Bioequivalence Part 2 Flashcards
What are the Methods for Assessing BA and BE?
In vivo measurement of active moiety or moieties in biological fluid (PK study)
In vivo pharmacodynamic (PD) comparison
In vivo limited clinical comparison
In vitro comparison (via disintegration or dissolution)
Any approach deemed acceptable (FDA)
Methods for Assessing BA and BE?
What do you test for in each method?
1) Plasma drug concentration
2) Urinary drug excretion:
1) Tmax, Cmax and AUC
2) - Cumulative amount of drug excreted in the urine
- rate of drug excretion in the urine
- time for maximum urinary excretion
Methods for Assessing BA and BE?
What do you test for in each method?
3) In vivo PD comparison
4) clinical endpoint study
5) in vitro studies
3) - max PD effect (Emax)
- time for max PD effect
- Area under PD effect-time curve
- onset time for PD effect
4) limited, parallel, comparative study using predetermined endpoints and done in patents
5) - comparative drug dissolution
- f2 similarity factor in vitro binding studies
e.g. cholestyramine resin- in vitro equilibrium and kinetic binding studies.
Factors Influencing BA
1) physiochemical properties of drug and formulation
If drug has low solubility in water
if dissolution rate is slow
particle size and surface area
some structural forms e.g. solvates dissolve poorly
2) Drug product
if there is a high ratio of excipients
or if it is needed or hinders absorption
3) drug stability
of drug and product affecting shelf life
API is unstable in some parts of GIT and needs coating
Other Factors Influencing BA
4) pH
5) dosage form surface and time for absorption
6) presystemic metabolism
7) food
8) drug-drug interactions
9) if drug or precursor is absorbed from certain site in GIT
10) efflux transporters
11) age and disease
12) dose dependent kinetics near/ in therapeutic range
Definition of a Prodrug
chemically modified drug
in an inactive form to improve solubility, chemical stability and bioavailability of the active drug by decreasing first pass metabolism.
After oral administration, the inactive prodrug is converted to the active drug generally by biotransformation or hydrolysis
Standard statistical requirements for bioequivalence studies
Data Handling
Analysis is based on log-transformed data.
Acceptance Criteria
Point estimate of the mean ratio (Test/Reference) for AUC and C_max must be between 80% and 125%.
90% Confidence Interval (CI) for AUC and C_max must also fall within 80% to 125%.
Review process for NDA vs ANDA
Brand-Name Drug NDA Requirements
1. Chemistry must be evaluated.
2. Manufacturing processes must be assessed.
3. Controls need to be established.
4. Labeling must be reviewed.
5. Testing is required.
6. Animal studies must be conducted.
7. Clinical studies are necessary.
8. Bioavailability must be determined.
Generic Drug ANDA Requirements
The same until 5. After this step Bioequivalence must be demonstrated.
Bioequivalence (BE) studies can be done for specific drug types and formulations to ensure that a generic drug performs similarly to its reference drug in terms of (ADME)
1) BE studies for oral, topical, inhalation and nasal sprays focus on local action/efficacy.
2) BE studies for Modified-Release (MR) Drugs focus on Alcohol Effects as it can cause dose dumping.
3) BE studies are required for Drug products with high intrasubject variability and Drug products with complex mixtures as the active ingredients
BE studies also can be done for Oral solution, Chewable tablets, Endogenous substances, Long half life drugs
You used In Vitro Dissolution Testing Instead of In Vivo BE Studies when…
1) Drug product is in same dosage form but diff strengths and is proportionally similar in active and inactive ingredients.
2) study of one or more of the lower strengths can be waived based on the dissolution tests and an in vivo study on the highest strengths
Issues in Establishing BA and BE
1) Drugs with high intrasubject variability
2) Drugs with long elimination half-life
3) Biotransformation of drugs
(Stereoselective drug metabolism, Drugs with active metabolites and polymorphic metabolism)
4) Nonbioavailable drugs for local effect
(Antacids, Local anesthetics, Anti-infectives and Anti-inflammatory steroids)
5) Dosage forms for nonoral administration
(Transdermal, Inhalation, Ophthalmic and Intranasal)
6) Bioavailable drugs e.g. Potassium supplements that should not produce peak drug levels.
7) Endogenous drug e.g Hormone replacement therapy
8) Biotechnology-derived drugs e.g. Erythropoietin interferon and Protease inhibitors
9) Complex drug substances e.g. Conjugated estrogens
In generic substitution, pharmacists may replace a brand-name drug with a generic equivalent based on the rules of a specific formulary.
Distinguish between positive and negative formulary.
Positive Formulary – lists therapeutically equivalent or interchangeable drug products that pharmacists may dispense
Negative Formulary – lists drug products that are not therapeutically equivalent, and/or the interchange of which is prohibited
Therapeutic Equivalence Assumed for a Generic Product if:
1) Approved as safe and effective
2) Are pharmaceutically equivalent
3) Are bioequivalent
4) Adequately labeled
5) Manufactured in compliance with Current Good Manufacturing Practice regulations
Define Modified-Release (MR)
What is meant by Controlled-Release?
What are some other terms?
Modified-release (MR) drug products are formulated to alter the timing, rate, or location of drug release in the body.
The term controlled-release was previously used to describe various types of extended-release oral dosage forms.
retard release, XL/XR (extended release), long-acting, slow release, and SR (sustained release).
Note;
MR drug products are designed based on the drug’s physicochemical properties, pharmacodynamic (PD) effects, pharmacokinetic (PK) behavior, and the materials used in the dosage form.
Types of MR Oral Drug Products
1) Extended release drug products
2) Delayed release drug products
3) Targeted-release drug products
4) Orally disintegrating tablets
Extended release drug products
Reduced dosing frequency – ER formulations allow at least a 2-fold reduction in how often the drug is taken compared to immediate-release (IR) forms.
Prolonged drug availability – The active drug is released gradually over an extended period after administration, maintaining therapeutic levels for longer.
Describe delayed-release (DR) dosage forms.
e.g. enteric coated
Delayed drug release – The dosage form releases one or more portions of the drug later, instead of immediately after administration. An initial portion may be released quickly.
Time or environment-dependent – Drug release depends on time (e.g., programmed release) or environmental factors (e.g., pH-sensitive coatings that dissolve in the intestines).
Describe Targeted-release drug products
Describe Orally disintegrating tablets
*Dosage form releases drug at or near the intended physiologic site of action
*Can be IR or extended-release characteristics
—————————
*Disintegrate rapidly in the saliva after oral administration
*Dispersed in saliva and swallowed with little or no water
Advantages of Extended Release Products
1) Sustained therapeutic blood levels of the drug
2) Improve patient compliance
3) Reduction in adverse side effects and improvement in tolerability
4)Reduction in healthcare cost
Disadvantages of Extended Release Products
1) Dose dumping – release of more than the intended fraction or greater rate
2)Less flexibility in accurate dose adjustments
3)Less possibility for high dosage
4)Increased potential for first pass clearance
5) Poor IVIV correlation
