Quiz 6 Flashcards
non-target drug delivery
most conventional dosage form - eventually reaches the site of action by distribution and passive diffusion
targeted therapies
reach the right site at the right dose at the right time for the correct duration - pick out the cancer cells
how targeted therapy is different from chemotherapy
uses drugs, targets the cancers specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. takes advantage of the difference between normal cells and cancer cells. sometimes they are used alone, but most often used in combination therapy
targeted therapy can work to
block or turn off chemical signals that trigger growth and division
change proteins inside the cancer cells
stop making new blood vessels that provide nutrition
trigger your immune system to attack cancer cells
carry toxins to the cancer cells to kill specific cells
targeted therapy strategies (4)
- monoclonal antibodies
- antibody directed enzyme prodrug therapy (ADEPT)
- immunotherapy (cellular immunotherapy, virotherapy/oncolytic virus therapy, MAbs)
- gene therapy
delivery carrier strategies
- vectors
- liposomes
- nanoparticles
monoclonal antibodies
the formation of a monoclonal antibody (mAb) is one of the most powerful techniques for incorporating a drug into a site-specific system- mABs are highly specific and recognize only one antigenic determinant or receptor site
naked mab
add nothing to mAB - trastuzumab - cause other tcells/bcells to get rid of what is attached - targets the extracellular domain of the HER2 protein
conjugated MABs
circulates until it finds its target antigen, once bound- releases a toxic agent. thus, less damage to normal cells
radiolabeled MAbs
goes to the side of action and kills, antibody against CD20, antigen on >20% B-cell lymphomas, target B cells if they have CD20 on their surface, non-hodgkins lymphoma, targets only what you want to kill
Ibritumomab tiuxetan
radiolabeled mAbs
trastuzumab
naked mab
chemolabeled MAbs ADC
antibody drug conjugates (ADC), mAb to CD30 attached to chemo drug MMAE, antigen on lymphocytes, hodgkin lymphoma - has a linker that is a synthetic protease-cleavable linker that covalently attaches MMAE to the CD30 directed antibody and releases the agent in the cell -MMAE binds to tubulin disrupting the microtubule network and arresting the cell cycle resulting in apoptosis of the cancer cell
drawbacks to chemolabeled MAbs
- off target toxicity- takes up normal cell if there is not a toxic cells (bistandard effect- once cell dies leads to kill of other cells nearby)
- mAb: linker needs enzymatic reaction, sometimes linker is weak and breaks out early causing cytotoxicity
antibody directed enzyme prodrug therapy
mab used to target the side, the enzyme breaks down the prodrug, works around the timor not in the tumor
bystander effect of ADEPT
capability to kill the surrounding non-dividing/non-expressing tumor cells and it amplifies the drug effect
good ADEPT canidates
small molecules with ability to diffuse inot the tumor tissue
targeted immunotherapy
non-specific immunotherapy and specific immunotherapy (cancer vaccines and virotherapy)
T-cell transfer therapy (CAR-T-Cells), immune checkpoint inhibitors (mAbs)
provenge
cancer vaccine, cellular immunotherapy
virotherapy
designed to replicate tumors (not normal tissue) and initiate an immune response to target cancer cells that have metastasized
CAR T-cells - cellular immunotherapy
engineers patients immune cells (T-cells) to treat their cancer
blood is drawn from patients and T-cells separated
viral vector gene coding for a specific antigen is inserted into the T-cells to produce receptors on their service called chimeric antigen receptors (CARs), speciic to a protein on tumor cells, Eg of antigen: Car T cell therapy furthest along in development target an antigen found on B cells called CD19
keytruda (pembrolizumab)
mAb targets PDL-1
gene therapy
fixing a defective gene in the cell by insertion of a functional gene or group of genes - gene control protein expressed, used to treat, cure or prevent disease by changing the expression of a person’s genes or providing a missing protein via delivery of the gene for that protein - effective in getting the right genes into the accurate cells
sucessful gene therapy requires two main components
- therapeutic gene
2. gene deliver system
why has gene therapy not been very successful
delivery vehicle to target genes to desired cells, internalized and reaches nucleus, not enough expression of the delivered gene
delivery carrier strategies - vectors
carrier- a transfection vector - delivers the therapeutic gene to a patients target cells
vectors used on viral and non-viral
viral vectors
carry a modified or foreign gene, most efficient method for gene transfer, infect target cell and transfer the therapeutic gene using their natural biological mechanism, primary requirement is that virus must be unable to replicate and have no lytic (ability to rupture a cell) activity
examples of viral vectors
retroviruses, adeno-associated virus, parvoviruses, herpesviruses, poxviruses
non-viral vectors- Why and what are they made of ?
naked DNA, because viral vectors cause toxicity, immune and inflammatory responses, gene control and tissue targeting (other approaches use liposome complexes and polymer DNA carriers)
liposomes
- alter the pharmacokinetic profile of drugs
- reduce off-target toxicity
- improve the therapeutic index
usually liposomes cannot release drug without interacting with cells
liposome interactions occur in several ways
- endocytosis
- adsorption
- fusion
- lipid exchange
doxil
liposomal doxorubicin
PEGylated liposome carrier loaded with cytotoxic anticancer drug doxorubicin
diffuses across blood vessels into normal tissues and tumors, retained within the blood pool except at sites of increased vascular permeability such as the liver, spleen and tumors - half life 100x longer than free doxorubicin
cardiotoxic risk is 7x lower than free drug
nanoparticles
improve deliver, therapeutic efficacy, patient outcome
Stealth-like features : evade the immune system • Protective layers : prevent the degradation of biologics (e.g. proteins, DNA) • Targeting moieties : improve specificity and tumor accumulation • Membrane-permeation moieties : improve cell uptake • Imaging agents : assess delivery and dosing • Endosome escape mechanisms : longer half-life • Target-dependent assembly or disassembly : control drug release • Microenvironment sensors. eg: pH, proteases : trigger drug release and cellular uptake • Intracellular targeting moieties : direct drugs to specific intracellular compartments
each new functionality elevates
complexity, cost, regulatory barriers
tumor biomarkers
are antigens and help target -
1. folate receptor 2. EGFR 3. HER2
nuclear medicine
branch of medicine that utilizes radioisotopes/ radionuclides and radiation in diagnosis and treatment of disease
radioactivity
radiation emitted as a result of spontaneous decay of unstable nuclei of atoms. break down/decay of unstable isotope - undergoes changes until stable state is reached - consists of alpha, beta, positron emission, gamma rays (PET< SPECT (, therapeutic (zevalin)
decay rate vs half life of radioisotopes
differ in rate of decay but definite time required for half of original atoms to decay
alpha particles
fast moving helium atoms - have high energy - due to their large mass they are stopped by just a few inches of air or a piece of paper
beta
fast moving electrons are ejected from nuclei, since electrons are much lighter than alpha particles, they are able to penetrate further, penetrate several feet of air or several millimeters of tissue or plastic
positrons are
counter parts to B particles
gamma
these are photons, except much higher energy, more than x rays, energy depends on the stability of nuclei that emits them. they pass through most materials, depending on their energy, they can be stopped by a thin piece of aluminum foil or they can penetrate several inches of lead
frequently used radionuclides/isotopes
Technetium -99m, indium 111, selenium 75, flourine 18, iodine 123, FDG, xenon gas
tc-99m
m - metastable
used in 80% diagnostic procedures, half life 6 hours, biological half life is shorter due to rapid renal cl, shorter biological half-life will clear excess drug from the body quicker providing better images
decay: gamma emission has no beta emission which minimizes patient exposure
technitium tc-99m
made in a molybdenum (Mo-99) generator, t 1/2 = 200000 years decays by beta emission
Tc-99m sestamibi injection (cardiolite) indications
myocardial perfusion, breast cancer, parathyroid
Tc-99m sestamibi injection (cardiolite) MOA
- Diffuses into myocardium amount of drug taken up is proportional to amount of blood flow in tissues
- Ischemic areas of myocardium can be visualized and occluded vessel leading to ischemic area can be determined
Tc-99m sestamibi injection (cardiolite) administration procedure
Initial dose: 14-17 mCi Tc-99m sestamibi IV, Initial imaging: Begin 1 hr after initial dose administration
Tc-99m sestamibi injection (cardiolite) stress test
walk on treadmill
fluorodeoxyglucose (FDG)
Fluorine-18 (F-18)
Decay: positron emission
t1/2: 110 mins (very short half-life)
Produced by bombardment of O-18 with protons
Used to detect cancers or tumors that cannot be visualized with MRI
fluorodeoxyglucose (FDG) F-18 indications
Cancer diagnosis – staging evaluation of
treatment response
Brain activity in seizure patients
Diagnosis of Alzheimer’s disease
fluorodeoxyglucose (FDG) F-18 MOA
Structure similar to glucose attached to
positro9n emitting F18 isotope
Imaging parallel to tissue uptake of glucose
Eg: cancer cells have high metabolic
requirements, so higher levels of glucose
uptake. FDG concentrates in tumors
fluorodeoxyglucose (FDG) F-18 admin procedure
Administration procedure
Initial dose: 14-16 mCi FDG I.V.
Allow patient to rest while drug distributes
Limit physical activity to reduce muscle uptake
If specifically imaging the brian, keep patient in a
dark room
Imaging begins 1 hr after dose administration
fume hood
ISO Class 5 • Laminar vertical airflow • Sides, back, and bottom are covered in 3⁄4” thick lead • Dose calibrators are lead- lined, 2” thick L-block is a 3/4 lead shield which provides protection while compounding
hot cell
Shielded nuclear radiation containment chamber
Used to protect individuals from radioactive
isotopes by providing a safe containment box in
which they can control and manipulate the
equipment required.
Used for handling high energy radiopharmaceuticals
like FDG
geiger meuller survey meter and pigs
• Pigs are used to transport
doses
• Usually made of tungsten
or lead
compounding kits
Kits are sterile ingredients made for specific
radiopharmaceutical preparations
Kits include: buffers, antioxidants, ligand, and reductant
The kit is mixed with the radioactive isotope to produce the
required product
Commercially available
Preferred in this environment, since they are “closed”
systems
Preparations can be made “in-house”, if needed, but the
process is complicated
radiation dosimetry
Important devices used to measure exposure over a certain period of time Types of dosimeters: Ring Badge Pen
radioactive decay - first order reaction
N = N0e-λt
N = number of atoms remaining at elapsed time t,
N0 = number of atoms originally present
� = decay constant for time (also disintegration or transformation)
Decay constant units– reciprocal seconds, minutes, hours, etc…
Half life (t1/2) = 0.693/λ
units for radioactivity
Curie (Ci)
That quantity of radioisotope in which 37 billion (3.7*1010) atoms disintegrate per second
Becquerel (Bq) – SI
1 disintegration per second, most common is multiples of this unit KBq, MBq, GBq
Doses currently expressed in both Bq as well as Ci (most common system in Cardinal
Health in nuclear pharmacy is still Ci).
Authorized User:
practitioner of the healing arts who is identified as an authorized user
on a license issued by the State Board of Health that authorizes the medical use of
radioactive material, hazards, and the applicable regulations of the U.S. Nuclear
Regulatory Commission.
Radiopharmaceutical:
Any substance defined as a drug which exhibits spontaneous
disintegration of unstable nuclei with the emission of nuclear particles or photons and
includes any such drug which is intended to be made radioactive.
Radiopharmaceutical Quality Assurance:
the performance of appropriate chemical,
biological and physical tests on radio-pharmaceuticals, and the interpretation of the
resulting data to determine their suitability for use in humans and animals, including internal test assessment authentication of product history and the keeping of proper records.
transdermal for PEDs
variable in younger children. teens are more viable because it has matured
parenteral dosage
drugs admin continuously via the IV route in small children typically require a syringe pump, the dose volume in very young patient is likely to be small yet each requires that there be sufficient volume to permit admin of the correct dose per hour.
pediatric population age
birth-18
geriatric population age
65 and older
pediatric absorption
Neutral gastric pH for first 2 weeks of life
Gastric pH slowly decreases to adult levels by 2 years of age
Neonates and infants can have variable GI motility and absorption
Infants and children have thinner, more hydrated skin
Neonates have scares musculature
pediatric distribution
Infants have increased volume of distribution of water-soluble drugs
Neonates have increased BBB permeability
Infants less than 6 months old have decreased albumin
pediatric metabolism
Ability to metabolize develops at varying rates
Some enzymes are not fully viable until 4 years of age
pediatric excretion
Renal function is highly variable, approaching full capacity between 6 months and 3 years of age
geriatric absorption
Increased gastric pH
Decreased GI motility, intestinal blood flow, and absorptive area
Thinner, less hydrated skin
Less musculature
geriatric distribution
Increased volume of fat distribution for fat-soluble drugs
Decreased albumin
geriatric metabolism
Decreased hepatic blood flow and metabolic capacity
why are pediatric patients therapeutic orphans
Children are the population most often excluded from medication dosing guidelines as only 20% of all medications have FDA-approved pediatric indications.
FDA approval requires testing on children, which brings major ethical dilemmas with it.
when considering dosage for a pediatric patient you need to examine
- ability of the patient to use the dosage form
2. patient acceptance of the dosage form
solid dosage form drawback -peds
locks you into a specific dose - most childeren can’t swallow tablets or capsules until age 6,
when are chewables good
appropriate for children eating solid food, especially if it reduces dose volume and unpleasant taste
orally disintegrating tablets
useful for school-age children
liquid dosage forms- peds
more freedom to individualize dose, addresses problem with inability to swallow pills
problems with excipients in liquid dosage forms with children
- elixirs are not suitable for the smallest patients due to adverse effects
- ethanol: CNS depressant, confusion, GI upset
- propylene glycol: hypotension arrhythmia, hemolysis
suspensions - peds
compounded suspensions should follow primary literature guidelines, suspensions are preferred to solutions because of masking of unpleasant taste - also challenge to patient acceptance due to texture
how does ADEPT work
utilizes mAb that target cancer cells to carry a pro-drug activating enzyme, patient is given prodrug via IV infusion, when the prodrug encounters the enzyme on the mAb that are bound to the receptors on the cancer cells, the prodrug is activated to its cytotoxic form
acetris (bentruximab vedotin)
chemolabeled mAb
immune checkpoint mAb
Immune checkpoint mAbs target antigens on tumor cells that tell the T-cell that they are normal cells. The mAbs block the inhibition of T-cells so that they will recognize and kill the cancer cells.
Now being combined with other immunotherapies to amplify the effects.
BSA
square root (((pt wt in kg)(pt ht in cm)/ 3600))
childs dose BSA
(childs BSA) (adult dose) / 1.73 m2
ideal body weight male
IBWm = 50 kg + 2.3 kg for each inch of height over 5 feet
ideal body weight female
IBWf = 45 kg + 2.3 kg for each inch of height over 5 feet
