1
Q
What are the 3 factors that affect bioavailability?
A
- properties of the drug
- physiological factors at site of absorption
- properties of dosage form i.e. formulation factors
2
Q
what is the result when intrinsic physicochemical properties of a drug are changed
A
alter the intrinsic activity of the drug, i.e. create a different drug entity
3
Q
Intrinsic properties (or drug properties) that influence bioavailability include (6 things)
A
- molecurlar weight
- lipophilicity
- solubility
- pKa
- chemical stability
- chemical structure
4
Q
what is an example of a type of intrinsic drug change that is beneficial to bioavailability
A
the formation of a prodrug e.g. bacampicilin
5
Q
what are some physical characteristics of a drug that affect bioavailability, and how do they impact bioavailability
A
- particle size and polymorphic form
- impact dissolution rate
6
Q
what is an example of a drug where particle size has a large impact on bioavailability
A
phenacetin
7
Q
What are the key parameters controlling drug absorption in the BCS
A
- Absorption Number (An)
- Dissolution Number (Dn)
- Dose Number (Do)
8
Q
what is the BCS
A
- Biopharmaceutical Classification Scheme
- a system to differentiate drugs based upon solubility and permeability and dissolution profiles
9
Q
What was the BCS developed from
A
- drug dissolution profiles and
- absorption models (permeability models based upon IV injection
10
Q
what is the BCS used for? (3 reasons)
A
- determining the conditions under which in vitro in vivo (IVIV) correlations are expected
- used to set drug bioavailability for immediate release products
- establish process for application of waivers for BA/BE studies in Post approval changes or ‘generic’ products
11
Q
What are the solubility class boundaries in the BSC based upon?
A
- highest dose strength of an immediate release product.
*
12
Q
If dissolution is rapid in the GI tract then absorption of Class I drugs are good or bad
A
Good
13
Q
When is a drug considered highly soluble?
A
- when the highest dose strength is soluble in a glass of water
- e.g. 250 ml or less of aqueous media over the pH range of 1 to 7.5.
14
Q
When is a drug considered highly permeable?
A
- when highly absorbed
- e.g. >90% of administered dose
15
Q
What are permeability class boundaries are based upon
A
- the extent of absorption and mass transfer across intestinal membrane
16
Q
What are dissolution class boundaries for IR drug
A
- Rapidly dissolving NLT 85% of label claim in 15 min
17
Q
What are the four classes of the BCS?
A
- Class I: High Permeability, High Solubility
- Class II: High Permeability, Low Solubility
- Class III: Low Permeability, High Solubility
- Class IV: Low permeability, low Solubility
18
Q
What are Class 1 drugs controlled by and why
A
- Gastric emptying
- because high permeability and solubility
- if gastric emptying delayed or sped up impacts absorption
19
Q
How is bioavailability measured for class I drugs
A
single point dissolution test
20
Q
This class of drugs have good Level A IVIV
A
Class II drugs
21
Q
Class II drugs require this type of dissolution profile due to their inability to ionize
A
multi dissolution profiles across the pH range are required to establish bioavailability
22
Q
The absorption of Class III and Class IV drugs are permeability or solubility controlled and as a result IVIVC is expected or unexpected
A
- permeability
- unexpected (limited or non-existent)
23
Q
What is the BDDCS?
A
Biopharmaceutics Drug Disposition Classification System
24
Q
how does the BDDCS differ from the BCS?
A
- it takes into consideration metabolic characteristics and absorptive/efflux transporter
- intent was to expand the number of drugs falling into class I as many Class I and Class II drugs are highly metabolized
25
which classes of drugs are available to apply for biowaivers and under what conditions
* Class I and Class III
* as long as inactive ingredients do not interfere with absorption of active
* must have rapid or very rapid dissolution profiles
26
what are the physiological factors of the GI tract that impact bioavailability
1. GI tract pH,
2. contents,
3. volume,
4. surface active agents (bile salts, mucin, enzymes)
27
what do physiological factors that affect bioavailability impact (3) and why is this important
* stability
* solubility (aq & lipid)
* dissolution
* these impact drug absorption
28
can physiological factors of the GI tract be controlled by the formulator?
No because they are patient specific
29
What do physiological factors often influence?
* choice of site of drug administration i.e. dosage form
* formulation
30
Food drug interactions are the result of these two things
* Physicochemical effects
* ingestion of certain foods
* e.g. metal ions in food and dairy chelating tetracycline
* physiological effects
* increased bile secretion, increasing absorption
* e.g. phenytoin
31
the amount of drug absorbed can be affected by this type of interaction
food-drug interactions
32
What are the formulation factors impacting bioavailability (4)
1. excipients
2. cosolvents/pH
3. additives
4. particle size
33
Explain the impact on bioavailability that each of the following formulation factors have:
* excipients
* cosolvents/pH
* additives
* particle size
* excipients
* High Conc. of sugar as an excipient can slow gastric emptying, retarding absorption
* hydrophilic polymers increase viscosity which slows absorption
* cosolvents/pH
* upon dilution with GI contents may ppte drug and reduce absorption
* additives
* enhance drug absorption
* particle size
* influences dissolution and bioavailability
34
Dissolution profiles take this common shape
sigmoidal curve i.e. non-linear
35
the lag phase in a dissolution profile represents which process in drug solubilization
disintegration
36
what is the process of dissolution of a oral solid drug
* disintegration, deaggregation, dissolves then absorbs
37
what are dissolution tests performed on
* finished dosage form
* pure drug
* excipients
38
what are sink conditions
the volume that allows dissolution of the entire dosage form
39
This test is required for product registration
dissolution
40
it is sufficient to study dissolution at a single pH level True/false
why
False, two levels are required pH 1 and pH 7 to simulate extremes in GI tract
41
what is sometimes added to dissolution media and what does it do
surface active agents to aid in wetting of drug e.g. bile salts
42
why are biorelevant media used in dissolution testing (4)
1. more representative of conditions of GI tract
2. represent early, middle and late phases of digestion
3. come in fed and fasted state
4. designed to have pH, osmolality, suface entsion and buffer capacity similar to those found in vivo
43
what are advantages of biorelevant dissolution equipment
* better reflect the mechanical and media flow shear stresses, mixing and gut motility as movement along the GI tract is difficul to simulate
44
what are IVIVC, and what are they used for?
* In vitro in vivo correlation
* used to establish a relationship between in vitro dissolution testing and in vivo results such that dissolution test can be used as a surrogate for in vivo testing
45
when can IVIVC be used
* when dissolution is the sole determinant of absorption
* when dissolution in vitro is reflective of that which occurs in vivo
46
How is dissolution assayed for modified release products; single or multi-point dissolution
* multi-point dissolution
47
what are the 3 correlation techniques used to establish IVIVC in modifed release products
* Level A: deconvolution
* Level B: statistical moments
* Level C: single point
48
which correlation level has these characteristics
* Point to point relationship between in vitro dissolution and in vivo results
* used with modified release
* demonstrates in vitro release rate independent of media
* surrogate for in vivo testing
* can be used to support post approval changes such as change in mfging site, method of manufacture, raw material supplier, minor formulation changes, and product strength without performing additional human studies
what is level A correlation
49
level A correlation
* Point to point relationship between in vitro dissolution and in vivo results
* used with modified release
* demonstrates in vitro release rate independent of media
* surrogate for in vivo testing
* can be used to support post approval changes such as change in mfging site, method of manufacture, raw material supplier, minor formulation changes, and product strength without performing additional human studies
50
Level B correlation utilizes which statistical principle
statistical moments
51
what does the statistical moments analysis compare
* mean in vitro dissolution time to mean residence time or mean in vivo dissolution time
52
Level C correlation relates a dissolution time point (t50% or t90%) to
* pK parameters such as AUC, Cmax, Tmax
* represents single point correlation
53
what are bioequivalence waivers
an approval from a Health Authority to forgoe in vivo testing
54
what are the rquirements that a company needs to meet in order to apply for a BE biowaiver for oral conventional release dosage forms (4)
1. there must be an already approved product
2. must include in dossier why and how they meet the exemption or waiver request cirteria
3. establish and IVIVC
4. generally only for Class I and Class III
* in vitro dissolution \> 85% in 15 min
* Class III higher risk due to limited abosorption
55
what drugs are excluded from BE requests
drugs with narrow therapeutic range of effect
56
Besides dissolution being the rate limiting step, what are other factors that can affect bioavailability (3)
1. absorption
2. permeability
3. metabolism
57
Absorptioin is impacted by these 3 things
1. presystemic metabolism
2. membrane transporters
3. effects of cellular barriers and intestinal mucosa on diffusion and permeability
58
how can absorbance be measured (3 ways)
1. using rat intestinal cell models
2. artificial membrane methods
3. semi-empirical methods based on molecurlar weight, membrane affinity to lipid bilayers and physiological facotrs
59
True/False
the permeability of substance undergoing active transport is **_easier or more difficult_** to predict than passivley tranported compounds
More difficult
60
what is the most important factor in drug absorption in poorly water soluble drugs
dissolution
