IVIVC Flashcards
What is the difference between generic and innovator?
- Generic = active ingredient w/o a brand name
- Innovator = new drug manufactured by a drug company w/ a trade name (if innovator is under patent, can’t be copied by anyone else)
What were bioavailability studies used for in the past?
- For every optimized formulation
- Ensure that optimized “new formulation” is similar to the “old formulation” of the same drug
Which drugs are dissolution testing typically done on?
Solid oral dosage forms
What is the difference between in vitro and in vivo?
- In vitro = within the glass (done outside a living organisms)
- In vivo = within the living (done inside a whole living organism, human or animal)
What is the definition of in vitro in vivo correlation (IVIVC)?
Predictive mathematical model describing relationship between an in vitro property of a dosage form and relevant in vivo response
What is generally the in vitro property of a drug?
Rate or extent of drug dissolution or release
What is generally the in vivo response of a drug?
Plasma drug concentration or amount of drug absorbed
Why was IVIVC developed?
To minimize the need for additional bioavailability studies as part of the formulation design
What is the main objective when developing IVIVC?
To enable the in vitro dissolution test to predict the in vivo bioavailability behaviour (drug release profile)
What needs to be considered when developing IVIVC?
- Physicochemical properties of drug (solubility)
- Biopharmaceutical properties (how easily drug can permeate across membranes)
- Physiology of human body (GI environment, skin)
What are the objectives of IVIVC?
- Serve as a surrogate for in vivo bioavailability studies
- Support biowaivers
- Establish dissolution specifications
- Support and/or validate dissolution methods
- Assist in quality control for certain scale-up and post-approval changes
What is a biowaiver?
Dissolution test used as a surrogate for bioequivalence testing of a certain drug product
What are the steps of IVIVC study design?
- 2-3 formulations (different dissolution rates)
- In vitro dissolution test (same dissolution conditions)
- Dissolution profile (if they differ significantly, over 10%, can adequately discriminate among formulations)
- In vivo bioavailability study (humans)
- Absorption profile
What is the purpose of in vitro dissolution in early stage of drug development?
- Select optimum formulation
- Evaluate drug
- Assess minor changes in drug products
- Quality control for uniformity of drug product quality
What is the purpose of in vitro dissolution from an IVIVC perspective?
As a surrogate for in vivo drug bioavailability testing
What is the purpose of in vitro dissolution testing?
Testing for drug release from the dosage form
What is the difference between dissolution and solubility?
- Solubility = measure of mass that is dissolving in a specific volume at certain conditions (eq’m property)
- Dissolution = measurement of drug release from a dosage form (dynamic property)
What must happen to a drug before it can be released from a solid dosage form?
- Must disintegrate into granules and deaggregate into finer particles before it can dissolve
- Must be in solution before drug can be released
Define dissolution rate
Amount of drug substance that goes into solution per unit time under standardized conditions
Which dosage forms require the dissolution test?
- Tablets, capsules
- Ointments, creams
- Suppositories
- Pessaries
- Transdermals
- Implants
What determines the selection of in vitro dissolution testing conditions?
- Type of dosage form (tablet, suspension, transdermal)
- Release pattern (immediate vs. modified release)
- Physiology of site of administration (GI, skin, buccal, sublingual)
What is the dissolution apparatus 1? Medium? Disadvantage?
- Rotating basket
- Medium = water, gastric, or intestinal buffers
- Disadvantage = dosage may clog to mesh screen
What determines the basket selection for dissolution apparatus 1?
Dosage form
What is the dissolution apparatus 2? Medium? Disadvantage?
- Paddle
- Medium = water, gastric, or intestinal buffers
- Disadvantage = cone formation and positioning of tablet
What are advantages to paddle and basket dissolution apparatuses?
- Widely accepted
- Apparatus of first choice for solid oral dosage forms
- Standardized
- Easy to operate
- Robust
- Broad experience
What are disadvantages to paddle and basket dissolution apparatuses?
- Limited volume (max. of 900 mL)
- Simulation of GI transit not possible
- Hydrodynamic conditions not known
What is the dissolution apparatus 3? Uses?
- Reciprocating cylinder
- Uses = solids, extended release
What can affect the dissolution results of apparatus 1 and 2?
Mechanical factors (shaft wobbling, location, presence of bubbles in dissolution medium)
What is the dissolution apparatus 4? Uses?
- Flow through cell
- Uses = low solubility drugs, rapid degradation, and media pH change
How can dissolution apparatus 4 vary?
- Size
- Flow rate
- Filter
- Open/closed system
Describe what occurs in dissolution apparatus 4
Drug sits in a reservoir and is pumped through a cell and collected in another reservoir
Which dissolution apparatus is best for solid dosage form w/ low water solubility?
Apparatus 4, flow through cell
What are advantages to dissolution apparatus 4?
- No limitation of media volume
- Suitable for drugs w/ low solubility
- Gentle hydrodynamic conditions
- Simulation of GI transit
- Suitable for special dosage forms (powders, granules, implants)
What are disadvantages to dissolution apparatus 4?
- Limited experience
- Pump precision influences results
Which drug products can be tested in dissolution apparatus 4?
Solids, semisolids, and liquids
Which dosage forms are used in apparatuses 5, 6, and 7? What is an advantage to these?
- Dosage forms = extended release and transdermals
- Advantage = change medium pH and flow rate
What is dissolution apparatus 5? Which dosage forms is it useful for?
- Paddle over disk
- Useful for transdermal patches, ointments, floaters, emulsions, and bolus
What is dissolution apparatus 6? Which dosage form is it useful for?
- Cylinder
- Useful for transdermal patches
What is dissolution apparatus 7? Which dosage forms is it useful for?
- Reciprocating holder
- Useful for transdermal patches, solid dosage forms, pH profile, and small volumes
What are general considerations that should be made in dissolution testing?
1) Physicochemical properties of drug (solubility, chemical stability, interaction w/ excipients)
2) Dissolution medium (use of surfactants for poorly-soluble drugs; buffers for weak acids or bases
3) Dosage form design
4) Acceptance criteria (standards for each country)
Which parameter is measured during in vitro dissolution testing?
Percent of drug dissolved per time
How is in vivo absorption assessed?
Calculating AUC (extent of absorption), Cmax, and Tmax (rate of absorption)
What is the key to developing an IVIVC?
Identify a dissolution test that is descriptive of the in vivo absorption of the test compound
What are the crucial parameters that affect dissolution?
- Physicochemical properties of a drug (ex: solubility)
- GI environment
What is drug permeability? When does it occur?
- Ability of the drug to penetrate across a membrane into the systemic circulation
- Occurs after the solid drug is converted into a solution form
What determines extent of permeability?
Physicochemical properties of the drug and blood perfusion
What are the 2 things needed to build IVIVC?
- Cumulative in vitro dissolution profile
- In vivo concentration time profile from a pharmacokinetic study
What are the 4 levels of IVIVC? What does this measure?
- Level A, B, and C and multiple level C
- Measure of the strength of correlation
Describe a level A correlation
- Point-to-point relationship between in vitro dissolution rate and in vivo input rate of drug from the dosage form
- Strongest level
- Desirable for regulatory compliance (ex: FDA)
Describe a level B correlation
- Not a point-to-point relationship
- Compares means (ex: mean dissolution time for in vitro and mean residence, absorption, or dissolution time for in vivo)
- Different in vivo curves may produce similar means
Describe a level C correlation
- Single time point correlation (one dissolution time point compared to one in vivo parameter)
- Doesn’t reflect entire shape of plasma drug concentration curve
- Weakest level
- Useful in early stages of formulation dev’t
Describe a multiple-level C correlation
- Extension of level C correlation
- Relates one or several in vivo parameters to in vitro drug release at several time points
- Should be based on at least 3 dissolution time points covering early, middle, and late stage of dissolution profile
- If this correlation is achieved, dev’t of level A correlation is likely
Most correlations are _____
Level B or C
What are advantages to IVIVC?
- Drug dev’t period is shortened
- Resources are economized
- Product quality improved
What are some limitations to IVIVC?
- Limited to certain drug products
- Can’t be used across products, must develop an IVIVC for each formulation (ex: immediate vs. extended release)
What is the purpose of the biopharmaceutical classification system (BCS)?
- Classifies drugs based on solubility and intestinal permeability
- Guideline for determining conditions under which IVIVCs are expected
BCS is useful in determining ____
If an IVIVC for a given drug is expected or not
What does it mean when a drug is highly soluble?
Highest dose strength is soluble in 250 mL or less of water over a pH of 1-7.5 at 37 C
What does it mean when a drug is rapidly dissolving?
At least 85% of the labeled amount of drug substance dissolves w/in 30 minutes in a volume of at least 900 mL buffer solutions
What does it mean when a drug is very rapidly dissolving?
At least 85% dissolves in 15 minutes
What does it mean when a drug is highly permeable?
Extent of absorption in humans is determined to be at least 90% of an administered dose
What are the 4 BCS classes and what are characteristics of each class?
- Class 1 = high solubility and high permeability
- Class 2 = low solubility and high permeability
- Class 3 = high solubility and low permeability
- Class 4 = low solubility and low permeability
What 3 factors does BCS take into account that govern rate and extent of drug absorption?
- Dissolution
- Solubility
- Intestinal permeability
BCS approach provides an opportunity to _____
Waive in vivo pharmacokinetic bioequivalence testing for certain categories of immediate-release drug products
What are the IVIVC expectations for immediate release products from each of the 4 BCS classes?
- Class 1 = IVIVC expected if dissolution rate slower than gastric emptying rate
- Class 2 = IVIVC expected if in vitro dissolution rate similar to in vivo dissolution rate, unless dose is very high
- Class 3 and 4 = limited or no IVIVC expected
When is IVIVC most likely predictable?
When the rate limiting step is drug release/dissolution, so BCS class 2 (highly permeable and poorly soluble)
When is IVIVC limited?
- When rate limiting step is gastric emptying (BCS class 1)
- When rate limiting step in absorption is low permeability (class 3 and 4)
