Fang PDFs Flashcards
What metric is used to define the rate of absorption?
Cmax
Comparing a drug product’s oral area under the curve (AUCo) to its own IV area under the curve (AUCiv) is an estimate of what?
Absolute Bioavailability
Comparing the Plasma Concentration vs. Time profile of a Test Product to its comparator Reference Product is an estimate of what?
Relative Bioavailability
What type of test volunteers should be used when conducting Comparative Bioavailability Studies?
Normal & Healthy Patients (as conclusions drawn from the study should hold true in populations).
How would we define ‘bioequivalence’?
Test Product is expected to have the same therapeutic effect & safety profile as its Reference Product.
What is a ‘Two Period Crossover’ study, and what benefit does it have over other study types?
-Same subject gets Test Product, then gets Reference Product at a different time.
-Intra-subject error is lower (in comparison to Inter-subject Error if we used more than one subject to compare the two products).
What is a ‘Replicated Crossover’ study? What pros & cons does it have compared to other study types?
-Each formulation (ie. Test & Reference Product) examined more than once in a patient.
-Less subjects required (good) but more patient appearances needed (bad).
What types of patients would it be suitable to conduct a ‘Crossover Without Washout’ type study?
For those whom abrupt drug discontinuation would be unethical or unsafe to do.
What types of drug products would it be advisable to conduct a ‘Parallel’ study type?
1) Long t1/2elim
2) Drug w depot effects
What four study factors influence how many subjects should be used?
1) Standard
2) Mean Difference (btw Test & Reference Formulations)
3) Intra-Subject Variance
4) Study Power
What is the bare minimum number of test subjects that should be used in Comparative Bioequivalency Studies?
12
In bioequivalence studies with more than twenty subjects, what percentage of patients can be excluded due to being considered “statistical outliers”?
No more than 5%
In bioequivalence studies with less than twenty subjects, what number of patients can be excluded due to being considered “statistical outliers”?
1
What two PK parameters are typically examined in the determination of statistical outliers?
AUC & Cmax
When conducting bioequivalence studies in the “Fasted State”, how long must subjects go without food? Water?
Food: 8hrs before drug administration (but no closer than that).
Water: Up to 1hr before drug administration.
In “Fasted” bioequivalence studies, after how many hours post-administration of drug are subjects okay to eat?
4hrs (so long as meals are standardized across patient groups).
How would water intake timelines differ in a “Fasted” study if the formulation of the product was an ODT (instead of a traditional IR oral tablet)?
IR: Water up to 1hr before drug admin, can drink water right after!
ODT: Water up to 1hr before drug admin, no water for 1hr after dose given!
If conducting a “Fed State” bioequivalence study, when should a meal be given?
30mins prior to drug administration
When giving a meal for a “Fed State” bioequivalence study, what kcal target should one aim for? What percentage of it should be derived from fats?
800 - 1000kcal ; 50% from fats.
Drug concentration sampling should last at least ___x the terminal half-life of the drug being examined.
3x
A bare minimum of ____ drug concentration samples per subject per dose should be taken.
12
What bodily fluid is used to measure drug concentrations?
Blood
What five things should bioanalytical methods be?
-Reproducible
-Selective
-Sensitive
-Precise
-Accurate
The 90% Confidence Interval of the Relative Mean AUC vs. Time profile should fall within what range of values?
80 - 125%
The 90% Confidence Interval of the Relative Mean Cmax values for Test Product (in comparison to the Reference Product) should fall within what range of values?
80 - 125%
When conducting systemic effect analysis, the study should be performed under ______ (Fed / Fasted) conditions.
Fasted
Bioequivalence for a MR dosage form must be demonstrated under which condition(s)?
Fed
Fasted
Both
Neither
Both
Why must bioequivalency be demonstrated in both fed and fasting states for a Modified Release (MR) dosage form?
Increased risk of adverse effects (such as GI Irritation) & increased likelihood of Inter-Subject Variability in F values!
The relative mean Cmin values for Test Products (vs. Reference Products) at steady state concentrations cannot be < ____%.
80%
The 90% Confidence Interval of the Relative Mean AUC vs. Time profile for a Narrow TI drug must fall within what range of values?
90 - 112%
The relative mean Cmax for a Narrow TI drug must fall between what range of values?
80 - 125%
What drugs would be considered “Critical Dose Drugs” in bioequivalency studies?
-Cyclosporine
-Digoxin
-Flecainide
-Lithium
-Phenytoin
-Sirolimus
-Tacrolimus
-Theophylline
-Warfarin
I’m conducting bioequivalency studies on Levothyroxine, a T4 hormone analogue… Briefly describe how I would determine exogenous drug levels.
-Obtain baseline levels of T4 from patient before administering drug, then gather total T4 levels at steady state & subtract those concentrations from baseline readings (to get just the exogenous drug concentrations).
Only Class __ & __ BCS drugs qualify for biowaivers (& can thus be exempt from bioequivalency studies).
Class I & III
Provided a drug falls within Class __ (ie. High Solubility & Permeability), it may qualify for a biowaiver in spite of existing as a different salt form than its Reference Product.
Class I
I have a category Class III drug (Rizatriptan 10mg ODT) that I want to get patented. Would it qualify for biowaiver status (& thus bioequivalency exemption status)?
NOOOOO… Biowaivers only applicable to IR, Oral dosage forms (ODTs would not qualify)!
What is the pH range for determining drug solubility?
1.2 - 6.8
When determining a Test Product’s solubility status, how many samples along the pH range must be taken?
Three or more!
Which of the following measured drug solubilities is used to classify a Test Product’s solubility status?
Highest
Intermediate
Lowest
All of the Above
Lowest
What classifies a Test Product as having “high permeability”?
-85% (or greater) Absolute Bioavailability
-85% (or greater) of the administered dose appears unchanged in the urine
What two categories of excipients can alter a Test Product’s extent &/or rate of absorption?
1) Sugar Alcohols (ie. Mannitol, Sorbitol)
2) Surfactants (ie. Sodium Lauryl Sulfate)
I have a drug that is considered to be Class I. We want to determine (based upon inclusion excipient status) if it’s eligible for biowaiver status.
Test Prod: 65g Mannitol
Reference Prod: 75g Mannitol
Is it eligible for a biowaiver?
65g / 75g x 100% = 86.67%
100 - 86.67 = 13.33%
-Test product is no good for biowaiver status! Not within +/- 10%!!!
I have a drug that is considered to be Class III. We want to determine (based upon inclusion excipient status) if it’s eligible for biowaiver status.
Test Prod: 65g Mannitol, 10g Sodium Lauryl Sulfate
Reference Prod: 65g Sorbitol, 10g Sodium Lauryl Sulfate
Is it eligible for biowaiver status?
NOOOOO!!! Although total masses of excipients are the exact same, we need them to be qualitatively (& quantitatively) the EXACT SAME (Mannitol is a different Sugar Alcohol than Sorbitol, so need to do bioequivalency studies).
