1
Q
What modified-release types are listed?
A
Extended release and delayed release
2
Q
What is extravascular administration?
A
Any route except direct introduction into the bloodstream
3
Q
What factors affect route selection?
A
- Drug properties
- onset needed
- site of action
- need to bypass first-pass metabolism
- need for high local concentrations
- side effects
- patient factors
- convenience
- cost
4
Q
Which route has the fastest onset overall?
A
IV
5
Q
Which non-IV route shown has the fastest onset?
A
Inhalation, and then sublingual/buccal
6
Q
What are the main advantages of IV administration?
A
- Rapid onset
- complete delivery to bloodstream
- controlled amount
- bolus or infusion possible
- large volumes can be given
7
Q
What are the main disadvantages of IV administration?
A
- Painful
- inconvenient
- needs trained personnel
- expensive
- vein access required
- toxicity/thrombosis risk
8
Q
What are the main advantages of IM administration?
A
- Rapid onset
- almost complete absorption
- predictable absorption after IV
- larger volumes than SC
- depot injections possible
9
Q
What are the main disadvantages of IM administration?
A
- Painful
- inconvenient
- absorption can vary by site/formulation
- large volumes cannot be administered (max 5-10ml)
- nerve damage or abscess possible
- needs trained personnel
10
Q
What are the main advantages of SC administration?
A
- Rapid onset
- slower and smoother absorption than IM
- almost complete absorption
- may be self-administered with minimal training
11
Q
What are the main disadvantages of SC administration?
A
- inconvenient and painful
- site of injection will influence extent of absorption
- limited volume of injection (<2 mL)
- absorption depends on blood flow and site
- repeated injections can be problematic
- may cause tissue damage.
12
Q
What are the main advantages of intranasal administration?
A
- Non-invasive
- easy to administer
- rich vasculature
- rapid absorption
- rapid onset
- can bypass hepatic metabolism/GI destruction
13
Q
What are the main disadvantages of intranasal administration?
A
- Efficiency depends on delivery system
- Need for formulation enhancers
- Small absorption site
- mucociliary clearance
- short residence time
- local irritation
14
Q
What are the main advantages of pulmonary/inhalation administration?
A
- Large surface for absorption (alveoli)
- Self-administration possible
- rapid absorption, quick onset
- local or systemic effect
- can bypass first-pass/GI destruction.
15
Q
What are the main disadvantages of pulmonary/inhalation administration?
A
- Strong dependence on formulation and delivery device (particle size/distribution, residence time, solubility of carrier)
- lung clearance mechanisms can reduce delivery
16
Q
What are the main advantages of sublingual/buccal administration?
A
- Avoids first-pass metabolism
- rapid absorption, rapid onset
- no stomach degradation
- dosage can be removed quickly if needed
17
Q
What are the main disadvantages of sublingual/buccal administration?
A
- Small dose only
- needs special excipients
- not good for irritants or large molecular weight drugs
18
Q
What are the main advantages of topical/transdermal administration?
A
- Non-invasive
- easy to administer
- useful for local effects
- can provide controlled/prolonged delivery
19
Q
What are the main disadvantages of topical/transdermal administration?
A
- Need for formulation enhancers
- Often slow absorption
- low bioavailability
- depends on drug properties and skin delivery
- local irritation possible
20
Q
What are the main advantages of ocular administration?
A
- avoids first pass metabolism
- Fast absorption
- quick onset
- high local concentration
- self-administration possible
21
Q
What are the main disadvantages of ocular administration?
A
- Limited drugs can be used
- special excipients needed
- not good for irritants or large molecular weight drugs
22
Q
What are the main advantages of rectal administration?
A
- No GI irritation
- can bypass first-pass metabolism
- useful in children/elderly/unconscious/vomiting patients
23
Q
What are the main disadvantages of rectal administration?
A
- Poor patient acceptance
- variable absorption
- requires empty rectum for best absorption
- limited drug suitability
24
Q
What are the main advantages of oral administration?
A
Safe, convenient, painless, inexpensive, easy dosing, good patient compliance
25
What are the main disadvantages of oral administration?
- First-pass metabolism
- food effects
- slower onset
- variable absorption
- GI degradation of some drugs
- not suitable for unconscious patients
26
What are the basic steps in oral absorption?
Disintegration -> dissolution -> absorption
27
What transport mechanisms across cells are shown?
- Transcellular passive diffusion
- carrier-mediated transport
- paracellular transport, transcytosis/endocytosis
28
When is absorption permeability-limited?
When dissolution is much faster than absorption
29
When is absorption dissolution-limited?
When dissolution is slow enough to limit absorption
30
What is an immediate-release dosage form?
At least 85% dissolves within 30 minutes
31
What is biopharmaceutics?
Study of how drug properties, dosage form, and route affect rate and extent of systemic absorption
32
Who is considered the originator of the biopharmaceutics field
Gerhard Levy
33
Oral absorption often follows what kinetics?
First-order kinetics.
34
What are the two major categories of factors affecting drug absorption
Physicochemical factors and physiological factors
35
What three processes are emphasized in oral absorption
Solubility, permeability, and dissolution
36
What equation is used to describe dissolution?
Noyes-Whitney
37
In the Noyes-Whitney equation, what does D represent?
Diffusion coefficient of the drug
38
In the Noyes-Whitney equation, what does S represent?
Surface area in contact with the diffusion layer
39
In the Noyes-Whitney equation, what does h represent?
Thickness of the diffusion layer
40
In the Noyes-Whitney equation, what does Cs represent?
Saturated solubility of the drug
41
In the Noyes-Whitney equation, what does C represent?
Concentration of dissolved drug at time t
42
In the Noyes-Whitney equation, what does V represent?
Volume of solution
43
What happens to the Noyes-Whitney expression under sink conditions?
It simplifies
44
What is D (diffusion coefficient) controlled by
Molecule size
45
For D (diffusion coefficient), the rate of dissolution is increased by what
Lower molecular weight and smaller sizes
46
What is S (surface area) controlled by?
Particle size
47
For S (surface area), rate of dissolution is increased by what
Larger surface area and smaller particle size
48
For H (diffusion layer thickness), rate of dissolution is increased by what
Higher stirring rate
49
What is Cs (the saturated solubility of the drug) controlled by?
Intrinsic solubility, composition of dissolution medium, and pH of medium
50
For Cs, rate of dissolution is increased by what
Composition of the dissolution medium
51
What is C (drug concentration in the bulk phase) controlled by?
Concentration of drug already dissolved and not removed from the system
52
For C (drug concentration in the bulk phase), rate of dissolution is increased by what
Sink-condition (use of larger fluid volume for the dissolution system)
53
What are the two dissolution testing apparatuses shown?
Apparatus 1: Basket; Apparatus 2: Paddle
54
How does Apparatus 1 work?
The tablet is placed inside a basket, which rotates vertically
55
How does Apparatus 2 work?
The tablet/capsule is placed at the bottom of the beaker
56
How can excessive magnesium stearate affect a formulation?
It may retard dissolution, slow the rate of absorption, and reduce the total amount absorbed
57
Why can different salt forms affect absorption?
Because they can have different solubilities
58
Why can different crystal forms affect absorption?
Because polymorphs can differ in bioavailability
59
What crystal-form example is given? (absorption)
Chloramphenicol palmitate has at least two polymorphs, and the B form is more bioavailable
60
What major process besides solubility and dissolution is required for oral absorption?
Permeability
61
The physicochemical-property rules mainly apply to what kind of absorption?
Passive diffusion through cell membranes
62
What kind of drugs are exceptions to those passive-diffusion rules?
Drugs actively transported by transporter proteins
63
What molecular property is specifically highlighted as affecting absorption?
Molecular weight
64
Why does LogP matter for oral absorption?
Because oral absorption depends on balancing solubility and permeability
65
Why can too many hydrogen bond donors and acceptors reduce bioavailability?
Because desolvation and formation of a neutral molecule become unfavorable, making movement from gut to blood harder
66
What exception to the hydrogen-bonding rule is mentioned?
Sugars, because they use special transport mechanisms
67
What guideline is presented as a form of QSPKR for passive diffusion?
Lipinski's Rule of 5
68
What overall formulation principle is emphasized for oral lipophilic drugs?
Absorption requires a delicate balance between solubility and permeability
69
For lipophilic drugs, what solubility target is recommended in the lecture?
Minimal threshold solubility—just enough to solubilize the dose throughout the GIT
70
Why should excess solubilizer be avoided?
Because maximizing solubility alone can upset the solubility-permeability balance
71
What does BCS stand for?
Biopharmaceutics Classification System
72
What is the purpose of BCS?
To relate dissolution and permeability to absorption and support in vitro-in vivo correlations
73
When is a drug considered highly soluble?
When the highest dose strength is soluble in less than 250 mL of water over pH 1 to 7.5
74
When is a drug considered highly permeable?
When the extent of absorption in humans is greater than 90% of the administered dose
75
When is a drug product considered rapidly dissolving?
When more than 85% dissolves within 30 minutes using USP apparatus I or II in less than 900 mL buffer
76
What are the characteristics of a Class I drug (BCS)
High solubility and high permeability
77
What are the characteristics of a Class II drug (BCS)
Low solubility and high permeability
78
What are the characteristics of a Class III drug (BCS)
High solubility and low permeability
79
What are the characteristics of a Class IV drug (BCS)
Low solubility and low permeability
80
What does IVIVC stand for?
In vitro-in vivo correlation
81
Why is BCS important in generic development?
It can be used to waive bioequivalence studies and save time and resources
82
What is the absorption rate control for a Class 1 drug (BCS)
Gastric emptying (IVIVC expected if dissolution rate is slower than gastric emptying rate)
83
What is the absorption rate control for a Class 2 drug (BCS)
Dissolution (IVIVC expected if in vitro dissolution rate is similar to in-vivo dissolution rate, unless dose is very high)
84
What is the absorption rate control for a Class 3 drug (BCS)
Permeability (absorption/permeability is rate determining, limited or no IVIVC with dissolution)
85
What is the absorption rate control for a Class 4 drug (BCS)
Dissolution and permeability, case by case (Limited or no IVIVC is expected)
86
Why does site of absorption matter?
Because different GI regions have different permeability and therefore different absorption
87
What ranitidine example is shown?
Ranitidine is absorbed much less extensively from the colon than from the small intestine
88
Why is ranitidine absorbed less from the colon?
Because the permeability-surface area product is much lower in the colon
89
Drugs with permeability below what value are likely to be incompletely intestinally absorbed?
1.0 × 10^-4 cm/sec.
90
Why do poorly permeable drugs often have low oral bioavailability?
Because they only spend about 2-4 hours in the small intestine, where permeability is highest
91
Where is permeability highest?
Small intestine (jejunum)
92
How does the stomach empty water?
Water leaves the stomach at a fast rate
93
How do digestible solids leave the stomach?
They begin to leave after a lag period and then leave slowly
94
How do large indigestible solids leave the stomach?
They are retained during the digestive period and then emptied rapidly later
95
Why can gastric emptying control the speed of drug absorption even for a solution?
Because absorption is greater in the small intestine
96
How can gastric retention sometimes be useful?
It can be used as a mechanism for sustained oral drug absorption from the small intestine
97
What drug example is used to show slowed gastric emptying?
Remifentanil slows gastric emptying and changes acetaminophen exposure-time profiles
98
99
What is an absorption window?
A limited intestinal region where uptake transporters allow effective absorption
100
Why are absorption windows a challenge for dosage-form design?
If the drug is not released before the dosage form passes the window, bioavailability will be poor
101
Why is a high-concentration bolus often not ideal at an absorption window?
Because uptake transporters are often saturable
102
What dosage-form strategy is specifically suggested for absorption-window drugs?
Gastroretentive dosage forms
103
What drug example is given for a gastroretentive dosage form?
Pranlukast
104
Why was a gastroretentive system developed for pranlukast?
Because it has extremely poor absorption in the lower GI tract
105
What is lag time?
The delay before first-order absorption begins after a single oral dose
106
What physiologic factors can cause lag time?
Stomach-emptying time and intestinal motility
107
For many drugs in solution given IM or SC, what usually limits absorption?
Perfusion rate
108
How does site of injection affect lidocaine absorption?
Different injection sites produce different peak plasma concentrations.
109
In the growth hormone example, which SC site absorbs faster?
The abdomen (shows a higher peak concentration and an earlier peak)
110
What process is illustrated by the IM chlordiazepoxide example?
Precipitation and redissolution at the injection site
111
Why does chlordiazepoxide precipitate after IM injection?
Because the acidic formulation enters tissue at pH 7.4, causing the base to precipitate
112
Once chlordiazepoxide precipitates, what limits absorption?
Dissolution of the precipitated drug
113
What is first-pass metabolism?
Presystemic metabolism before the drug reaches systemic circulation
114
What first-pass metabolism interaction example is shown?
Simvastatin with grapefruit juice
115
What effect did grapefruit juice have on simvastatin?
It altered first-pass metabolism in the gut wall and increased plasma concentration
116
What mechanism caused the grapefruit juice interaction with simvastatin?
Inhibition of a drug-metabolizing enzyme
117
What transporter-mediated interaction example is shown?
Rifampicin and digoxin
118
How does rifampicin affect digoxin absorption?
Rifampicin pretreatment reduces digoxin absorption
119
What mechanism explains rifampicin's effect on digoxin?
Increased intestinal expression of P-glycoprotein
120
Food may affect which two major aspects of absorption?
Rate and extent of absorption
121
How can food affect solubility and dissolution?
By stimulating acid secretion and bile secretion
122
How can delayed gastric emptying affect an acid-labile drug?
It prolongs residence time in the stomach
123
If a drug is stable in the stomach and reaches the small intestine dissolved, how can food affect absorption?
It may increase the rate and extent of absorption, especially for BCS Class 2 and 4 drugs
124
How can increased intestinal transit time affect a stable drug?
It may increase extent of absorption and delay the rate
125
What does the FDA require regarding food-effect studies?
Food-effect studies for all new drugs and formulations, especially oral sustained-release products
126
What meal does the FDA specify for food-effect testing?
A high-fat breakfast
127
Food effects are dependent on what?
The drug and the dosage form
128
How does food affect gastric transit time of pellets?
It increases gastric transit time, especially for large single pellets
129
What is a negative food effect?
Food decreases absorption or exposure
130
What likely mechanism explains the ciprofloxacin-dairy example from lecture context?
Chelation with calcium reduces exposure: Do not take the liquid or tablets with dairy products or calcium-fortified drinks
131
What is a positive food effect due to solubility?
Food increases absorption by improving dissolution or prolonging time available for dissolution
132
What drug example is used for positive food effect from solubility?
Albendazole
133
Why can a fatty meal increase albendazole exposure?
Food delays gastric emptying, giving more time for dissolution before the drug reaches the intestine
134
How can a delayed stomach emptying produce a double peak for a highly water-soluble drug?
Part of the dissolved drug empties into the duodenum first, then the remainder empties later and produces a second absorption peak
135
What is enterohepatic circulation?
Drug or metabolite is secreted into bile, stored in the gallbladder, released into the small intestine, reabsorbed, and returned to the liver
136
How can enterohepatic circulation contribute to multiple peaks?
Re-release into the intestine allows reabsorption and can create another peak
137
What proof-of-concept for enterohepatic circulation is given?
Activated charcoal adsorbs drugs in the intestine, preventing absorption and future enterohepatic circulation: (Paracetamol, carbamazepine, phenobarbital, phenylbutazone, and estriol)
138
What is organ clearance?
The volume of blood cleared of drug by an eliminating organ per unit time
139
What is hepatic clearance (CLH)?
The volume of blood from which drug is removed completely by the liver per unit time
140
What is extraction ratio (E or ER)?
The fraction of drug eliminated by an organ during one passage through that organ
141
How is extraction ratio conceptually estimated?
From the steady-state drug concentration entering the organ versus exiting the organ
142
What does an ER close to 0 mean?
Most of the drug escapes elimination during a single pass through the organ
143
What does an ER close to 1 mean?
Most of the drug is eliminated during a single pass through the organ
144
What is intrinsic clearance (CLint)?
The ability of the organ, especially the liver, to remove drug in the absence of flow limitations and binding to cells or proteins in the blood
145
What is systemic clearance?
A measure of the ability of the entire body to eliminate the drug
146
Why is oral clearance called "apparent" clearance?
Because it is based on oral dose and observed AUC after oral administration rather than direct systemic input
147
What major factor connects oral dosing to clearance concepts?
First-pass metabolism / hepatic bioavailability
148
How are high extraction ratio hepatic drugs defined?
EH > 0.7
149
How are low extraction ratio hepatic drugs defined?
EH < 0.3
150
How are intermediate extraction ratio hepatic drugs defined?
0.3 < EH < 0.7
151
What is another name for high ER drugs?
High clearance drugs
152
What is another name for low ER drugs?
Low clearance drugs
153
What are high ER drugs also called in terms of clearance behavior?
Flow-dependent drugs
154
What are low ER drugs also called in terms of clearance behavior?
Capacity-limited drugs
155
What mainly controls hepatic clearance of high ER drugs after IV administration?
Blood flow
156
High ER drug hepatic clearance is relatively insensitive to what two factors?
Binding to blood components (fu) and enzyme/transporter activity (CLint)
157
What mainly influences hepatic clearance of low ER drugs after IV administration?
Blood binding (fu) and intrinsic hepatic clearance (CLint)
158
Low ER drug hepatic clearance is relatively insensitive to what factor?
Liver blood flow
159
Which type of drugs typically undergo extensive first-pass metabolism?
High ER drugs
160
Which type of drugs typically have a low degree of first-pass metabolism?
Low ER drugs
161
Why do high ER drugs often have lower hepatic bioavailability?
Because a large fraction is removed during a single pass through the liver
162
Why do low ER drugs have less first-pass loss?
Because most of the drug escapes elimination during a single pass
163
For high ER drugs, a change in liver blood flow will have what effect on hepatic clearance?
It can substantially change hepatic clearance
164
For high ER drugs, changes in fu or CLint usually have what effect on hepatic clearance?
Relatively little effect
165
For low ER drugs, changes in fu can have what effect on hepatic clearance?
They can significantly affect hepatic clearance
166
For low ER drugs, changes in CLint can have what effect on hepatic clearance?
They can significantly affect hepatic clearance
167
For low ER drugs, changes in liver blood flow usually have what effect on hepatic clearance?
Little effect
168
How do intermediate ER drugs behave?
Their hepatic clearance is sensitive to blood flow, plasma protein binding, and drug metabolism/excretion
169
Why is it important to know whether a drug is high, intermediate, or low ER?
It helps predict whether changes in blood flow, protein binding, or intrinsic clearance will alter PK parameters
170
Give examples of high ER drugs listed
Morphine, metoprolol, verapamil
171
Give examples of intermediate ER drugs listed
Codeine, midazolam, nifedipine, metformin, cimetidine
172
Give examples of low ER drugs listed
Phenytoin, indomethacin, cyclosporine, amoxicillin, digoxin, atenolol
173
What is a generic drug?
A medication created to be the same as an already marketed brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use
174
What law is highlighted as key to generic drug development?
The Hatch-Waxman Act
175
What application pathway is associated with generic drug approval?
ANDA (abbreviated new drug app)
176
In what context is the term "bioequivalent" mainly used?
Legal or regulatory context
177
What is the main purpose of bioequivalence standards?
To decide whether two products have similar enough rate and extent of absorption to be substituted for one another in therapy
178
Bioequivalence standards are based on what?
Arbitrarily defined standards based on statistical considerations
179
What is the FDA-style definition of bioequivalence?
The rate and extent of absorption of the drug product do not show a significant difference from those of the listed drug product when given at the same molar dose under similar experimental conditions
180
What is the order of preference for bioequivalency testing?
1. In vivo measurement of active moiety (or moieties) in biological fluids 2. In vivo pharmacodynamic measurements 3. In vivo clinical comparison 4. In vitro comparison
181
What PK parameter is the primary measure of extent of absorption in BE testing?
Log AUC
182
What PK parameter is the primary measure of rate of absorption in BE testing?
Log Cmax
183
What PK parameter is a secondary measure of rate in BE testing?
Tmax
184
What overall difference in rate and extent of absorption did the FDA decide is most likely not therapeutically significant?
About ±20% (After log transformation, 80% to 125% is acceptable)
185
What are the 4 criteria for two products to be considered bioequivalent?
1. The antilog of the mean difference of log AUC from the two treatments is between 0.8 and 1.25 2. The antilog of the mean difference of log Cmax from the two treatments is between 0.8 and 1.25 3. The 90% confidence interval of the mean difference of log AUC ratio is between 0.8 and 1.25 4. The 90% confidence interval of the mean difference of log Cmax ratio is between 0.8 and 1.25
186
Does the FDA generally prefer single-dose or multiple-dose BE studies?
Single-dose
187
Why are single-dose studies preferred?
They are more sensitive in detecting differences between products
188
Why is food-condition testing important, especially for sustained/controlled-release products?
Because dose-dumping is possible with food
189
How many subjects are generally used per BE trial?
Generally 18-24 subjects
190
If the dose is increased how are Cmax and AUC affected
Both increase on proportion with increased dose
191
If the F value increases (higher bioavailability) how are Cmax and AUC affected
Cmax and AUC increase in proprotion with increased F
192
When ka increases (faster absorption) how is Cmax affected
Peak concentrations (Cmax) are higher and earlier
193
When ka increases, how is Tmax affected
Tmax gets smaller
194
What happens when ka < kel
The drug's absorption controls the fall in Cp at later times, known as Flip-flop kinetics. Common to sustained-release products
pkpd exam 3
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