Exam 3 - Dadey Flashcards
Immediate physiological processes involved drug administration:
Drug injected/absorbed into systemic circulation –>
drug moves through systemic circulation –>
drug is free and/or bound to proteins –>
Drug is distributed throughout body
Physiological processes involved in in distribution:
Four possible outcomes:
- Drug is perfused into tissues
- Drug partitions into fat
- Drug reaches target site (produces pharmacologic response)
- Drug reaches non-target site; non-receptor tissue; non-therapeutic receptors (potential side/adverse effects)
Passive diffusion:
A process in which drugs move from an area of high concentration to an area of low concentration and is
described by Fick’s Law of Diffusion
Fick’s Law of Diffusion equation:
dQ/dt = (-DKA(Cp - Ct))/h
What do each of the following variables stand for in the Fick's Law of Diffusion equation: D K A Cp Ct h
D = Diffusion Constant K = Lipid-Water Partition Coefficient A = Surface Area of the Membrane Cp = Drug Concentration in Plasma Ct = Drug Concentration in Tissue h = Thickness of the Membrane
What is hydrostatic pressure (pushing force)?
A process in which drugs move through the capillary wall due to pressure within the arteriole wall
Hydrostatic pressure process:
Arterial end:
- Fluid coming from the heart exerts “pushing force” on interior of vessel
- Higher pressure inside vessel than tissue creates gaps in vessel wall
- Solutes move out of vessel through gaps into interstitial space
- Solutes that are too large remain in vessel
Venous end:
- “Concentrated” blood proteins produce osmotic colloid effect
- Pressure is lower than in interstitial space
- Water is pulled into venue from interstitial space to re-establish equilibrium
- Colloid osmotic pressure is also called Oncotic Pressure
Generally speaking, do drugs that interact with protein do so reversibly or irreversibly?
Reversibly
What types of processes are involved in protein binding?
Ionic bonding
Hydrogen-bonding
Van der Walls Interactions:
Dipole-dipole
Dispersion forcesWhat process usually occurs in irreversible protein binding?
Covalent bonding (i.e. reactive species produced from APAP metabolism that binds with liver proteins)
What are the most common proteins found in the blood?
- Albumin
- A1-acid glycoprotein
- alpha1-, alpha2- , beta-, and gamma-globulins
- Lipoprotein
Protein binding equilibrium constant (K) equation:
KA = [PD] / [P][D] KA([P][D]) = [PD]
In protein binding, r = ?
r = moles of drug bound / total moles of protein
What is the equation for protein binding of one drug molecule to one molecule protein?
r = (KA[D]) / (1 + KA[D])
What is the equation for protein binding of more than one drug molecule to one molecule of protein?
r = (n KA[D]) / (1 + KA[D]); where n = number of IDENTICAL binding sites on one molecule of protein
What is the equation for protein binding if there is more than one INDEPENDENT binding site on the protein molecule for the SAME drug?
r = [(n1K1[P]) / (1 + K1[D])] + [(n2K2[P]) / (1 + K2[D])] + …
WHERE: (1) n1 and n2 represent independent binding sites for a specific drug on one protein
molecule
(2) K1 and K2 represent the individual association constants for each binding site
What is a Double Reciprocal Plot?
PLOT 1/r vs 1/[D] to give a straight line.
(1/r) = {1/(nKA[D]} + (1/n)
This equation assume ONE type of binding site on the protein molecule and assumes NO interaction of binding sites.
What is a Scatchard Plot?
Plot r/[D] vs r
r/[D] = nKA - rKA
Used when there are two different and independent binding sites
In equilibrium dialysis, a measurement of protein binding, what is the equation for calculating the concentration of protein-bound drug?
[Dbound = [Dtotal] - [Dfree] * 2
r = [Dbound] / [Ptotal]
Remember, the equation for the Scatchard Plot is:
r/[D] = nKA - rKA
Is the Scatchard Plot for used to measure one experiment or multiple experiments?
Multiple experiments; one experiment = one data point
Where does absorption occur for orally administered drugs?
Absorption for orally administered drugs can occur anywhere along the GI tract; however, the duodenum region is the optimum site for drug absorption
How does the presence of food in the GI tract affect absorption?
- Delays gastric emptying
- Stimulates bile flow
- Changes pH
- Increases splanchnic blood flow
- Interacts (physically and/or chemically) with drugs
The FDA provides what to the pharmaceutical industry regarding the assessment of bioavailability of Immediate-Release Drug Products in the fasted and fed states?
Guidance; the FDA recommends the a food-effect BA study be conducted for NCEs during the IND period
In practice, what does the FDA say regarding Food Effects on Drug Products?
The FDA says that it is difficult to determine the exact mechanism by which food changes the BA of a drug product without performing specific mechanistic studies
What does the FDA recommend to do to determine the food-effect BA and fed BE of a drug product?
Perform a Test Meal; this would be a study that is conducted using meal conditions that are expected to provide the greatest effects on GI physiology so that systemic drug availability is maximally affected
What are some ways that the presence of food in the GI tract can alter BA?
- Decreases the BA when compared to the fasted state (Flomax)
- Increases the BA when compared to the fasted state (Skelaxin)
- Little to no effect on the BA when compared to the fasted state (Neurontin slight increase)
What did investigators use “the capsule” to measure in determining the PK profile of celecoxib?
Healthy subjects:
- Gastric emptying time (GET); normal was 5 hours or less
- Small bowel transit time (SBTT); normal was 2.5 to 6 hours
- Colonic transit time (CTT)
- Whole gut transit time (WGTT)
In patients with:
- Suspected delayed gastric emptying
- Chronic idiopathic constipation
Generally, what is the absorption window for most drugs following oral administration?
- 4 to 8 hours (GET + SBTT) post dosing under fasting conditions
- 8 to 12 hours (GET = SBTT) post dosing under fed conditions
Generally, how should the release of the drug substance from the drug product be designed?
It should be designed to coincide with the absorption window in order to maximize plasma drug levels
Define drug substance:
API that is the chemical that produces the pharmacologic effect
Define drug product:
The final form of the drug substance(s) = inactive ingredients that is provided to the patient
Define inactive ingredients:
Substances, materials, etc. that are used in combination with
the API to manufacture the drug product
Define bioavailability:
Rate and extent to which the API is absorbed from a drug product and becomes available in the systemic circulation. RECALL bioavailability (absolute or relative) is calculated as F
Define bioequivalence (between two different dosage forms of the same API):
When the absorption (rate and extent) of an alternative drug product is equivalent to the absorption (rate and extent) of the innovator’s drug, then the alternative drug product met the conditions of bioequivalence and is said to be bioequivalent to the reference-listed drug (RLD)
Define reference-listed drug:
Drug product specified by the FDA that can be used as the
comparator in bioavailability/bioequivalence (BA/BE) clinical studies
Define biosimilar:
Used to describe a GENERIC version of a biological product (primarily proteins for now…)
Even though BOTH proteins produce the identical pharmacologic response (both lower blood glucose levels at the same rate and to the same extent), can the European version be considered a GENERIC of the US version and not be required to undergo the same toxicological evaluation that the innovator HAD to conduct in order to receive marketing approval?
Yes, it can be considered a generic because the drug product is equivalent to the absorption (rate and extent) of the innovator’s drug
What are some of the reasons why a pharmaceutical company may develop a generic drug product?
- The innovator conducted the R & D to identify the drug
- The innovator manufactured the drug on a commercial scale
- The innovator completed the toxicity testing and showed that the drug was safe
- The innovator showed that the drug was:
- Safe
- Did not degrade to toxic products
- Developed “Good Manufacturing Practices” for commercial production
- The innovator proved the efficacy in Phase 1, 2, and 3 clinical studies
- The innovator submitted the NDA to the FDA and received marketing approval
- The generic company must only show the AUC and Cmax of the generic version matches the AUC and Cmax of the innovator’s product
- The cost to bring generic product to market is significantly cheaper
- The development time is significantly shorter (2 to 5 years for generic vs 10 to 20 for innovator)
What are the concerns regarding the development of a generic product?
- Significant competition
- First company to secure approval of generic is granted 6 month exclusivity
- Company must prove that it doesn’t infringe on the innovator’s patent
- Generic company is typically sued for patent infringement (gives innovator 30 month stay)
- May be a “race to zero” following the introduction of multiple generics
Will the generic version of the innovator’s product produce the same pharmacologic effect?
Yes, as long as the drug product is equivalent to the absorption (rate and extent) of the innovator’s drug
What are the procedures for determining the BA or BE of drug products according to the FDA?
- In vivo test in humans in which the concentration of the API (or its active metabolites) are measured in appropriate biological fluids measured as a function of time
- In vivo test in humans in which the urinary excretion rate of the API (or its active metabolites) are measures as a function of time (at intervals as short as possible to measure the elimination rate constant is accurate)
- A currently available in vitro test acceptable to FDA (usually a dissolution rate test) that ensures human in vivo bioavailability
Is it necessary to measure the urinary excretion rate for drugs where urinary excretion is not a significant mechanism of elimination to satisfy the FDA BA and BE requirements?
No
What is the equation for the Arithmetic mean?
AM = (a1 +a2 +a3 +a4 +a5 +…+an) / N
What is the equation for the geometric mean?
GM = n / √(a1 · a2 · a3 · a4 · … · an)
Define confidence interval:
Provides the most likely range for the value in question
What are the steps to calculate the BE of a generic drug product to that of the innovator?
For example, the AUC of 16 patients receiving a new antibiotic as a tablet
- Calculate the AM AUC values of the 16 patients receiving the innovator’s product.
AM = (AUC1 + AUC2 + …) / 16 - Calculate the GM AUC values of the 16 patients receiving the innovator’s product.
GM = 16√(AUC1 * AUC2 * …) - and 4. Then do the same to determine the AM and GM values for the generic product
- Calculate the % ratio as the GMgeneric / GMinnovator
- Calculate the 90% Confidence Interval
7. Calculate the Standard Deviation for the generic product
SD = σ = √[(Ʃ (Xauc – Xam)^2) / (N-1)]
N = number of subject
Xauc = individual AUC values
Xam = arithmetic average
- Calculate the Standard Error
SE = σ / √N - Calculate the Margin of Error:
90% is 1.65; 1.65 * SE = Margin of Error - (AM + ME) - (AM - ME) = 90% Confidence Interval
What does a Confidence Interval of 90% indicate?
It indicates that there is a 90% chance that the AUC for this drug in a patient will be within the a certain range of AUC values (i.e. 3438.7 to 3037.1 μg·h/mL)
It also indicates that there is a 10% chance that the AUC for the drug product will be outside of this range
Generally, establishment of BE to an RLD is attained through the conduction of clinical trials and the demonstration that CMAX and AUC values are within what range when compared to the innovator’s product?
80-125%
Are there some cases when it is not necessary to conduct clinical trials to prove BE?
Yes, if the dosage form and the composition of the TEST product are essentially the same as the RLD, it may be possible to rely on in vitro dissolution data to establish BE
Is it reasonable to predict that the PK curve for the TEST article and the RLD would be the same if the dissolution curves are comparable via administration of the same route?
Yes
A tablet containing 100 mg of drug A is placed in the basket and immersed in 900 mL of 0.10 N HCl. Samples of the dissolution media are collected periodically and analyzed for drug content. What does the dissolution curve look like? Can this curve be used to compare a TEST drug to the RLD to satisfy BE requirements and avoid clinical trials?
Maximum Concentration = Label Claim (i.e. 100 mg / 900 mL = 111.1 μg/mL)
At time = 1.24 hours, concentration = 94.4 μg/mL; there for 94.4 μg/mL / 111.1 μg/mL = 0.85 = 85% = Q
Yes, If Q-values at specific time(s) for the TEST and RLD are the same, then it is possible that BE requirements are met and no clinical trials are needed
