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Kinetics - Test 2 > IVIVC > Flashcards

IVIVC Flashcards

1
Q

What is the difference between generic and innovator?

A
  • 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)
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2
Q

What were bioavailability studies used for in the past?

A
  • For every optimized formulation

- Ensure that optimized “new formulation” is similar to the “old formulation” of the same drug

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3
Q

Which drugs are dissolution testing typically done on?

A

Solid oral dosage forms

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4
Q

What is the difference between in vitro and in vivo?

A
  • In vitro = within the glass (done outside a living organisms)
  • In vivo = within the living (done inside a whole living organism, human or animal)
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5
Q

What is the definition of in vitro in vivo correlation (IVIVC)?

A

Predictive mathematical model describing relationship between an in vitro property of a dosage form and relevant in vivo response

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6
Q

What is generally the in vitro property of a drug?

A

Rate or extent of drug dissolution or release

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7
Q

What is generally the in vivo response of a drug?

A

Plasma drug concentration or amount of drug absorbed

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8
Q

Why was IVIVC developed?

A

To minimize the need for additional bioavailability studies as part of the formulation design

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9
Q

What is the main objective when developing IVIVC?

A

To enable the in vitro dissolution test to predict the in vivo bioavailability behaviour (drug release profile)

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10
Q

What needs to be considered when developing IVIVC?

A
  • Physicochemical properties of drug (solubility)
  • Biopharmaceutical properties (how easily drug can permeate across membranes)
  • Physiology of human body (GI environment, skin)
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11
Q

What are the objectives of IVIVC?

A
  • 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
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12
Q

What is a biowaiver?

A

Dissolution test used as a surrogate for bioequivalence testing of a certain drug product

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13
Q

What are the steps of IVIVC study design?

A
  • 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
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14
Q

What is the purpose of in vitro dissolution in early stage of drug development?

A
  • Select optimum formulation
  • Evaluate drug
  • Assess minor changes in drug products
  • Quality control for uniformity of drug product quality
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15
Q

What is the purpose of in vitro dissolution from an IVIVC perspective?

A

As a surrogate for in vivo drug bioavailability testing

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16
Q

What is the purpose of in vitro dissolution testing?

A

Testing for drug release from the dosage form

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17
Q

What is the difference between dissolution and solubility?

A
  • 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)
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18
Q

What must happen to a drug before it can be released from a solid dosage form?

A
  • Must disintegrate into granules and deaggregate into finer particles before it can dissolve
  • Must be in solution before drug can be released
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19
Q

Define dissolution rate

A

Amount of drug substance that goes into solution per unit time under standardized conditions

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20
Q

Which dosage forms require the dissolution test?

A
  • Tablets, capsules
  • Ointments, creams
  • Suppositories
  • Pessaries
  • Transdermals
  • Implants
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21
Q

What determines the selection of in vitro dissolution testing conditions?

A
  • Type of dosage form (tablet, suspension, transdermal)
  • Release pattern (immediate vs. modified release)
  • Physiology of site of administration (GI, skin, buccal, sublingual)
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22
Q

What is the dissolution apparatus 1? Medium? Disadvantage?

A
  • Rotating basket
  • Medium = water, gastric, or intestinal buffers
  • Disadvantage = dosage may clog to mesh screen
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23
Q

What determines the basket selection for dissolution apparatus 1?

A

Dosage form

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24
Q

What is the dissolution apparatus 2? Medium? Disadvantage?

A
  • Paddle
  • Medium = water, gastric, or intestinal buffers
  • Disadvantage = cone formation and positioning of tablet
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25
Q

What are advantages to paddle and basket dissolution apparatuses?

A
  • Widely accepted
  • Apparatus of first choice for solid oral dosage forms
  • Standardized
  • Easy to operate
  • Robust
  • Broad experience
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26
Q

What are disadvantages to paddle and basket dissolution apparatuses?

A
  • Limited volume (max. of 900 mL)
  • Simulation of GI transit not possible
  • Hydrodynamic conditions not known
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27
Q

What is the dissolution apparatus 3? Uses?

A
  • Reciprocating cylinder

- Uses = solids, extended release

28
Q

What can affect the dissolution results of apparatus 1 and 2?

A

Mechanical factors (shaft wobbling, location, presence of bubbles in dissolution medium)

29
Q

What is the dissolution apparatus 4? Uses?

A
  • Flow through cell

- Uses = low solubility drugs, rapid degradation, and media pH change

30
Q

How can dissolution apparatus 4 vary?

A
  • Size
  • Flow rate
  • Filter
  • Open/closed system
31
Q

Describe what occurs in dissolution apparatus 4

A

Drug sits in a reservoir and is pumped through a cell and collected in another reservoir

32
Q

Which dissolution apparatus is best for solid dosage form w/ low water solubility?

A

Apparatus 4, flow through cell

33
Q

What are advantages to dissolution apparatus 4?

A
  • 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)
34
Q

What are disadvantages to dissolution apparatus 4?

A
  • Limited experience

- Pump precision influences results

35
Q

Which drug products can be tested in dissolution apparatus 4?

A

Solids, semisolids, and liquids

36
Q

Which dosage forms are used in apparatuses 5, 6, and 7? What is an advantage to these?

A
  • Dosage forms = extended release and transdermals

- Advantage = change medium pH and flow rate

37
Q

What is dissolution apparatus 5? Which dosage forms is it useful for?

A
  • Paddle over disk

- Useful for transdermal patches, ointments, floaters, emulsions, and bolus

38
Q

What is dissolution apparatus 6? Which dosage form is it useful for?

A
  • Cylinder

- Useful for transdermal patches

39
Q

What is dissolution apparatus 7? Which dosage forms is it useful for?

A
  • Reciprocating holder

- Useful for transdermal patches, solid dosage forms, pH profile, and small volumes

40
Q

What are general considerations that should be made in dissolution testing?

A

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)

41
Q

Which parameter is measured during in vitro dissolution testing?

A

Percent of drug dissolved per time

42
Q

How is in vivo absorption assessed?

A

Calculating AUC (extent of absorption), Cmax, and Tmax (rate of absorption)

43
Q

What is the key to developing an IVIVC?

A

Identify a dissolution test that is descriptive of the in vivo absorption of the test compound

44
Q

What are the crucial parameters that affect dissolution?

A
  • Physicochemical properties of a drug (ex: solubility)

- GI environment

45
Q

What is drug permeability? When does it occur?

A
  • Ability of the drug to penetrate across a membrane into the systemic circulation
  • Occurs after the solid drug is converted into a solution form
46
Q

What determines extent of permeability?

A

Physicochemical properties of the drug and blood perfusion

47
Q

What are the 2 things needed to build IVIVC?

A
  • Cumulative in vitro dissolution profile

- In vivo concentration time profile from a pharmacokinetic study

48
Q

What are the 4 levels of IVIVC? What does this measure?

A
  • Level A, B, and C and multiple level C

- Measure of the strength of correlation

49
Q

Describe a level A correlation

A
  • 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)
50
Q

Describe a level B correlation

A
  • 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
51
Q

Describe a level C correlation

A
  • 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
52
Q

Describe a multiple-level C correlation

A
  • 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
53
Q

Most correlations are _____

A

Level B or C

54
Q

What are advantages to IVIVC?

A
  • Drug dev’t period is shortened
  • Resources are economized
  • Product quality improved
55
Q

What are some limitations to IVIVC?

A
  • Limited to certain drug products

- Can’t be used across products, must develop an IVIVC for each formulation (ex: immediate vs. extended release)

56
Q

What is the purpose of the biopharmaceutical classification system (BCS)?

A
  • Classifies drugs based on solubility and intestinal permeability
  • Guideline for determining conditions under which IVIVCs are expected
57
Q

BCS is useful in determining ____

A

If an IVIVC for a given drug is expected or not

58
Q

What does it mean when a drug is highly soluble?

A

Highest dose strength is soluble in 250 mL or less of water over a pH of 1-7.5 at 37 C

59
Q

What does it mean when a drug is rapidly dissolving?

A

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

60
Q

What does it mean when a drug is very rapidly dissolving?

A

At least 85% dissolves in 15 minutes

61
Q

What does it mean when a drug is highly permeable?

A

Extent of absorption in humans is determined to be at least 90% of an administered dose

62
Q

What are the 4 BCS classes and what are characteristics of each class?

A
  • 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
63
Q

What 3 factors does BCS take into account that govern rate and extent of drug absorption?

A
  • Dissolution
  • Solubility
  • Intestinal permeability
64
Q

BCS approach provides an opportunity to _____

A

Waive in vivo pharmacokinetic bioequivalence testing for certain categories of immediate-release drug products

65
Q

What are the IVIVC expectations for immediate release products from each of the 4 BCS classes?

A
  • 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
66
Q

When is IVIVC most likely predictable?

A

When the rate limiting step is drug release/dissolution, so BCS class 2 (highly permeable and poorly soluble)

67
Q

When is IVIVC limited?

A
  • When rate limiting step is gastric emptying (BCS class 1)

- When rate limiting step in absorption is low permeability (class 3 and 4)

Kinetics - Test 2 (7 decks)

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