meeting: must consult with FDA before beginning Phase III
What class must areas for CSP preparation be?
At least ISO 5
Extended-Release
At least a twofold reduction in dosage frequency compared to immediate-release formulations
Sterilization method that employs steam at 121 degrees C at 15 psi
Autoclaving
Source of stem cell transplants
Autologous: patient is own source Allogeneic: stem cells from different individual
What is rituximab used to treat?
B-cell-related disorders: non-hodgkins lymphoma, leukemia, auto-immune disorders
What is a metered dose inhaler? A. A device that uses an external energy source to disperse and deliver drug solid solutions and suspensions B. A device that uses a pressurized system to disperse and deliver drug solutions and suspensions C. A device used that uses breath-power to aerosolize and deliver solid solutions and solid suspensions
B. A device that uses a pressurized system to disperse and deliver drug solutions and suspensions
Which statement is true regarding small molecule drugs and protein drugs? A. Protein therapies have more established guidelines for manufacturing and testing than small molecule drugs B. A protein therapy can be generated for every defective gene since the human genome has been sequenced C. Protein therapies are more stable than small molecule drugs D. Small molecule drugs exist for every therapeutic target
B. A protein therapy can be generated for every defective gene since the human genome has been sequenced
Which is NOT an example of biologics? A. Monoclonal antibodies B. Aspirin C. Adeno-associated viral gene vectors D. Cytokine
B. Aspirin
Which center in the FDA regulates most prescription and over-the-counter drugs? A. CBER B. CDER C. CDRH
B. CDER
_______________ are small "protein factories" that produce therapeutic proteins before they are isolated and lyopholized. A. Chemical reactions B. Cells C. DNA plasmids D. Transfection reagents
B. Cells
TRAIL is a potent anticancer protein. Creation of a TRAIL-based protein therapy begins with isolating the _____________? A. Protein isolation B. DNA cloning and assembly C. Cell culture D. Cancer cells sensitive to TRAIL
B. DNA cloning and assembly
________________ are natural weak spots in proteins where fragmentation commonly occurs. A. N-terminus B. Hinge regions C. C-terminus D. Binding pockets
B. Hinge regions
Inclusion of antioxidants: A. Likely has no impact on disulfide bridge formation B. Reduces formation of disulfide bridges C. Increases formation of disulfide bridges
B. Reduces formation of disulfide bridges
Lyophilization improves protein stability by removing _____________ that is/are the primary culprit of protein destabilization. A. Antioxidants B. Water C. DNA D. Polymers
B. Water
Which of the following is a disadvantage of nebulizers? A. propellant is required for dispersion B. long treatment time compared to inhalers C. depends on patient inspiratory force D. requires coordination of inhalation and actuation
B. long treatment time compared to inhalers
What kind of pyrogenicity tests can be performed?
Bacterial endotoxins test Endotoxin test Rabbit test
An IND must be submitted when?
Before beginning Phase I studies
When does an MDI have to be primed?
Before first use If it hasn't been used in more than 14 days It has been dropped
Phase I clinical trials
Begin 30 days after submission of IND 20-80 healthy subjects Duration: 1-2 years Determine side effects associated with increasing doses Establish PK profile May identify drug interaction issues May gain early evidence of efficacy
In a lyophilization of an aqueous protein solution the shelf temperature during the initial freezing needs to be:
Below the eutectic point
The role of the chelating agent in preparing 99mTc radiopharmaceuticals is to:
Bind 99mTC
Anatomic Sources of Stem Cells
Bone Marrow (BM) • Peripheral Blood Stem Cells (PBSC) • Umbilical Cord (UC)
What is an example of nuclear medicine?
Bone scan with 99mTc-Methylene Diphosphate (MDP)
More rapid approval of a drug for which therapy indicates substantial improvement over available therapies?
Breakthrough therapy
Local therapy meds for pulmonary delivery:
Bronchodilators Corticosteroids Antibiotics and DNAase (an enzyme) for cystic fibrosis Others for various pulmonary conditions
What routes are sometimes systemic?
Buccal, Vaginal, Nasal
What is a primary advantage of pulmonary vs. oral drug delivery for a systemically active drug?
Bypasses first-pass metabolism, Rapid absorption into systemic circulation
When stem cells are re-implanted into the patient from which they were derived, this is an example of? A. Syngeneic transplant B. Embryonic stem cell therapy C. Autologous transplant D. Allogeneic transplant
C. Autologous transplant
Where are drug particles with a diameter between 2 to 5 microns most likely to deposit? A. Oropharynx B. Alveoli C. Bronchioles
C. Bronchioles
One challenge with the formulation of protein therapies is the requirement of a high dose. A challenge with formulating protein therapies at high does is: A. Low viscosity that can limit injection B. Induction of rapid degradation C. High viscosity that can limit injection
C. High viscosity that can limit injection
Which of the following is typically a requirement for therapeutic agents introduced into cell-based drugs: A. Must kill the producer cell B. Must NOT be secreted C. Must be engineered into the genome (ie: a protein or peptide)
C. Must be engineered into the genome (ie: a protein or peptide)
When considering Phase I clinical trials, which of the following is true? A. Phase I studies look solely at efficacy of the new chemical entity. B. The FDA requires Phase I trials to be conducted in non-human primates. C. Some Phase I studies may be completed after Phase II studies.
C. Some Phase I studies may be completed after Phase II studies.
Systemically administered pulmonary drugs are absorbed in which part of the lung? A. trachea B. bronchiole C. alveoli
C. alveoli
What the primary route of transport of peptide drugs across the nasal epithelium? A. paracellular transport B. transcellular transport C. transcytosis
C. transcytosis
What PEC is used with hazardous CSPs?
CACIs
Which FDA Center reviews new gene therapies?
CBER
Which FDA center reviews new gene therapies?
CBER
What two branches of the FDA approve biologics?
CBER and CDER
Gene editing
CRISPR •Correct mutated genes •Introduce new genes or remove existing genes
tomography
CT scans
single dose acute studies
CV: dog or monkey Respiratory: rat CNS neurobehavioral: rat
What is a peripheral venous catheter?
Catheter inserted into peripheral vein Plastic tubing that attaches to connectors for infusion sets or injection ports
What type of chemical is benzalkonium chloride?
Cationic wetting agent
What causes hypersensitivty reactions from antibody treatments?
Caused by pre-existing serum antibodies that cross-react with the murine fragments of cetuximab
What is a peripherally inserted central catheter (PICC)?
Central catheter inserted into a peripheral vein in the arm and threaded into the superior vena cava
What is a Hickmann catheter?
Central catheter inserted surgically by tunneling subcutaneously for 5-10 cm before threading through the subclavian vein to the superior vena cava
Overcoming Eprex Toxicity
Changed formulation and packaging type: reversed toxicity •Placed Teflon-coated stoppers in prefilled syringes •Issued strict storage guidelines that emphasized importance of keeping product at 2-8 °C •Required intravenous administration, not subcutaneous
Safety: How to Characterize Cell Therapies
Characterization strategy •Test multiple parameters over time •Establish a "pattern"; understood there will be variability •Refine production over time May require the development of new assays and new methods tools for characterization
Which of the following statements about chemical modifications of nucleic acids are true?
Chemical modifications are used to enhance the stability of nucleic acids
A newer method to produce antibodies is to use
Chinese Hamster Ovary cells (CHO) • Grow in serum-free media, allow easy scale-up to >5000 liter fermentation • High yield of Ab, up to 10 grams per liter of culture media
What does the Mucociliary escalator consist of?
Ciliated cells and goblet cells in the bronchi
Problems with Producing Biosimilars
Complexity of protein synthesis, generation, and packaging allow generation of biologic products that are similar but not identical to existing products
503A
Compounding pharmacies
The trachea through the terminal bronchioles composes the _______ _______, which is a zone that has no gas exchange
Conducting zone
Phase 3 clincal trials include
Confirm effectiveness in different populations
What is a gravity (drip) administration set?
Connects LVP to patient and controls the flow rate with a clamp and drip chamber
the drug is released from the Carrier at a ___________ rate in osmotic drug release
Constant
_____ region of an antibody mediates immune response
Constant • Different classes of constant region generate different responses • Different isotypes have different properties
Eye drops are packaged almost entirely in plastic dropper bottles
Convenience of use by the patient • Decreased contamination potential • Lower weight; Lower cost
In pMDIs, ethanol functions as a:
Cosolvent
What do companies do to extend the life of patented drugs?
Create new formulations Design a new method of administration Switch chirality Find new indications Combine two or more existing drugs
Why is lactose a good carrier in traditional DPIs?
Crystalline with good flow and low hygroscopicity (use mannitol if lactose allergies are present)
What describes nanocrystals and how they release drug?
Crystals with high surface area are often given IM or SC where drug elutes over time
Which is NOT a use of recombinant DNA technology: A. Creation of human protein therapies B. Creation of unique diagnostic fusion proteins C. Creation of unique therapeutic fusion proteins D. Creation of small molecules to produce therapies
D. Creation of small molecules to produce therapies
Phase IV clinical trials involve: A. At least 2 species of animals B. 20 - 80 healthy volunteers C. In vitro laboratory studies D. Post-marketing surveillance
D. Post-marketing surveillance
When administered via the intranasal route, what is the deposition site for dry powder particles with diameters less than 1 micron? A. trachea B. nasal cavity C. alveoli D. outside of the body due to exhalation
D. outside of the body due to exhalation
Antisense oligonucleotides
DNA, bind to their targeted RNA and use endogenous RNase H1, an enzyme that cleaves the RNA in an RNA/DNA heteroduplex.
What does PEG-anti TNF Fab do?
Decreases dosing
What is a characteristic of a modified release dosage form?
Delivery that is altered from immediate release after dosage form administration
What is a characteristic of a modified-release dosage form?
Delivery that is altered from immediate release after dosage form administration
Immunogenicity of Nucleic Acid Therapies
Delivery vehicle/vector Encoded protein can cause immunogenicity Nucleic acids
What is an elastomeric pump?
Disposable, non-powered pump, flow restrictor (ex/ HomePump)
Creating drugs in a typical pharma program?
Does it work? Yes, we can make it
You should not mix TOBI with:
Dornase alfa
Generic drugs must maintain:
Dosage form Strength Route of administration Intended use Demonstration of bioequivalence
What is a disadvantage of membrane controlled systems?
Dose dumping can occur if membrane breaks; cannot split/crush tablets
What was the first lipid nanoparticle published?
Doxil
How does free doxorubicin compare to doxil in the body?
Doxil stays in the body a lot longer; only have to administer once a week. Decreases toxicity
Solutes
Drug Antimicrobial; antioxidant pH control (buffer); tonicity adjuster suspending agent, emulsifying agent, viscosity modifying agent Cryoprotectant (for freeze dried products)
What evidence must an NDA provide?
Drug is safe and effective Benefits outweigh the risks Proposed labeling is appropriate Manufacturing methods and controls maintain drug identity, strength, quality, and purity
Osmotic controlled systems follows:
Drug release obeys zero order kinetics
PMDIs and liquid aerosol formulation factors
Drug solubility - Solutions - Stable suspesions Vapor pressure - Droplet size - Velocity (deposition) Surface tension affects droplet formation Hygroscopicity affects particle size Density (stability of suspension)
Types of terminal sterilization methods
Dry heat sterilization Autoclaving Gas sterilization Radiation sterilization (Aseptic filtration = terminal filtration)
DPI stands for:
Dry powder inhaler
What is one way to target tumors?
EPR effect
Stem Cell Reinfusion
Each bag of stem cells are defrosted separately in a warm water bath and then drawn up into a syringe to be reinfused over 3-5 minutes
Nucleic acid therapies are multi-component drugs. ______ ______ the drug can induce an immune response:
Each part
What are some factors contributing to phase 2?
Efficacy Competitive environment Dosage form Cost of goods (COG) Safety Dose/Schedule Manufacturing Pipeline
Factors in allowing drugs to move on to Phase III
Efficacy Safety Competitive environment Dose/schedule Dosage form Manufacturing Cost of goods Pipeline
What are examples of beta decay?
Emission of Negatrons (b-) Emission of Positrons (b+) Electron Capture
EPR effect
Enhanced permeation and retention effect- happens in cancers where newly formed blood vessels are leaky, allowing for nanoparticles to pass through when they wouldn't permeate through normal blood vessels
What is the function of nasal turbinates?
Enlarge the surface area of each cavity to ~75 sq cm
What does priming do?
Ensures content uniformity
PRCA Occurred in _____ Patients
Eprex
Dry eye
Evaporation of lacrimal fluid resulting in gritty or itchy feeling in eyes
The most appropriate imaging modality for 18F-labeled radiopharmaceuticals is:
F18 is radioactive; PET
Sources of contamination
Facility, equipment, process, materials, utilities, personnel
(T/F) Because of the small size of the droplets suspended in aerosols, they are generally regarded to be thermodynamically stable
False
(T/F) Biologics are considered the same and approved through the exact same process by the FDA
False
(T/F) Biologics can be prepared in a non-sterile environment
False
(T/F) Drugs that deposit in the bronchi and upper airways are well absorbed systemically
False
(T/F) Nasal drops are very suitable for drug delivery due to good dosing precision
False
(T/F) Propellants are needed in nebulizers to help push the liquids out
False
(T/F) The variable region of an antibody mediates immune response
False (constant region)
(T/F) Albumin plays a major role in delivering hydrophilic molecules to target tissues
False (hydrophobic)
(T/F) The constant region of an antibody mediates binding
False (variable region)
Mipomersen treats
Familial Hypercholesterolemia
More rapid approval of a drug for which no current therapy exists would be done through which pathway?
Fast Track
4 FDA expedited programs for serious conditions
Fast Track Breakthrough Accelerated Approval Priority Review
What is a needle-less injector?
Fluid-jet (ex/ Pharmajet)
How to make antibody therapies last longer:
Form hybridomas (tumor cells + B-cells producing antibodies)
What can cause precipitation?
Formation of insoluble salts pH changes Dilution of drugs solubilized by cosolvents Dilution of drugs solubilized by surfactants
Which type of PEG is most immunogenic?
Formation of neutralizing IgG typically occurs when PEG is bound to a tetrameric protein
A micro nucleus assay is part of _____ toxicity study required for an IND
Genetic
How is rituximab administered and what is the half life?
Given IV for 100% bioavailability • 30-40 hour half-life
Container closure systems
Glass: different types, amber, particulates Rubber: elastomers, leachables, sorption, moisture vapor transmission Plastic: polymers, leachables, air and moisture transmission
At which side chains does deamidation normally occur?
Glutamine and asparagine
Humanized antibody
Grafted mouse hypervariable CDR region into human backbone 95% human Reduced immunogenicity Laborious to create and optimize
Humanized Ab
Grafted mouse hypervariable CDR region into human backbone • 95% human • Reduced immunogenicity • Laborious to create and optimize
Chimeric antibody
Grafting entire Fab region onto human antibody backbone ~65% human but still some immunogenicity
Chimeric Ab
Grafting entire Fab region onto human antibody backbone • ~65% human but still elicited immunogenicity
Large volume parenteral (LVPs)
Greater than 100 mL Plastic bags, glass bottles
Interferons - nomenclature
Greek letters Arabic numerals to denote subcategories
Erythropoietin - nomenclature
Greek letters to denote differing compositions
If patients will receive cetuximab, what is the recommended pre-treatment?
H1 antagonist Blocks histamine receptor to repress of diminish reaction
Recommended premedication for cetuximab
H1-receptor antagonist
Bone marrow transplantation =
HSCT (hematopoietic stem cell transplant)
USP 800
Hazardous Drugs - Handling in Healthcare Settings
What is the best way to eliminate endotoxins from glassware?
Heat to 250 decrees C for 2 hours (depyrogenation)
Oxidation can be catalyzed by:
Heat, light, pH, metal
Natural weak spots in protein
Hinge regions
What does the number on a pMDI indicate?
How many actuations are left
Phase 2 clinical trials include
Human efficacy, side effects in people with disease
Phase 1 clinical trials include
Human subjects, safety in healthy volunteers, dosage
What is the the fastest growing class of therapeutic to enter the clinic?
Humanized and fully human mAbs
Liposomes can be surface-decorated with:
Hydrophilic polymer
What ISO class is room air?
ISO 9
USP 797 requires that most sterile compounding be done with an ____
ISO class 5 PEC
Direct compounding area
ISO class 5 or cleaner. Inside the PEC
Buffer area
ISO class 7 or cleaner where PEC is physically controlled
Ante area
ISO class 8 or cleaner Hand hygiene and garbing procedures, staging of components, order entry, CSP labeling, and other particulate generating activities performed here
What routes are always systemic?
IV
Three types of IV infusion
IV bolus (push) Continuous Intermittent
Premedications for Onpratto
IV cortiocosteroid oral paracetamol IV H1 blocker IV H2 blocker
What are the different types of parenteral products?
IV, IM, subcutaneous, intradermal
Routes that can be systemic
IV, SUBQ, transdermal, oral, inhalation, buccal, nasal
Photon energy is useful for:
Imaging and uptake evaluation
What are some benefits of PEGylation?
Improved solubility Increased stability Reduced dosing "stealth" properties that allow for longer circulation times
What Studies Must be Completed Before Beginning Clinical Trials?
In vivo (animal) •Drug Metabolism and Pharmacokinetics (DMPK) •Absorption, Distribution, Metabolism, Elimination (ADME): whole body radiography •Toxicology (ADMET) •Dose range finding studies •Single-dose acute studies
What studies must be completed before beginning clinical trials?
In vivo (animal) - Drug metabolism and pharmacokinetics - ADME Toxicology - Dose-range - Single-dose acute studies In vitro - Metabolite ID - Protein binding - Enzyme induction - Transporters - Genetic toxicity studies Pharmaceutical development - Physicochemical properties - Formulation studies - Manufacturing - Storage and handling
Recombinant DNA technology
In your body, peptides/proteins are built by translation and elongation •In cells, the ribosome attaches to mRNA •Each amino acid is added to the chain •Sequence is determined by DNA
What do absorption enhancers do?
Increase the permeability of the nasal epithelium to accommodate absorption larger hydrophilic molecules
What do bioadhesives/viscosifying agents do?
Increase the residence time of drug in nasal cavity
What does TRAIL do?
Induces apoptosis in cells expressing TRAIL receptors
Limitations of pulmonary drug delivery
Inefficient delivery Irritation of the respiratory tract Toxicity and side effects if drug deposits in the wrong place Taste
What kinds of things do we try and avoid when using parenteral products?
Infection Thrombosis Hemolysis Phlebitis Extravasation Air emboli
What are things to avoid with injectables?
Infection Thrombosis Hemolysis Phlebitis Extravasation Air emboli
Parenteral suspensions
Insoluble drug Suspending and/or viscosity improving agent wetting agent (so particles don't stick) flocculating agent to prevent caking
Systemic therapy meds for pulmonary delivery:
Insulin Antipsychotics Other experimental formulations of hormones/peptides
Humalog
Insulin lispro Onset of action: ~15-30 mins Peak effect: 1 hour Duration of effect: 3-4 hours Brief activity - less chance of inducing hypoglycemia
What are some secondary routes of injection?
Intra-thecal Intra-arterial intra-ocular intra-articular intra-peritoneal
What type of injection can overcome the blood brain barrier
Intrathecal
Primary routes of administration for injectable products:
Intravenous Intramuscular Subcutaneous Intradermal Also: Epidural Intrathecal Intra-arterial Intra-articular Intraperitoneal Intraocular Intracardiac
DNA- or mRNA mediated gene therapy
Introduction of a gene of interest Replacement: Gene product/protein missing Augmentation: Gene product inactive- mutation Correction: Gene product less active - mutation
1. Which of the following is NOT a type of Beta Decay? Emission of Negatrons (b-) Emission of Positrons (b+) Electron Capture Isomeric Transition
Isomeric Transition
What kind of nebulizer is PARI LC PLUS?
Jet Nebulizer
Drug release from osmotic device is constant because:
K is constant The difference in osmotic pressure is constant A and h are constant Drug conc. In the tablet is constant
What was the most prominent cause of failure during phase 2?
Lack of efficacy was most prominent in Phase 2 (safety failures also still apparent).
Advantages of anatomic Sources of Stem Cells (umbilical cord)
Large # of stem cells • Greater HLA disparity acceptable • Decreased risk of GVHD (graft vs. host disease)
Serious problems with Cremophor and EtOH
Leaches tubing from standard infusion sets Hypersensitivity reaction Rash, chest pain, tachycardia, angioedema Leads to axonal degeneration and demyelination (results in peripheral neuropathy)
What can cause the flaking or delamination of glass?
Leaching or etching
How many phase I trials advance to phase II?
Less than 1/3
Single dose (SDV)
Less than 100 mL Preservative free
Small volume parenterals (SVPs)
Less than 100 mL Single dose (SDV) Multiple dose (MDV) Plastic bags
Multiple dose (MDV)
Less than 100 mL always have preservatives
Insulin detemir
Levemir Long-acting insulin Onset: 2 hours Maximal duration effects: ~24 hours Insulin analog with fatty acid side group
Onpratto
Lipid nanoparticles deliver siRNA -decreases the production of ATTR through RNA interference -Indication: hereditary ATTR amyloidosis
Matrix based systems
Lipophillic matrix, hydrophilic matrix, porous matrix
Administration technique for DPIs
Listen for CLICK Do not open cap unless taking a dose Do not block the vent above the mouthpiece with fingers Do not breathe into mouthpiece Inhale in quickly and deeply You may not feel or taste the medication Keep dry at all times (avoid humidity and DO NOT WASH) Cleaning: gently wipe mouthpiece with dry cloth
Local means that the drug is primarily delivered to just one _____, _____ or ______ ______ in the body
Local means that the drug is primarily delivered to just one region, tissue or cell type in the body
How does lipid tail length affect phase transition temperature?
Longer tail = higher phase transition temperature
In an air jet nebulizer, liquid is pulled up into a (low/high) pressure vacuum above the drug formulation
Low
Limitations and challenges of therapeutic antibodies
Low potency Difficult and expensive to produce, formulate, and scale-up Low patient compliance with final dosage form and administration schedule Hypersensitivity (allergic) and immune responses can occur Formulation and stability issues common with protein therapies
Polyethylene glycol
Low toxicity, highly miscible in solvents and water, hydrophilic (improves solubility)
Benefits of local therapy
Lower efficacious doses Minimize systemic exposure Rapid onset of action Minimize risk for interactions
Ways to prevent protein aggregation
Lower temperature Adjusting pH Additives Detergents
Patient factors in particle deposition
Lung anatomy Disease state Breathing patterns Inhaler technique
Regional delivery examples
Lungs, mouth, rectum, vagina, skin
Abraxane
Lyopholized cakes of paclitaxel nanoparticles •Reconstituted with saline solution to reform paclitaxel nanoparticles
Macrophages have dominant presence in_____/_____ and this contributes to drug-induced_____ _____
Macrophages have dominant presence in liver/spleen and this contributes to drug-induced liver toxicity
What do preservatives do?
Maintain sterility
Bevacizumab
Malignancies Humanized mAb Directed against VEGF: Blocks VEGF in neovascularization
Biggest challenge with cell therapies:
Manufacturing
A generic drug that is AB equivalent means:
Meets necessary bioequivalent requirements
Mobilization
Method used to enrich the content of stem cells in the peripheral blood GCSF Chemomobilization (chemotherapy plus GCSF) Plerixafor + GCSF
Beyond use dates take into consideration...
Microbial, chemical, and physical stability
Mucoadhesive Dosage Forms
Microspheres float on stomach contents and adhere to stomach during gastric emptying
Suspensions, oily solutions, and implants are generally designed for:
Modified-release
The bronchioles consist of:
Mostly ciliated cells Few secretory and goblet cells
A goblet cell produces _______
Mucus
Therapeutic Stem Cells
Multi-potent hematopoietic stem cell: • Responsible for maintaining marrow function throughout the life of the individual • Characterized by presence of CD34 • Capable of self-renewal
A 90-mL parenteral parenteral solution containing a preservative is a:
Multiple dose small volume parenteral
HSCT is commonly used to treat:
Multiple myeloma • AML (for those without unrelated donors) • Relapsed testicular and germ cell cancers
Why do nanomedicines behave differently than larger materials or medicines?
Nanomedicines have a greater number of surface atoms per volume compared to larger materials
What is the role of nanoparticles in medicine and pharmacy?
Nanoparticles are used to deliver poorly soluble drugs
Long acting injectable are examples of
Nanosuspensions
In DPIs, where do particles in the following diameters deposit? > 10 microns 1-10 microns < 1 micron
Nasal cavity Lungs Exhaled
A source of radionuclides not typically used for medical applications is:
Naturally occurring radionuclides
Purification
Need to purify antibodies to eliminate contaminants (serum proteins, DNA, RNA, etc.) • Often purify by chromotographyon purification columns
Limitations of injectable drugs
Needs sterility Difficult to administer Dose is difficult to remove after administration
Beta
Negatrons; too many neutrons in the nucleus. A neutron is converted to a proton. Positron decay: Proton is converted to neutron. Diagnostic
What is the leading cause of vision loss in people over 65 years of age?
Neovascular (Wet) Age-Related Macular Degeneration (AMD)
What is an NDA?
New Drug Application Formal proposal for the FDA to approve a new drug for sale in the US
Can an ANDA be filed before an Innovator's patent has expired?
No
The bronchi consist of:
No ciliated secretory cells Cliated cells Goblet cells
Advantages of nebulizers over MDIs:
No propellant Does not require coordination of inhalation with actuation Can administer higher doses of drug (10s-100s of mg)
What makes DPIs distinct from pMDIs?
No spacer required No button to press No spray No need to prime before using No need to coordinate breath and administration No need to store upright No washing
Does passing the solution through a 0.22 micron filter remove endotoxin?
No; it does remove bacterial and fungal contamination
Membrane controlled systems (reservoir)
Non-porous membranes or semipermeable porous membranes
Advantages to systemic pulmonary delivery
Noninvasive Potential for peptides Bypass first-pass metabolism Effective absorption Rapid onset
The upper airways consist of the ______, _______, _______, and __________
Nose, mouth, pharynx, larynx
Disadvantages of nebulizers:
Not portable Expensive Refrigeration required for medication Long administration
Purified water
Not pyrogen free
Phase III Clinical Trials
Often a global program (for many drugs, need two well-controlled, large clinical trials) 1000-3000 patient volunteers Duration: ~2-7 years Confirm effectiveness and safety of drug Address additional questions (special populations, drug interactions, PK issues, etc)
On average, for 10,000 compounds evaluated in preclinical studies, about _____ compounds enter clinical trials and about _____ compound finally receives regulatory approval by the US FDA.
On average, for 10,000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials and about 1 compound finally receives regulatory approval by the US FDA.
What routes are mostly systemic?
Oral, Stomach
Activatable systems
Osmotic pressure, erosion
503B
Outsourcing facilities
Breakdown of proteins can occur via:
Oxidation Deamidation Aggregation Fragmentation
PEG on nanoparticle vs unbound PEG
PEG on nanoparticle invokes a stronger antibody response than unbound PEG
Pre clinical testing includes
PK/PD studies, animal toxicity
HFA indicates that the drug formulation is probably a:
PMDI
Delayed-Release
Part or all of the drug is released at a time other than the time of administration
Why would an injected suspension or oily solution have a longer onset of action than an aqueous solution
Partitioning
Why would an injected suspension or oily solution have a longer onset of action than an aqueous solution?
Partitioning
What is the main source of contamination in a sterile environment?
Personnel
Which type of buffer should be avoided when lyophilizing protein solutions because it may cause the proteins to crystallize?
Phosphate
What kind of buffer can crystalize during freezing?
Phosphoric Acid/Phosphate
Visudyne (verteporfin for injection)
Photosensitive drug injected IV as liposomal preparation Binds to LDL and concentrates at LDL receptors in the endothelium of choroid neovasculature and RPE
Types of stabilities considered in BUDs
Physical Chemical Microbial
Parenteral incompatibilities
Physical changes in appearance Accelerated chemical degradation Leaching of packaging component into drug Loss of drug onto packaging material Combining different drugs
What types of stability issues may result from adsorption of drug?
Physical stability Therapeutic stability
What is a central venous catheter?
Plastic tubing is threaded through a smaller vein (usually subclavian) into the superior vena cava for infusing prolonged or irritating drug therapy or nutrition solutions
Theories for Eprex-induced immunogenicity?
Polysorbate 80 formed EPO-micelles which resembled foreign pathogens Polysorbate 80 reacted with rubber stoppers
What is a Y site?
Port that allows for the attachment of a second infusion to the primary infusion line
What is a subcutaneous infusion pump?
Portable, programmable pump (ex/ AccuCheck Spirit)
What is an example of an implantable venous access chamber?
Portacath
Phase 4 clinical trials include
Post-marketing studies, Additional safety testing, Monitoring for rare adverse events
What are pre-filled syringes or pens?
Pre-filled syringes with needles (ex/ NovoLog Flex pens)
PMDI stands for:
Pressurized metered dose inhaler
Biosimilars may differ by:
Primary amino acid sequence Modification of amino acids Higher-order structure - Folding - Quaternary structure
Steps to pMDI administration
Prime Shake Exhale Position mouthpiece Coordinate inhalation/actuation Hold breath Wait to administer second puff *Clean actuator at least once per week
More rapid approval of a drug for which a therapy would provide significant improvement in safety or efficacy?
Priority review
Biotechnology Product: Raw material Variability/heteroability: Product definition: Process, testing: Scale:
Product: cultured cells generate product Raw material: seed cell lines Variability/heteroability: limited Product definition: well defined, definable products Process, testing: est. early in process Scale: mosty bulk process
Cell therapy Product: Raw material Variability/heteroability: Product definition: Process, testing: scale:
Product: living cells are the product Raw material: unique, primary tissue Variability/hetero-ability: Substantial Product definition: product defined through trial Process, testing: evolve through trial scale: patient-specific products are common
What is a smart infusion pump?
Programmable device that calculates infusion rate and infuses drug from a reservoir
Most of the liquid contained in a pMDI canister consists of:
Propellant
Soft-mist inhaler:
Propellant-free metered-dose inhaler that uses mechanical energy (spring tension) to force a drug solution through a mouthpiece that generates an aerosol plume
What are the pros and cons to synthesizing peptides with recombinant technology vs. solid-phase chemistry?
Pros: specific control, can get things not occurring in nature, quicker, easier Cons: missing the things that a cell naturally does: no editing, glycosylation, folding, etc
What do propellants do?
Provide pressure to release droplets from device
What type of USP water is not pyrogen free?
Purified water
Mucus Penetrating Particles (MPP)
Quickly penetrate across tear film without aggregation, leading to prolonged retention
Two main functions of an antibody
Recognize and bind antigen Induce immune response after binding
What is the primary advantage of pulmonary drug delivery compared to oral drug delivery?
Reduces systemic drug exposure
Stannous chloride (SnCl2) is a(n) _________ when preparing 99mTc radiopharmaceuticals
Reducing agent
Humulin R
Regular insulin Short-acting ~30 min - 1 hour onset Peak effect: 2-3 hours Duration of action: 4-6 hours Monomers of regular insulin assemble into hexamers
What is an inline filter?
Removes large particles from LVP solutions before they reach patients
How many stem cells does transplantation need?
Requires 2-6x 10 ^ 6 stem cells / kg body weight
Fate of a 4-micron drug
Respiratory bronchioles due to gravitational sedimentation (2-5)
The respiratory zone extends from the _______ ________ to the ______
Respiratory bronchioles, alveoli
Multi-potent hematopoietic stem cell
Responsible for maintaining marrow function throughout an individual's life Characterized by presence of CD34 Capable of self-renewal
A CACI is a type of...
Restricted-Access Barrier System
Tomographic imaging of radionuclides that decay by Isomeric Transition is:
SPECT
_______ and __________ are __________ tomographic imaging modalities used for diagnostic
SPECT and PET are nuclear tomographic imaging modalities used for diagnostic
What must be proven for cell therapies?
Safety, efficacy, purity
In what ways must a generic product be comparable to an Innovator's product?
Same dosage form, strength, route of administration, intented use, demonstration of bioequivalence Does not have to be the same color / demonstrate clinical efficacy
What do extended-release dosage forms avoid?
Sawtooth characteristics
Ultrasonic nebulizers cannot be used for drugs in suspension due to risk of (flocculation/sedimentation)
Sedimentation
Most important factor in patients getting therapeutic effect from inhalers:
They were properly counseled and use it correctly
As you proceed down the airway branches, the diameter of each branch gets (thinner/thicker)
Thinner
Phase 3 clinical trials usually involve how many patients?
Thousands
Why does Cetuximab induce more HIR incidences in NC?
Tick bites (Lonestar tick) • Generates IgE antibodies to alpha-gal • Cetuximab contains alpha-gal moieties
What is the primary reason for HSCT?
To facilitate the ability to deliver high dose chemotherapy (with stem cell "rescue")
Why are albumin nanoparticles used to deliver paclitaxel?
To increase the circulation half-life and tumor deposition of paclitaxel
Why do some parenteral suspension contain flocculating agents?
To prevent caking of the solids
A generic drug that is AT equivalent indicates that it is a ______ product
Topical
What are some drawbacks of PEGylation?
Toxicity Can result in strong anti-PEG responses Small % of people are highly allergic
Anions form precipitates with:
Trace metals
Fate of a 60-micron drug
Trachea due to intertial impaction (>60)
The primary route of transport for large peptides and proteins into the nasal epithelium is (paracellular/transcytosis)
Transcytosis
What routes are often systemic?
Transdermal, Rectal Targeted Oral Delivery
(T/F) A limitation of intranasal drug delivery is the maximum delivered volume is 25-200 microL
True
(T/F) Abraxane reduces side effects, improved the response rate of patients with metastatic cancer, and allows higher doses of paclitaxel to be tolerated by patients
True
(T/F) Albumin accumulates in tumors
True
(T/F) Biologics are allowed to fall within a wider range to get approved because of the added complexity and heterogeneity within the products compared to small molecule drugs
True
(T/F) Drug delivery and solubility take on profile of polymer, not protein
True
(T/F) The number of goblet cells decreases as you move down the bronchioles
True
(T/F) Type 2 pneumocytes produce pulmonary surfactant, which reduces the surface tension within the alveoli a, promoting functional gas exchange
True
Spacer:
Tube or extension device that adds space and volume between the pMDI and mouth (no one-way valve)
Positron annihilation results in the conversion of a positron and an electron to:
Two gamma photons of equal energy
What type of pneumocytes are responsible for gas exchange?
Type I
The alveoli consist of:
Type I pnuemocytes Type II pneumocytes
Designated drug nomenclature agency
US Adopted Names (USAN) council
Advantages of solid-phase synthesis vs recombinant DNA
Unique sequences / amino acids Smaller scale-up Cheaper
Radioactive decay
Unstable nucleus leads to the emission of mass and/or energy
Ultrasonic nebulizer
Uses acoustic energy to disperse drug solutions
Air jet nebulizer
Uses compressed air or pressurized oxygen gas to aerosolize a liquid drug formulation
Fully human Ab
Uses phage display
Choroidal neovascularization can result from an overexpression of
VEGF
_____ region of an antibody mediates binding
Variable • Antigen affinity determined by variable region • Confers specificity for antigen
What does the phase transition temperature of lipids affect?
Vesicle stability (in circulation and in storage) of liposomes
High concentrations of proteins may lead to ______ solutions
Viscous
Types of vehicles
Water, water miscible co-solvent Non aqueous solvent, advanced delivery system
Creating a cell therapy product
We know it works But, can we make it?
disadvantages of anatomic Sources of Stem Cells (umbilical cord)
Weight limit (recipient must be <60kg) • Delayed engraftment • Engraftment failure
Questions for patient asking why new inhaler isn't as good as old?
What was the old inhaler (color)? What happens after using the new one that is different from the old one? How many doses are left? Are you cleaning inhaler weekly? How are you using it?
Air emboli
a blood vessel blockage by air bubbles
The "End-of-Phase 2 meeting" with the FDA is a critical point where
a decision to advance the drug is made.
European Union was first to adopt
a formal approval procedure for protein drugs termed "biosimilars,"
disinfection
a process that removes infection potential by destroying microorganisms but not usually bacterial spores
Valved holding chamber:
a spacer with a one-way valve to contain the aerosol until inhaled and direct exhalation away from the aerosol in the chamber
More rapid approval of a drug for which no current therapy exists would be done through which pathway? a. Fast Track b. Breakthrough Therapy c. Accelerated Approval d. Priority Review
a. Fast Track
How many months/years do Phase 2 trials typically last?
about 2 years
Small-volume nebulizer:
aerosol device that converts liquid drug solutions or suspensions into aerosol and is powered by compressed air, oxygen, a compressor, or electricity
What are some methods to minimize contamination?
air, breath, skin, hair & clothing, working surfaces, drug and excipients, container/closure system
Etching
alkaline attack; dissolution of the surface layer of glass
Major class of antitumor agents employed in HSCT are:
alkylating agents Busulfan, Cyclophosphamide, Melphalan
3 types of decay
alpha, beta, gamma
Valved holding chambers (VHC)
also hold puff before inhalation to reduce effects of poor actuation/inhalation coordination
<2.5 μm will deposit in
alveoli
Where is the optimal site of drug absorption for systemic delivery via the pulmonary route?
alveoli
Dry-powder inhaler (DPI):
an aerosol device that delivers drug in a powdered form, typically with a breath-actuated dosing system
Insulin detemir is an insulin ____
analogue with a fatty acid side group -Quickly resorbed and binds to albumin in the blood -Slowly dissociates producing action
A patient receives an infusion of Cetuximab as anti-cancer therapy. During the infusion, the patient exhibits shortness of breath, disorientation and a rapid drop in blood pressure. What is the cause of the symptoms?
anaphylaxis Hypersensitivity reactions can occur in response to antibody infusions
The NIOSH list maintains a list of:
antineoplastic and other hazardous drugs used in healthcare settings
bacteriostat
anything that arrests the growth of bacteria
Bactericide
anything that kills bacteria
Visudyne is activated by
application of a nonthermal laser after infusion
Supporting clean areas
area immediately adjacent to aseptic processing line: at least ISO 7 Area beyond this boundary is appropriate for less critical activities: at least ISO 8
Critical area
area where the sterilized drug product, containers, and closures are exposed to environmental conditions that must be designed to maintain product sterility ISO 5
Common antioxidants in injectable products
ascorbic acid sodium metabisulfite chelator: edetic acid alpha tocopherol (Vitamin E) Butylated hydroxyanisole
Dose range finding studies
at least 2 species (rodent + non-rodent) single dose + repeated dose GLP toxicology studies (14-28 day)
Extended release
at least a two fold reduction in dosage frequency compared to immediate-release formulation
Sterilization method that employs steam at 121 degrees C at 15 psi
autoclaving
Sterilization methods
autoclaving (steam sterilization) dry heat sterilization aseptic filtration gas sterilization radiation sterilization
Example of MAb treatments
autoimmune, blood disorders, cancer, diabetes, infectious disease, CV disease, HIV infection
For every 5,000 compounds discovered, how many will advance through the clinical trial phases and how many will ultimately be approved by the FDA? a. 10/1 b. 5/1 c. 10/3 d. 50/5
b. 5/1
What is a passive dry powder inhaler? a. An electrically powered device used to deliver solid aerosols b. A breath-powered device used to deliver solid aerosols c. An electrically powered device used to deliver liquid aerosols d. A breath-powered device used to deliver liquid aerosols
b. A breath-powered device used to deliver solid aerosols
Which FDA Center reviews new gene therapies? a. CDER b. CBER c. CDRH d. CFSAN
b. CBER
Which of the following is the primary advantage of local pulmonary drug delivery compared to oral drug delivery? a. Bypass first-pass metabolism b. Reduces systemic drug exposure c. Rapid absorption into the circulation
b. Reduces systemic drug exposure
An IND must be submitted.... a. before beginning pre-clinical studies b. before beginning Phase 1 studies c. after beginning Phase 2 studies d. after beginning Phase 3 studies
b. before beginning Phase 1 studies
For something to clear the kidneys it must be:
be less than 5000 MW
Chromotography uses _____ purification
bead • Protein A (bacterial protein) is bound to beads in large columns • Protein A binds IgG Fc region • Antibodies secreted in cell culture media are purified and concentrated by passing supernatant through Protein A affinity columns
An IND must be submitted....
before beginning phase 1 studies
What is the most common ophthalmic preservative?
benzalkonium chloride
Examples of antimicrobial agents
benzyl alcohol, m-cresol, phenol, methylparaben, propylparaben, chlorobutanol, thimerosal
Thrombosis
blood clot
The primary posterior barrier to ophthalmic delivery is the
bloodretinal barrier
The Hatch-Waxman Act involved submission of... a. INDs b. NDAs c. ANDAs d. INDAs
c. ANDAs
Which route is most appropriate for administering corticosteroids to treat allergic rhinitis? a. Oral b. Oral inhalation c. Intranasal
c. Intranasal
Phase 3 clinical trials usually involve how many patients? a. Tens b. Hundreds c. Thousands d. Millions
c. Thousands
Types of hazardous drugs
carcinogenicity teratogenicity or developmental toxicity reproductive toxicity organ toxicity at low doses genotoxicity new drugs that mimic existing hazardous drugs in structure or toxicity
Generally, potency refers to the ability of cell therapy to cause:
cause a functional response in a patient
Replacing murine elements with human elements would reduce
chance of immune reaction and improves circulation
Many formulations (e.g. nanoparticles) are quickly recognized and
cleared from circulation
What was the most prominent cause of failure during phase 1?
clinical safety
What are the primary causes of failure categories for terminated compounds?
clinical safety, efficacy, clinical toxicology, rationalization of company portfolio
Routes than can be local
colonic, buccal, rectal, vaginal, topical (skin), intranasal, pulmonary, ophthalmic, otic
503B are required to:
comply with cGMP be inspected by FDA meet other conditions (adverse reporting, etc)
503 A
compounding pharmacy
excipients in Ventolin HFA (04/01)
contains no other excipients
The primary anterior barrier to ophthalmic delivery is the
cornea
Biggest risk of CAR-T therapy
cytokine release syndrome
What is the optimal site of drug absorption for systemic delivery via the pulmonary route? a. trachea b. bronchi c. terminal bronchioles d. alveoli
d. alveoli
US Adopted Names (USAN) council
designated drug nomenclature agency •Responsible for developing rules designed for coining informative, non-proprietary names of drugs and biologics
Hemolysis
destruction of red blood cells
Examples of PET in brain imaging
detecting amyloid plaques, and dopamine expression. It can help determine if treatment is working.
Kymriah
diffuse large B-cell lymphoma & acute lymphoblastic leukemia
Yescarta
diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma
Leaching
diffusion controlled ion exchange process of components within the surface layer of glass
Extravasation
drug leaks "around the vessel"
Which of the following drugs are NOT suitable for delivery as gastroretentive dosage forms?
drugs that exhibit high solubility at high pH
drug for injectable suspension
dry solids that, upon the addition of suitable vehicles, produce a suspension for injection
drug for injection
dry solids that, upon the addition of vehicles, produce a solution for injection
Both humanized and fully human Ab function closer to:
endogenous Ab
Visudyne activated drug provides:
energy to produce reactive oxygen species
Visudyne damages:
epithelium and occludes choroidal neovasculature. Temporary photosensitivity
Drug concentration is roughly _____ in the blood
equal
excipients in ProAir HFA (10/04)
ethanol
excipients in Proventil HFA A (08/96)
ethanol, oleic acid
Single-dose DPIs
evacuate powder medication from a punctured capsule
When do the numbers decrease drastically during the drug development process?
from Phase 1 (safety) through Phase 3 (efficacy in large populations).
What is a side effect of doxil?
hand and foot syndrome
Oxidation can be catalyzed by:
heat, light, pH, metal
What enhances leaching or etching?
high pH, increasing ionic strength and osmolality, and surface:volume ratio
Challenges with Paclitaxil
highly hydrophobic; require organic solvent (ethanol or castor oiL)
Johnson & Johnson created the first recombinant
human EPO but required complex manufacturing •Numerous biosimilar EPO products were created with identical amino acid sequences •Follow-on products had highly varied glycosylation and biologic activity (70-200%)
Non-human cells eliminates risk of
human pathogens
Drug discovery includes
identifying targets, developing candidates
Muromomab CD-3:
immunosuppression Murine mAb • 1 rst mAb approved for clinical use in humans • Acts on CD3 receptors • Prevents graft rejection in renal transplant patients
Where are sterile hazardous drugs compounded?
in a containment primary engineering control (C-PEC) that has ISO-5 or better
Albumin nanoparticles are used to _______ the circulation half-life of paclitaxel.
increase
What modifications can be made to a drug formulation to increase corneal penetration of topical ophthalmic drugs?
increase drug conc. increase lipophillicity increase contact time w/ eye (pH adjustment, increase viscosity, suspensions)
intradermal injection
injection placed just below the epidermis
An example of protein therapy
insulin
Which route is most appropriate for administering corticosteroids to treat allergic rhinitis?
intranasal
Phlebitis
irritation to blood vessel
A PEC is a device that
is used to reduce the # of airborne particles and microorganisms in a compounding enviornment
_______ is usually the carrier in traditional DPIs
lactose
•What proportion of Phase 1 trials advance to Phase 2?
less than 1 in 3
What type of formulation is Ambisome?
liposome because it is composed of lipids and contains a phospholipid bilayer and hydrophilic core
Non-viral vectors
liposomes, "naked" nucleic acid
injectable emulsion
liquid preparations of drug substances dissolved or dispersed in a suitable emulsion
injectable suspension
liquid preparations of solids suspended in a suitable liquid medium
drug injection
liquid preparations that are drug substances or solutions thereof
Final potency not known until
long-term fate of cell is known
What is the largest therapeutic biologic?
mAbs
Rituximab:
malignancies • Chimeric mAb • 1st chimeric IgG-1 mAb • Directed against CD-20 on B-cells
Multiple-dose DPIs
measure doses from a powder reservoir or disperse individual doses through premetered blister strips
Bevacizumab is used to treat
metastatic cancers Gained accelerated approval for brain cancer (currently no successful treatments)
What are barriers common to oral, pulmonary, buccal, and nasal delivery?
mucus
At the end of phase 2 meeting-
must consult with the FDA before beginning Phase III
Cell therapies must be screened to ensure absence of
mycoplasma
At "normal" chemotherapeutic doses, dose limiting toxicity is
myelosuppression
Water for injection
non-sterile; pyrogens must be quantified
Can salts induce an immune response?
not usually, they are too small
Non-clinical toxicology failures represent:
one of the key challenges still facing the industry (pre-clinical).
Which Route/s of Administration Is/Are Used to Primarily Achieve Local Effects?
ophthalmic, otic
503B
outsourcing facilities
Materials greater than 100 nm are general taken up by __________ When a therapy is less than 100 nm they can be taken up by _________
phagocytic, most cells
What are factors that affect the stability of parenteral products?
physiochemical products (pH, osmolarity), additives (preservatives), container closure systems
intrathecal injection
placement of substances into the subarachnoid space
Paclitaxel is a chemotherapeutic drug that is:
poorly soluble in water.
Positron
positively charged electron ex. (PET scan)
Phase 4 Clinical Trials
post-marketing surveillance
How can hypersensitivity to antibody treatments be prevented?
premedication
All patients should recieve _____ prior to Onpratto administration to reduce risk of _____
premedication, infusion related reactions
Why do some parenteral suspension contain flocculating agents?
prevents caking
before using MDI for the first time,
prime the inhaler
Sterilization
process where all viable forms of microorganisms are removed or destroyed, based on probability
Soft-mist inhaler:
propellant-free metered-dose inhaler that uses mechanical energy (spring tension) to force a drug solution through a mouthpiece that generates an aerosol plume
Recombinant DNA technology was developed so:
protein therapies could be more easily manufactured.
bacteriostatic water for injection
pyrogen free
sterile water for irrigation
pyrogen free
Pre-clinical formulation
rarely different for any two MAb - Typical ingredients - Moderate concentration
Clinical formulations
rarely the same for any two MAb - "Typical" ingredients - High concentration - Low viscosity - Lyophilized products
When a cell wants to undergo programmed cell death, it expresses ______
receptors for TRAIL on it's surface
Gamma decay
release of gamma photons; useful in diagnostic.
IND
request submitted to FDA to allow human exposure to the experimental drug An ongoing file at FDA containing data on drug as it passes through drug development process
USP 797
requirements for the compounding, preparation, and labeling of sterile drug preparations Enforceable by the FDA and most State Boards of Pharmacy
2-5 μm will deposit in
respiratory bronchiole
HEPA filters
retain particulate matter by multiple mechanisms working together.
Viral vectors
retrovirus, adenovirus, adeno-associated virus
Multi Unit-Dose DPI
rotating wheel with blisters of medication • one blister mechanically punctured when the cover is lifted
What did abraxane do?
safety, better formulation -eliminated side effects of paciltaxil
3 things to consider when creating a cell therapy
safety, efficacy, purity
What do extended-release dosage forms avoid?
sawtooth effect
Screening includes
screen compounds, optimize lead
Antisense therapy or RNA interference therapy
sequence is complementary to mRNA of interest Deletion/Knockdown of gene product responsible for disease state -siRNA (short interfering RNA) -antisense DNA
Pressurized metered-dose inhaler (pMDI):
small, portable self-contained drug/device combination that dispenses multiple doses by a metered valve
Intradermal injections have a ________ injection volume than subcutaneous injections and they also persist _______ than subcutaneous injections.
smaller, longer
In the lab, peptides/proteins are built by
solid-phase synthesis
Sterile water for injection
sterile and pyrogen free
Antiseptic
substance that arrests or prevents the growth of microorganisms by inhibiting their activity w/o necessarily destroying them
viricide
substance that kills viruses
Spacers allow the MDI propellant...
sufficient time and distance for evaporation
Ophthalmic administration may result in
systemic drug exposure via drainage into the nasolacrimal duct
5-10 μm will deposit in
terminal bronchiole
USAN works with
the FDA's CBER and the WHO
How do you choose a buffer for an injectable product?
the buffer will have a pKa within the desired pH range. ex. use acetic acid for a pH range of 4-6 bc the pKa is 4.8
ISO classes are defined by:
the max number of particles of a specific size range per cubic meter of air
Mobilization
the method used to enrich the content of stem cells in the peripheral blood: 3 methods: •GCSF alone (granulocyte colony-stimulating factor) •Plerixafor + GCSF
phase transition temperature
the temperature needed to cause a change in the lipid physical state from the ordered gel phase (where hydrocarbon chains are fully extended and closely packed) to the disordered liquid crystalline phase (where hydrocarbon chains are randomly oriented and fluid)
Immune cells recognize:
these cells, localize with the cells, allow TRAIL to engage it's receptor •This induces death in recipient cells
If a compounder does not meet criteria for compounding under 503A and chooses not to register as an outsourcing facility under 503B, then _____
they are subject to the laws regulating manufacturing under FD&C act
Phase 3 clinical trials usually involve how many patients?
thousands
What is the purpose of the drug quality and security act?
to create a new section of 504B where a compounding facility can be an outsourcing facility
Rationale of HSCT
to facilitate the ability to deliver high dose chemotherapy • Also known as high dose chemotherapy with stem cell "rescue"
Quality and scaling requires not only total cell number, but ______
total number of viable cells
10-60 μm will deposit in
trachea
Transfection
transferring DNA into mammalian cells
Extracellular barriers in nucleic acid delivery (extravasation and accumulation)
transport across the capillary wall
spacer
tube or extension device that adds space and volume between the pMDI and mouth -does not have a one-way valve
Adsorption of paclitaxel to albumin increases its ________
tumor deposition.
What are some advantages of IV injection?
unlimited volume can be administered injection is quick and extensively diluted avoids first pass metabolism no absorption step (rapid onset of action) predictable response (bioavailability = 100%)
Kymriah Manufacturing
uses a patient's own cells • Patient cells are harvested, frozen, and shipped to their facility • The cells are engineered with the CAR, frozen, and shipped back to the hospital • Cells are thawed in a water bath and infused back into the original donor patient -completed in about 20 days
RNA interference (RNAi)
utilizes the multi-protein RNAi-induced silencing complex (RISC) containing a siRNA to specifically degrade the targeted RNA.
Recombinant DNA technology allowed new
variants to be created -Chimeric Ab -Humanized Ab -Fully human Ab
What are the components of injectable parenteral products?
vehicle, solutes, container closure system
The phase transition temperature of lipid affects the ________ of liposomes
vesicle stability
Pure red cell aplasia (PRCA) is a very rare, potentially fatal disorder in which
which maturation stops in erythrocyte precursors
US FDA is now adopting process
with first biosimilars entering the market
Local delivery can be achieved
with targeting or physical location
Can topical ophthalmic drugs get absorbed into systemic circulation?
yes
Disadvantages of Plastic
• Adsorption or permeation of some drugs • Weight loss by water vapor transmission • Evaporation of volatile preservatives such as chlorobutanol • Translucent
Some indications of Intravitreal Medications
• Age-related macular degeneration • Macular edema • Infections of the vitreous compartment
Therapeutic antibodies can be created that:
• Block cancer-promoting receptors; activate death-inducing receptors • Localize lethal drugs to specific cells • Localize radioactive molecules to kill cancer • Localize drug-loaded nanoparticles
Local Therapy
• Bronchodilators • Corticosteroids • Antibiotics and DNAase (an enzyme) for cystic fibrosis • Others for various pulmonary conditions
Vibrating Mesh Nebulizers
• Handheld • Rapidly declining costs (bulk costs ~$10-25 per nebulizer) • High delivery efficiency • Shorter administration times (as short as a few mins)
Benefits of Humanization
• IV is preferred because 100% of the product is bioavailable Human anti-mouse antibody response develops 7-10 days after administration of murine antibody
Drawbacks of mouse antibodies
• Induce allergic reactions (anti-drug Ab) • Short half-life • Inefficient at triggering antibody-dependent toxicity and complement activation
Systemic Therapy
• Insulin • Antipsychotics • Other experimental formulations of hormones/peptides
Development of Humanized Antibody Therapies
• Leverages genetic cloning plasmids as starting material • Desirable post-translational protein modifications for proper function • Efficiently engineered, fast-growing, stable
Limitations and Challenges of Therapeutic mAbs
• Low potency • Difficult and expensive to produce, formulate, and scale-up • Low patient compliance with final dosage form and administration schedule • Hypersensitivity (allergic) and immune responses can occur • Formulation and stability issues common with protein therapies (ie.: aggregation, oxidation, fragmentation)
Intravitreal Medications
• Lucentis (ranibizumab) • dexamethasone • ganciclovir • vancomycin • amphotericin B
Myelosuppressive/Myeloablative
• Make space in the marrow for infused stem cells to settle and propagate • Required for autologous and allogeneic HSCT
Advantages of Nebulizer Over MDI
• No propellant • Does not require coordination of inhalation with actuation • Can administer higher doses of drug (10s-100s of mg)
Disadvantages of Jet Nebulizers
• Not portable • Relatively expensive • Refrigeration required for medication • Long administration time
Mobilization/Collection
• Process by which stem cells are forced into peripheral blood and collected • Stem cells may be collected from: ----Direct bone marrow aspiration ---- Mobilization and peripheral blood apheresis
2 functions of an antibody
• Recognize and bind antigen •Induce immunes response after binding
Blood-retinal barrier
• Retinal capillary endothelial cells and retinal pigment epithelium cells (RPE) also contain tight junctions • RPE permits selective transport and is being investigated as a mechanism for targeted delivery
Cons of benzalkonium chloride
• accumulates in ocular tissue • conjunctival irritation • dose-dependent corneal cytotoxicity • incompatible with salicylates, nitrates, and anionic compounds
Pros of benzalkonium chloride
• excellent antimicrobial activity and chemical stability • active against P. aeruginosa especially when combined with EDTA
Modeling Disease with iPS:
• iPSC can be used to create disease-specific cells: neurons, cardiomyocytes, etc. • Allows true disease modeling in a dish that was never before available
What do spacers do?
• slows droplet velocity • allows evaporation • controls inhalation rate • traps large droplets
Potency
•"the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through administration of the product in a manner intended to effect a given result"-FDA
What are hydrogels?
•3-D, mostly hydrophilic, polymeric network that can absorb up to thousands of times their dry weight in water or biological fluids
targeted release
•A dosage form that releases drug at or near the intended physiologic site of action
Humulin R (regular insulin) (onset, peak, duration)
•Also known as "short-acting" •~30 min to 1 hour onset •Peak effect in 2 - 3 hours •Duration effect: 4 - 6 hours
Phase 2 clinical trials
•Assess a drug's effectiveness in treating a particular disease or medical condition •Usually evaluate more than 1 dose (dose-ranging) Establish safety profile with longer term dosing
Significant Advances in Production (biologics)
•Bacterial cells are highly efficient at producing proteins •Production in human cells improves biologic activity •Challenging to create safe system producing large enough quantities of the drug
Phase 1 clinical trials
•Begin 30 days after submission of IND •20-80 healthy subjects •Duration: 1-2 years •Safety and dosage: determine side effects associated with increasing doses •Establish PK profile •May identify drug interaction issues •May gain early evidence of efficacy
Lessons from Eprex
•Biosimilars are not always identical to parent drug •Minor changes in formulation can results in dramatic effects in the clinical setting •Changes in manufacturing can result in critical changes when used in patients
TRAIL Therapy
•Cancer cells also selectively express TRAIL receptors •Postulated that TRAIL could be used to kill cancer cells Goal: Create Recombinant TRAIL for Cancer Therapy
half life of chimeric, humanized, and recombinant humanized
•Chimeric: 4-15 days • Humanized: 3-24 days • Recombinant Humanized: 11-24 days
Using Antibodies to Overcome the BBB
•Concept is to start by creating antibody fusions •Idea is that antibody can target endothelial cells in BBB •Through transcytosis, antibody and drug will be transported across the BBB and have access to the brain
What is the purpose of phase 3 clinical trials?
•Confirm effectiveness and safety of drug •Address additional questions such as special populations, drug interactions, PK issues, etc.
Potency assays
•Designed to give real-time feedback •Need to correlate preclinical with clinical findings
Manufacturing Cell Therapies
•Despite their promise, there is an immaturity of production technologies •Most process rely on methods use lab scale/academic technology: no robotics, room for human error • There is a significant need to move technology from "academic" to industrial scale
Timed-release colon delivery
•Dosage form is constructed in a way that the active ingredient is released at a specific time after ingestion. Achieved by: •Manipulating the internal capsule fill formulation •Using an erodible capsule coating
During NDA and FDA approval, companies must provide sufficient evidence for the FDA to decide:
•Drug is safe and effective •Benefits outweigh the risks •Proposed labeling is appropriate •Manufacturing methods and controls maintain drug identity, strength, quality, and purity
Drug delivery via hydrogels
•Drugs release mechanisms include: -Passive diffusion from the hydrogel -Diffusion due to external stimulus -Release due to degradation of the hydrogel
Albumin-bound Paclitaxel
•Drugs with high hydrophobicity can be solubilized using albumin •Paclitaxel is hydrophic •Paclitaxel binds to albumin with high affinity, yet is released at tissue •Paclitaxel was non-covalently bound to a 130-nanometer albumin
General types of raw material
•Embryonic stem cells •Somatic stem cells •iPS cells •Transdifferentiated stem cells
Interactions
•Energy, mass, and charge Radiation either escapes the body or is absorbed by tissue
Eprex Manufacturing-induced Immunogenicity
•Experiments showed polysorbate 80 formed small micelles that created EPO-micelles which resembled foreign pathogens •This causes breakdown of immune tolerance and triggered immune reaction--> caused people to become anemic
Extension of Gastric Retention Time
•Floating Systems (Low Density Systems) •High Density Dosage Forms (Sedimentation or sinking of pellet/tablet) •Mucoadhesive Dosage Forms •Expandable Systems •Superporous Hydrogel Systems
What are some limitations of colon delivery?
•Fluid volume in colon is lower than in upper GI-tract => limiting factor for poorly soluble drugs •Smaller surface area than the small intestine •Relatively low permeability of tight junctions
IND NDA ANDA
•IND: Begin human trials •NDA: Market drugs •Post-Marketing Surveillance •ANDA: Approval of Generics
In vitro studies (before dosing in an animal)
•Identification of metabolites •Protein binding •Enzyme induction •Transporters •Genetic toxicity studies (bacterial mutation assay, mouse lymphoma assay, micronucleus assay) *must be done before beginning clinical trials
What are some benefits of modified release drug delivery?
•Increases efficacy by maintaining a constant plasma drug level in the therapeutic window range for an extended period of time •Reduces dosing frequency •Eliminates drug accumulation in the body •Minimizes toxicity of drug •Can increase patient compliance •Can reduce the cost of patient treatment
Known side-effects of Cremophor include
•Leaches tubing from standard infusion sets •Hypersensitivity reaction •Rash, Chest pain, Tachycardia, Angio-edema
Insulin detemir (Levemir) (onset, duration)
•Long-acting insulin •Onset: 2 hours •Maximal duration effects: ~24 hrs
Molecular imaging plays a big role in cell tracking. This includes:
•MRI, PET-CT, SPECT •Nanoparticle and contrast agents required
Neutral Protamine Hagedorn (NPH)
•Mimics insulin the human body •Lowers blood glucose at a consistent rate •Onset of action is 1 - 2 hours •Peak effect 4 - 8 hrs •Maximal duration of action is up to 24 hours -Activity tapers off in last 10 hours
Humulin R monomers assemble into:
•Monomers of regular insulin self-assemble into hexamers -Hexamers can be stabilized with zinc ions -Humulin R is formulated as a zinc-insulin crystalline suspension
Common Safety Tests for Cell Therapies
•Mycoplasma-bacterial contamination •Viruses-ensure absence of HIV, Hepatitis B &C, and others •Endotoxin-screens for toxins or pyrogens •Karyotype analysis-screens for chromosomal abnormalities
Mycoplasma Testing
•Mycoplasma: type of bacteria commonly unaffected by antibiotics •Amplification of culture samples in bacteria growth media •Can take weeks for results, but many cell therapies need to be administered in days •New PCR-based testing kits are now commercially available •Assay for mycoplasma in hours
Production of Protein Therapies
•Need to produce enough therapy to treat our patient •Can't simply increase scale of the chemical reaction •Instead, we increase the scale of the producer cells •Has to all be done in a sterile environment
Disadvantages of gastro-retentive dosage forms
•Not suitable for drugs that have low solubility in the stomach •Not suitable for drugs that are unstable at acidic pH •Not suitable for drugs that cause irritation in the stomach Systems require high levels of fluid in the stomach for efficient floating
Phase 3 Clinical Trials
•Often a global program •For many drugs, need two well- controlled, large clinical trials •1000-3000 volunteers • 2-7 years
Quality and Scaling
•Once safe and potent, need to produce adequate quantities for patient treatment •Cells can be stored allowing several batches to be developed to achieve desired cell number •Need to determine purity •Typically use flow cytometry to detect surface markers to characterize cells
Humalog (insulin lispro) (onset, peak, duration)
•Onset of action: 15 - 30 min •Peak effect at 1 hour •Duration of effect: 3 - 4 hrs
Delayed release
•Part or all the drug is released at a time other at time of administration
•Particle decay (specifically ______ and ______) is very useful in therapeutic applications
•Particle decay (specifically negatron and alpha) is very useful in therapeutic applications
Therapeutic
•Particles (alpha, negatron) •Charged mass •Many specific ionizations in tissue
PET in Clinical Trials
•Phase 0 (Useful in biodistribution studies) •Phase 1 (Biodistribution, Receptor binding) •Phase 2/3 (Confirmation of efficacy)
Diagnostic
•Photons (gamma, positron) •Weak interactions
What are some drawbacks of modified release drug delivery?
•Poor formulations can lead to dose dumping •The drug often can not be removed from the system
Pharmaceutical development studies (before beginning clinical trials)
•Pre-formulation - physicochemical properties (stability, solubility, salt screening) •Formulation studies (excipients) •Manufacturing (Chemistry, manufacturing, and Controls) •Storage and Handling
Albumin accumulates in tumors:
•Precise mechanism unclear •Tumors secrete albumin-binding proteins •May promote preferential accumulation of albumin around tumors
Reasons for Enteric Coating
•Preventing degradation of drugs in the acidic pH of stomach (acid-labile drugs) •Preventing irritation of the gastric mucosa •Preventing the release of drugs that impede digestion in the stomach •Targeting drugs to a specific region for local effect (obtaining higher concentrations) •Delaying release
Assessing Fate of Therapeutic Cells is important for development and regulatory issues:
•Provides insights into biologic function •First assessed in animal models •Explore how manufacturing impacts function •Patient monitoring
Radioactivity in Drug Development; imaging studies
•Receptor binding •Dose escalation •Therapy monitoring
What is the Impact of Extended and Other Modified Release Formulations?
•Releases a bioactive drug over an extended period of time -Avoids sawtooth characteristics
Albumin
•Reversibly binds hydrophobic molecules allowing these substances to be transported in the body and released at the cell surface •Through receptor binding, albumin initiates transcytosis of unbound and albumin-bound constituents across endothelial cells into the interstitial space
Final Formulations
•Screened for safety, efficacy, stability etc. •Protein therapy is typically lyopholized •Shipped to hospitals and pharmacy's •Use to treat patients as prescribed
What problems could arise from differences between biosimilars and originator proteins?
•Small differences in impurities, breakdown products, and formulations have significant clinical impacts •New regulations are being put in place to address these concerns
Overcoming the Limitations of Paclitaxel Vehicles
•Specialized tubing with in-line filters •Prolonged drug infusion rates •Pre-medications: •Corticosteroids •Infection, ulcers, withdrawal symptoms (fatigue, fever, stiffness) •Antihistamines •Minor side effects •Does not eliminate all effects of cremophor and ETOH
pH controlled colon delivery
•Systems rely on the increase in pH in GI-tract (stomach to small intestine) •Use polymers with appropriate pH/solubility profile -insoluble at the lower pH in the stomach and upper small intestine -soluble in the higher pH of the distal small intestine
TRAIL
•TNF-α-related apoptosis-inducing ligand (TRAIL) naturally occurring protein that is arrayed on the surface of immune cells
New Drug Application (NDA) and FDA Approval
•The NDA is the formal proposal for the FDA to approve a new drug for sale in the US
Clearance in the liver/spleen challenges to systemic delivery
•Tissue-resident macrophages or other organ-specific cell types -Macrophage job is to sequester and eliminate foreign invaders
Raw Material
•Undifferentiated cells in the body that can differentiate into specialized cells and divide to produce more stem cells •Various types of stem cells exist •Each has distinct functions that confer benefits and limitations in use
Radioactivity in Drug Development; ADME studies
•Use radioactivity to assess absorption •Ascertain distribution using radioactive compounds •Radiolabel NMEs to determine metabolic pathway •Draw conclusions regarding excretion of new molecules
enzymatic release colon delivery
•Use starch-based coatings that are resistant to digestion in the stomach and small intestine •Use materials that are degradable by microbial (normal gut flora) enzymes in the colon
Potency requires
•design of cell-specific tests •Ie: ES-derived cardiac cells should be evaluated for beating cultures in vitro
Radiation therapy
•external source directed to patient •therapeutic
Radiology
•external source passing thru patient •diagnostic
Eprex Formulation Change
•human serum albumin (HSA) was removed from Eprex as a stabilizer due to concerns of mad cow disease transmission in Europe •HSA was replace with polysorbate 80 as a stabilizer
Insulin lispro has less chance of
•inducing a hypoglycemic reaction several hours later due to brief activity •Product of recombinant DNA technology
Nuclear medicine
•internal source detected externally •mostly diagnostic
How do nucleic acids induce an immune response?
•siRNA or antisense oligos can be recognized by the innate immune system •Toll-like receptor 3 (TL3) recognizes double-stranded RNA and TL7 and TL8 recognize single-stranded RNA Sequence optimization and chemical modifications can partially address the immunogenicity issues
Recombinant erythropoetin is commonly used to:
•treat anemia associated with a variety of cancers, HIV, and renal failure
Side effects of Muromomab CD-3
Skin reaction, fatigue, fever, chills, nausea Voluntarily pulled from market due to reduced usage. Newer variants now available
Subcutaneous injections
Slower onset of action Volume up to 2 mL No dilution opportunity Absorption is a diffusion controlled process
Purpose of spacers:
Slows droplet velocity Allows evaporation Controls inhalation rate Traps large droplets
Environment for production
Small molecules: benchtop, fume hood Biologics: sterile cell culture hood, bioreactor
Starting material Small molecules: Biologics:
Small molecules: chemical or powders Biologics: DNA
Method of Production Small molecules: Biologics:
Small molecules: chemical reaction Biologics: protein expression in living cells
Purity of production material
Small molecules: contains primarily target drug Biologics: Contains therapeutic protein mixed with many other proteins
Time for synthesis Small molecules: Biologics:
Small molecules: hours to days Biologics: weeks to months
Strategy for scaling Small molecules: Biologics:
Small molecules: larger-scale chemical rxn Biologics: grow (expand) producer cells
Able to target any disease (theoretically)
Small molecules: maybe? Biologics: yes
Complexity of drug Small molecules: Biologics:
Small molecules: usually simple Biologics: highly complex
Interventions for dry eye
Solutions, suspensions, emulsions, ocular inserts
Are targeted therapies systemic or local?
Some are delivered systemically, but targeted to enhance uptake in certain regions, although the drug is systemic
Ways to overcome limitations of Paclitaxel vehicle
Specialized tubing with in-line filters Prolonged infusion rates Pre-medications - Corticosteroids - Antihistamines
What are auto-injectors?
Spring-loaded, pre-filled syringes with needles (ex/ EpiPen)
Effects of PEGylation of a drug?
Stealth properties that allow for longer circulation times
What is another type of pre-treatment for patients receiving monoclonal antibody treatment?
Steroid modulation
Lyophilization is dependent on
Sublimation
GM-CSF nomeclature
Suffix - gramostim
G-CSF nomeclature
Suffix - grastim
In pMDIs, oleic acid functions as a:
Surfactant
Examples of solubilizing agents
Surfactants Complex formation agents Co-solvents
What types of ingredients may cause leaching?
Surfactants, cosolvents, oily solvents
Floating devices
Swellable membranes, effervescent layer with CaCO3 +citric acid, conventional sustained release pill
Alphagan Reformulation
Switch of preservatives from benzalkonium chloride to PURITE
Drug administration to the alveoli is usually intended for (local/systemic) drug delivery
Systemic
Delivery to posterior eye
Systemic (PO, IV) Intravitreal, Periocular, Subretinal
Systemic means the drug is delivered ________, more or less equally
Systemic means the drug is delivered throughout the body, more or less equally
What can be used to deliver drugs to the eye?
Systemic or local administration
What is TRAIL?
TNF-alpha-related apoptosis-inducing ligand (TRAIL)
EPR effect
Taking advantage of leaky vasculature in tumors to allow macromolecules to enter and be retained in the tumor. Nanoparticles will selectively leak into the tumor but spare healthy tissue.
How was Eprex-induced immunogenicity fixed?
Teflon-coated stoppers Strict storage guidelines (between 2-8 C) Required IV administration
Fate of a 15-micron drug
Terminal bronchioles due to intertial impaction (10-60)
How long after submitting an IND must you wait before beginning clinical trials?
The FDA has 30 days to put a 'clinical hold' on your study
How does the content of stem cells in the peripheral blood compare to that in the bone marrow cavity?
The content of stem cells in the peripheral blood is much less than in the bone marrow cavity: • In bone marrow 3-5% of cells are CD34+ • In blood stream only .03-.05% of cells are CD34+
Why does a suspension or oily solution have a longer onset of action?
The drug needs to be liberated first.
What is affected by phase transition temperature?
The drug release from liposomes during circulation and at the disease site
ISO Classes in an aseptic manufacturing area are determined by:
The maximum number of particles of a specific size range per cubic meter of air
Phase transition temperature
The temperature required to induce a change in the lipid physical state from the ordered gel phase where the hydrocarbon chains are fully extended and closely packed, to the disordered liquid crystalline phase, where the hydrocarbon chains are randomly oriented and fluid
