III Flashcards
IV Time to Effect
30-60 seconds
IM Time to effect
10-20 minutes
SC Time to effect
15-30 minutes
Oral Time to effect
30-90 minutes
Sublingual Time to effect
3-5 minutes.
Inhalation time to effect
2-3 minutes
Transdermal time to effect
minutes to hours.
Rectal Time to effect
5-30 minutes
IV dose is limited by the _________ of the drug.
Solubility
Which routes of administration require a trained health professional?
IV and IM injections.
What are the volumes of IM and SQ injections?
3-5 mL (IM)
1-3 mL (SQ)
T or F: The site of an injection will influence the absorption.
True.
Subcutaneous absorption is limited by ________
Blood Flow
Pulmonary route of administration must by pass both ______ clearance and __________ in order to deliver the dose to the alveoli.
- Mucociliary Clearance
- Alveolar Macrophages.
T or F: Drugs absorbed through the sublingual route undergo significant first pass metabolism.
False
The sublingual route of administration is not suitable for what drugs.
Irritant Drugs and Large MW drugs.
Approximately 60% of small molecules drugs are administered via which route?
Oral
What is the pH of saliva, and how long is an orally absorbed drug subject to it?
pH: 6.5-7.5
Time: ~1 minute
What is the pH of the upper stomach? How long is an orally absorbed drug subject to it?
pH: 4.0-6.5
time: 30-60 minutes
What is the pH of the lower stomach? How long is an orally absorbed drug subject to it?
pH: 1.5-4.0
Time: 1-3 hours
What is the pH of the duodenum? How long is an orally absorbed drug subject to it?
pH: 7.0-8.5
Time: 30-60 minutes
What is the pH of the small intestine? How long is an orally absorbed drug subject to it?
pH: 4-7
Time: 1-5 hours
What is the pH of the large intestine? How long is an orally absorbed drug subject to it?
pH: 4-7 hours
Time: 10 hours
Folds of Kerkring
Mucosal Folds of the small intestine.
SA = 10000 cm^2
Villi
Small finger like projections in the small intestine. These increase the surface area available for absorption.
SA= 100,000 cm^2
Microvilli
microscopic cellular protrusions which increase surface area for diffusion. These are found in the small intestine.
SA= 2,000,000 cm^2
Dissolution
Solid drugs must be dissolved before they can be absorbed.
Disintegration
Breakdown of solid drugs into smaller particles.
Passive Transcellular Transport
Transport of solutes without energy. This is bidirectional and occurs along a concentration gradient.
Molecules involved are: Lipophilic and unionized.
Active Transcellular Transport
Carrier Mediated Transport (Transporter). This occurs in a substrate dependent direction.
What are limitations of active transcellular transport?[3]
- Saturable
- Stereo chemically dependent
- Inhibitable
What molecules undergo active transcellular transport primarily?
Hydrophilic molecules.
What is paracellular diffusion?
Bidirectional diffusion along a concentration gradient by passing through the intracellular space between cells.
What are the limitations of paracellular diffusion?
- Low capacity
- Saturable
What molecules undergo paracellular diffusion?
Hydrophilic molecules.
Transcytosis
Receptor mediated endocytosis. This is where macromolecules are captured in vesicles and ejected to the other side of the cell.
What is the direction of transcytosis
Mucosal layer–> serosal layer
What is the driving force of transcytosis?
Active transport
What are the limitations of transcytosis?[3-4]
- Low capacity
- Saturable
- Likely stereo chemically dependent
- Can be inhibited
What molecules undergo transcytosis?
macromolecules.
For most drugs; is dissolution rate faster or slower than absorption rate?
Dissolution rate is either the same or faster than absorption rate.
Is it possible for absorption rate to be faster than dissolution rate?
No, because you cannot absorb the entire drug if it has not been dissolved. Furthermore, slow dissolution is considered to be a rate-limiting factor of absorption.
Immediate Release Definition
85%+ is absorbed within 30 minutes of administration.
Extended Release
Modified Dosage Form which prolongs the time of drug release. (note the time of effect is not delayed.)
Delayed Release
Modified dosage form which delays the time until the drug is released following administration. However, once the drug is released it is absorbed at a similar rate to an immediate release product.
Scientific Discipline that examines the interrelationships of the physiochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of drug absorption.
Biopharmaceutics
Inventor: Gerhard Levy
Oral absorption of drugs often approximates _____ kinetics.
First Order
First Order Absorption Rate Constant
Ka
First Order Absorption Half-Life
0.693 / Ka
First Order Absorption Rate
Ka * Aa
Aa= Amount remaining to be absorbed.
Compare and Contrast First Order and Zero Order Kinetics
First Order = Concentration Dependent
Zero Order = Concentration Independent.
Zero-Order will go to zero. Where first order will never do this.
Cmax
The peak concentration following administration of a drug.
Tmax
The time at which the peak concentration occurs following the administration of a drug.
How do you calculate the remaining drug to be absorbed?
X= Dose * Bioavailability
What is the Bateman Function and what is its purpose?
(See page 6 of notes)
The bateman function is used to calculate the plasma concentration at any time following a single oral dose.
What are the major PK parameters?
Absorption Parameters(F, Ka)
Disposition Parameters(Cl(Kel), V)
What does the Bateman Function Assume?
First Order Elimination
Ka is normally __________ than Kel
Ka is normally faster than Kel, therefore it is usually presumed that Kel is the rate limiting factor of oral absorption.
Remember, Kel is the elimination rate constant.
The method of residuals works best if:
1)___________
2) ____________
1) Both absorption and elimination are first order processes.
2) One rate constant is at least five times larger than the other. (ka or kel)
What is the slope of a semi-log graph of Cp vs time?
Kel
What is Y-intercept of a semi-log graph of Cp vs time?
Co= Initial Plasma Concentration
How are the residual values calculated in the method of residuals?
Cp(late) - Cp
What is the slope of the residuals graph?
Ka
The Y-intercept should be the same as the Terminal slope graph.
How do we calculate the elimination half-life in the method of residuals?
0.693/Kel
This is assuming kel is less than Ka. Otherwise Ka would be the rate limiting factor in elimination.
How do we calculate the absorption half-life in the method of residuals?
0.693/Ka
What is a mathematical check to verify the method of residuals?
Ka/Kel = 5+ (needs to be greater than 5)
How do we calculate the volume of distribution using the method of residuals if we do not know the bioavailability of the drug?
Rearrange the bateman function for (V/F)
How do we calculate the clearance using the method of residuals if we do not know the bioavailability of an orally administered drug?
Use CL/F = Kel/(V/F)
How can we approximate AUC?
Bioavailability * Dose
Remember: AUC is the cumulative systemic exposure of a drug.
How do you determine the absolute Bioavailability of a drug?
By comparing the AUC (oral) to the AUC (IV).
See page 8 of study guide for formula.
What is relative bioavailability and how do we calculate it?
Relative bioavailability is used to compare two oral formulations, particularly when there is not an IV formulation available for use.
See page 8 of study guide for formula.
What are the determinants of Tmax
Ka, Kel (CL, V)
See page 9 of study guide for equation.
What are the determinants of Cmax
D,F,Tmax (ka, CL, V)
See page 9 of study guide for equation.
How do you calculate AUC?
(Bioavailability * Dose) / Clearance
What formula do we use to calculate the plasma concentration of a drug following multiple dose administration?
See page 10 of study guide.
How do we calculate the minimum concentration at steady state of a drug following multiple dose administration?
See page 10 of study guide.
How do we calculate the minimum concentration at steady state of a drug following multiple dose administration? If Ka > Kel?
See page 10 of study guide.
How do you calculate the average steady state concentration of a drug? How do you manipulate this to find the maintenance dose or dose rate?
See page 10 of study guide.
AUC0-Inf after the first single dose is ________ to AUC0-Tau at steady state.
Equal (see study guide page 10 for further clarification).
Time to steady state is dependent on _________.
Elimination Half-Life
How can we achieve steady state faster?
Loading dose
How long does it take to reach steady state.
3-5 Half lives (exact time will vary depending on the drug.)
How do we calculate accumulation ratio?
1.) Use the ratio between AUC at the first dose and at steady state.
2.) Use the ratio of Cp at the first dose and at steady state. (however, this only works when Ka»_space; Kel)
__________ controls the degree of accumulation.
Dosing Frequency
Increased Dosing Frequency = __________ accumulation
More accumulation. (less drug is cleared between doses.)
Increased Dosing Interval = ________ Fluctuation
Increased Fluctuation
Fluctuation
Difference between Peak and Trough of dosing regimen.
Do changes in dosing frequency effect the time to steady state?
No, only half-life alters the time to steady state. However, it will alter the steady state concentration due to accumulation and fluctuation.
When Ka»_space; Kel, the ___________ controls the fall in Cp at later times.
Drugs Elimination is the rate limiting factor.
In immediate release products what is usually the relationship between Ka and Kel?
Ka»_space; Kel
T or F: IV and Oral Formulations typically have similar half-lives for products which Ka»_space; Kel
True.
If Ka»_space; Kel, then the terminal slope from IV dose _________ the terminal slope from the oral dose.
They are equal.
What is flip flop kinetics?
Ka «_space;Kel, in this case Ka becomes the rate limiting factor which controls the fall in Cp at later times. This is because drug is basically being cleared as soon as it is absorbed.
In Flip Flop Kinetics, the terminal slope from an IV dose is _____________ the terminal slope from an oral dose?
Greater
What results from Flip Flop Kinetics?
A more prolonged absorption results and thus slower drug elimination.
What kind of kinetics do sustained release products typically have?
Flip FLOP ( Ka < kel). This means absorption is the rate limiting factor in drug elimination.
Why is the drug amount in a modified release product typically proportionally larger than the dose in a conventional immediate release product?
This is because it is given less frequently and typically releases drug over time.
Compared to an immediate release product a modified release product exhibits:
_______ Fluctuation
_________ terminal Half-life
________ time to steady state
Little Fluctuation
Prolonged Terminal Half-Life
Increased time to steady state.
What is the Noyes Whitney Equation?
This equation describes the rate of dissolution based off of Fick’s Law parameters.
T or F: Different Polymorphs have the same solubility and dissolution characteristics?
False: Crystalline forms dissolve slower than amorphous forms.
Describe the relationship between surface area of the diffusion layer and absorption.
Increased surface area = increased dissolution.
Describe the relationship between thickness of the diffusion layer and absorption.
Increased thickness = decreased dissolution
Describe the relationship between particle size and absorption.
Decreased particle size = increased surface area = absorption
Describe the relationship between MW and absorption?
Increased Molecular weight = Decreased Diffusion Coefficient = Decreased Absorption
Describe the relationship between stirring rate and dissolution.
increased stirring rate = increased dissolution.
Between Powders, Capsules and Tablets which has the fastest rate of dissolution?
Powders due to their decreased particle size.
What is the relationship between dissolution volume and rate of dissolution?
The greater the dissolution volume the faster the rate of dissolution.
How do disintegrants effect ka?
Increase
How do lubricants affect ka?
decrease
How does enteric coating affect ka?
decrease
How do sustained release tablets affect ka?
decrease
How do waxing agents affect ka?
decrease
What is the effect of magneisum stearate?
it is a hydrophobic lubricant which serves to decrease Ka. This slows dissolution rate as it makes the surrounding environment hyprophobic. This also lowers the AUC of the drug.
Lipinski’s rule of 5
H-Bond donors <5
MW <500 Da
Log P </= 5
H-Bond Acceptors </= 10
Remember these rules only apply to drugs which undergo passive diffusion. Drugs which undergo active transport are the exception to this rule.
What is the Lipinski rule of 5 based off of?
90-percentile values of drugs, only applies to those undergoing absorption by passive diffusion.
What are the effects of increased logP?
Increased receptor binding, P450 binding, absorption, plasma protein binding, hERG heart ion channel activity (QT prolongation).
Decreases aqueous solubility
What is the problem with too many hydrogen bonds on a drug?
This makes desolvation unfavorable. Prevents the drug from getting to the blood from the gut.
Desolvation
Process where water molecules are displaced to allow for the interaction between a ligand and its substrate.
QSPKR
Quantitative Structure Pharmacokinetic Relationships.
Which is more important to drug absorption; solubility or permeability?
Neither, they both must be balanced in order to optimize drug absorption.
How was the absorption of carbamazepine increased?
By adding PEG400 to increase solubility. However, it was determined a maximum concentration of 60% yielded the best absorption. This was due to optimization of solubility versus permeability.
What is the difference between in vitro and in vivo.
In vitro = lab
In vivo = living organism
Highly Soluble Definition
Highest dose strength is dissolvable in <250 mL of water.
Over a pH range of 1 to 7.5
Highly Permeable Definition
Extent of absorption is >90% of administered dose. Based on comparison to IV dose.
Rapidly Dissolving definition.
> 85% of labeled amount of drug substance dissolves with in 30 minutes using USP apparatus I or II in a volume of < 900 mL of solvent.
BCS Class I
High Solubility
High Permeability
BCS Class II
Low Solubility
High Permeability
BCS Class III
High Solubility
Low Permeability
BCS Class IV
Low Solubility
Low Permeability
What is the absorption rate control for BCS Class I drugs?
Gastric Emptying
What is the absorption rate control for Class II drugs?
Dissolution
What is the absorption rate control for Class III drugs?
Permeability
What is the absorption rate control for Class IV drugs?
Solubility or Permeability
How can we convert a BCS Class II Drug to a Class I drug?
By increasing solubility.
This can be done via:
pH adjustment | Solid Dispersion | Particle Size reduction | Salts | Co-Solvents | Micellar Solutions | Emulsions | SEDDS/SMEDDS
How can we convert a drug from Class III to Class I
Increase Permeability:
Efflux inhibitors | Tight Junction opener | Metabolic Inhibitors | Motility Modifier | Pro-Drugs
How can we convert a Class IV drug to a class I
Improve both solubility and permeation.
What change in formulation could we perform for a drug that is better absorbed in the intestines?
Enteric Coating–> protects acid labile drugs from the acidic environment of the stomach. And delays release until the drug reaches the reaches the intestine.
If absorption rate is rate limiting a drug undergoes ________.
Flip Flop Kinetics
Human Jegunal Permeability
Fraction of dose intestinally absorbed after oral administration.
Drugs with permeabilities < ___________ are likely to be incompletely intestinally absorbed.
1 E -4 cm/sec
Drugs with low perameability have low bioavailability, why?
This is because they spend the least time in the intestine, where permeability is highest due to the increased surface area of villi and microvilli.
Compare the rate at which substances leave the stomach:
Water, Digestible Solids, Indigestible Solids
Water: leave stomach at fast rate.
Digestible Solids: (<2-3 mm) –> Leave slowly after a lag time.
Indigestible Solids: (>5-7 mm)–> Retained in stomach during digestive period. rapidly cleared afterwards.
Increased size of solid –> Increased time of absorption.
Pyloric Spincters
Gateway between stomach and intestines.
What does feedback by nutrients in the small intestine cause.
Relaxation of fundus
Phasic and tonic contraction of pyloric spincter
Negative feedback on antrum–> Prevents chyme from being pumped through pyloris
For drugs where absorption is greater in the intestine, what is the rate limiting factor?
Gastric Emptying. –> Therefore, gastric retention can be used for sustained oral absorption from the small intestine.
How does remifentanil interact with acetaminophen?
It decreases acetaminophen oral absorption by delaying gastric emptying.This is because acetaminophen oral solution is absorbed in the intestines.
How does the side you sleep on effect acetaminophen concentrations?
Right Side = Higher Concentration.
This was due to increased gastric emptying.
Absorption Windows
Result if intestinal absorption of a drug is mediated by uptake transporters and the location is limited to a relatively small area of the intestine.
Why can’t we simply present a high concentration bolus dose to the absorption window of a drug in the intestine?
This is because the associated uptake transporters are often saturable. Therefore a slow sustained exposure from drug release upstream from the window would be preferred.
What is a proposed approach to addressing absorption windows for drugs?
Gastroretentive Dosage Forms.
These keep the dosage form upstream of the intestines longer, allowing drug release to occur and optimize intestinal absorption of the drug.
Pralukast was a drug which exhibited an absorption window, what was done to optimize absorption of this drug?
A gastroretentive dosage form was used. This kept the drug in the stomach longer and increased the AUC. This was especially seen after the evening meal as high caloric loads slow down gastric emptying. This prolongs the amount of time the drug is upstream of the absorption window even longer. Thus increasing the AUC or total systemic exposure of the drug.
What is Lag time?
The time delay after administration before first order absorption occurs.
This usually occurs due to stomach emptying or intestinal motility.
For Intramuscular and Subcutaneous injections, what is the rate limiting factor of systemic absorption?
Perfusion. (BF/V)
When utilizing a drug for local effect (injections such as an epidural), do we want high or low systemic absorption of the drug?
Low –> Less off target effects.
Why don’t we want a high speed of absorption for a locally injected anesthetic?
This would decrease exposure at the local site of action, and decrease the duration of action.
Is absorption faster from the abdominal site or thigh?
Abdomen.
For abdominal and thigh injections, what is the rate limiting factor of drug elimination?
Absorption (ka)
For injections, how can we change the duration of action?
By changing formulations.
IV = limited by Kel = much shorter
SQ = Limited by Ka = Much longer
Why is Chlordiazepoxide formulated in an acidic pH for injection?
This causes the drug to precipitate when it is injected into plasma (pH 7.4). This slows dissolution and the absorption process. This leads to flip flop kinetics where absorption is the rate limiting factor in elimination as well. This extends the duration of action of this drug from hours to many days.
Can we utilize pH differences to extend the duration of action of IV formulations?
No, this would be dangerous as it would cause the drug to precipitate and form an embolus in our blood stream.
How does Simvastatin interact with grape fruit juice?
Grape fruit juice inhibits CYP3A4 which causes simvastatin concentrations to increase significantly. A western blot was used to verify this.
How does Rifampicin interact with Digoxin?
Rifampicin induces p-glycoprotein expression. Therefore, after 10 days an increase in this transporter is exhibited. This increase in p-glycoprotein leads to a signifcant decrease in digoxin concentration. This can be harmful to a patient due to the drug not maintaining therapeutic levels. it should be noted this interaction only occurs with oral dosing and not IV b/c in IV dosing the drug is administered directly to the blood stream.
Positive Food Effect
Administer with food increases absorption.
Negative Food Effect
Administer with food decreases absorption.
How does food affect absorption?
Food may stimulate bile acid secretion (may affect ionization of drug), or stimulate bile secretion (increase fecal elimination of a drug).
Food can even delay gastric emptying which depending on the drug may increase absorption.
Which drug classes may benefit from food effect delaying gastric emptying?
BCS II and IV. This is because these drugs have poor solubility. Therefore this would give the drug more time to dissolve in the stomach before moving to the highly permeable intestinal tract where they could be absorbed. Remember drugs will not be absobed if they are not first dissolved. Dissolution is rate limiting to absorption just like permeability.
What does the FDA classify as “Food”
High Fat Breakfast Foods
Why are we especially concerned about food effects for sustained release dosage forms?
Dose Dumping
How do large meals effect transit times throughout the GI tract.
It was found that large meals delay gastric emptying. Increasing time in the stomach. However, they were found to have no effect on small intestine transit time.
What is typically done with albendazole to increase absorption.
It is recommended to take with a fatty food to increase absorption. This is the case because the fatty food delays gastric emptying giving more time for the drug to dissolve and thus increase absorption in the intestinal tract.
How does dose dumping result from positive food effect?
Certain foods may cause premature and exaggerated release of a drug from a modified release dosage form.
Not a concern for many drugs, however for those with narrow therapeutic windows this can be quite concerning due to the increased risk of an overdose.
Explain Double Peak Phenomenon
This occurs with drugs that exhibit high water solubility.
Dissolution of the drug in the stomach, and partial emptying into the duodenum leads to the first absorption peak.
A delay in gastric emptying results from this leading to a second absorption peak as the remainder of the dose is emptied into the duodenum.
This is not observed for crushed tablets.
Hatch Waxman Act
Implemented Modern System of Generic Regulation.
Launched Expedited pathway to obtain FDA approval.
Lows to shield generic applicants from charges of patent infringement until such time as they request approval to market the drug from the FDA.
ANDA
Abbreviated new drug application.
Used for generic drugs.
Must demonstrate it is the same as the already approved drug.
No clinical trials just proof of bioequivalence.
Eroom’s Law
Observation that drug discovery is becoming slower and more expensive over time despite improvement in technology.
Opposite of Moore’s Law–> Talks about the exponential advancements in technology over time.
Bioequivalence
Rate and extent of absorption of the drug product do not show a significant difference from the rate and extent of absorption of the listed drug product when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple dose form.
What is the order of preference for bioequivalence testing?
- In vivo of biological fluids
- In vivo pharmacodynamic
- In vivo clinical comparison
- In vitro comparison
In bioequivalence studies how do we assess extent and rate of pk?
Extent: log AUC
Rate: Log Cmax, Tmax (secondary)
The FDA has decided that a __________- difference in the rate and extent of absorption most likely will not produce any significant therapeutic difference between agents.
+/- 20%
Log-Transformed Data Adjustment to FDA bioequivalence rule
80-125%
Bioequivalent Criteria (4)
The following are between 0.8 and 1.25
1. Antilog of the mean difference of log AUC
2. Antilog of the mean difference of log Cmax
3. 90% confidence interval of the mean difference of log AUC ratio.
4. 90% confidence interval of the mean difference of log Cmax ratio.
It should be noted failure of any one of the four criteria means the drug is not bioequivalent.
What is a confidence interval?
How often the result will fall within a given interval.
Confidence Interval of 90: means the amount absorbed should fall within the given interval 90 times out of 100.
How do you calculate confidence interval?
See page 28 of notes.
How do you calculate the higher and lower bounds of a confidence interval?
See page 29 of thes study guide.
When evaluating bioequivalence should we look at single dose kinetics or multi dose?
Single Dose: More sensitive to detecting difference between products. Preferred by FDA.
Should bioequivalent studies be completed with or without food?
Currently, food effect is studied to address potential of dose dumping.
How many subjects are typically involved in bioequivalence studies?
18-24
Should Bioequivalence Studies be completed in target populations?
FDA does not require or recommend this?
Are there tighter regulations for bioequivalence for drugs with narrow therapeutic indexes?
No
How often should bioequivalence trials be conducted?
Only once
Who should conduct bioequivalence trials?
Currently, the generic manufacturers themselves.
Bioequivalence for highly variable drugs.
See page 29 of study guide.
