Exam 1 Flashcards
Do oral or IV administration dosage forms directly enter the systemic circulation?
IV
The drug is considered _________ until it enters the blood stream
Outside the body
For a PK curve describe Tmax and To for an IV bolus
Tmax = To
For a PK curve describe Tmax and To for an oral dose
Tmax does not equal To
For oral doses what causes the Cmax delay?
Absorption: access of the drug to the systemic circulation
All extravascular delivery routes rely on what process?
Absorption
Kinetically, the absorption of most drugs follow what order process?
First order
What are the 3 key steps in drug absorption?
- Disintegration (for solid dosage forms)
- Dissolution (for solid dosage forms)
- Diffusion across the GI membrane
Compare the stomach to the small intestine
Stomach: relatively smooth (low SA)
Small intestine: numerous folds and projections (high SA)
How many L’s are secreted by the GI tract?
8-10L
When going from the stomach to the duodenum what happens to pH and enzymes?
Rapid change (pH 5-8)
More enzymes are introduced
In the GI tract what areas are the most efficient for drug absorption?
Duodenum, jejunum, and upper illeum
Where do drugs have longer residence time in the GI tract?
Duodenum
What is the typical range of absorption half-lives for oral solutions and rapidly disintegrating DF?
From 15 min to 1 hour
What are the underlying one-compartment model assumptions?
- Passive diffusion is operative at all times
- Both absorption and elimination of a drug follow a first order process
- Drug is eliminated in an unchanged form (i.e. no metabolism occured)
Elimination half-life, elimination rate constant, the apparent volume of drug distribution, and system clearance are _______ of ROA
Independent
Absorption of a drug from a tablet dosage form includes the following steps?
Disintegration to disssolution to diffusion through the membranes
Which PK parameters are independent of ROA?
Volume of distribution, elimination half-life, clearance, and elimination rate constant
Ka = what order constant?
First-order
What is the value that shows the fraction of drug available at the absorption site (GIT) that is absorbed per unit of time?
Ka
A high Ka = what
Rapid absorption
At Tmax
Ka = what
Ke
Elimination phase
Ke __ Ka
> >
Absorption phase
Ke __ Ka
«
When does the elimination process begin after the drug is administered?
Almost immediately
What is affect by both absorption and elimination during the absorption phase?
Cp
The amount of drug in the body (Db) ______ if the rate of drug absorption larger than the elimination rate
Increases
Drug Y (150mg) is given as an oral solution and has the following PK parameters: t1/2 = 8 h, ka = 0.25 h-1, Vd = 10 L, F = 1. What will be the plasma concentration at 12 hours after the dose is administered?
7 mg/L
Manini et al (2005) reported a case of adverse drug reaction in a previously healthy young man who ingested a recommended dose of an over-the-counter (OTC) cold remedy containing pseudoephedrine. Forty-five minutes later, he had an acute myocardial infarction (MI). Elevations of cardiac-specific creatinine kinase and cardiac troponin I confirmed the diagnosis. Cardiac magnetic resonance imaging (MRI) confirmed a regional MI. Cardiac catheterization 8 hours later revealed normal coronary arteries, suggesting a mechanism of vasospasm.
Why the patient developed a sever adverse reaction at a therapeutic dose?
The elimination process in the patient is not as fast as expected
For an oral dosage form, which expression correctly describes the relationship between Ka and Ke at the absorption phase?
Ke = Ka
Ke > Ka
Ka > Ke
Ka»_space; Ke
Ka»_space; Ke
What is a tool that allows us to tear apart the absorption rate from the elimination rate?
The method of residuals
The are the method’s prerequisites?
- The absorption rate constant is larger than the elimination rate constant
- Both drug absorption and elimination process follow first-order kinetics
- The drug PK follows one-compartment model
What is the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action?
Bioavailability
What is the fraction of administered dose that enters the systemic circulation?
Bioavailability fraction (F)
A single intravenous dose of an antibiotic is 250 mg. What would be the corresponding oral dose of the drug, if it has an oral bioavailability of 90%?
278 mg
A lower bioavailability = ____ drug plasma concentration (Cmax)
Lower
Why is bioavailability of oral DF incomplete?
- Excipients
- Particle size of API
- Polymorphic/solvate form of API
BA is measured as the API concentration vs ______ in the systemic circulation
Time
Cmax =
Highest drug concentration in the plasma
Tmax =
The time required to reach Cmax
AUC =
Area under the plasma concentration-time curve
AUC is ______ affected by the absorption rate
NOT
Does the relative BA provide the value of the absolute BA of the individual products?
No
What are the two types of BA?
Absolute and Relative
Measurement of drug concentration in blood, plasma, or serum after drug administration is the most ______ method of assessing systemic BA
Direct
What are the two method of computing AUC?
- Using blood level equations
- Using the trapezoidal rule
What are the 3 prerequisites for using blood level equations?
- Known administered dose
- Well-fitted blood level curve
- 1st order elimination kinetics (most drugs)
BA of drugs with dose-dependent PK (AUC is not directly proportional to the dose) is _______ to evaluate
Difficult
What are the 2 prerequisites for the trapezoidal rule?
- No blood level curve fitting done
- No PK data available
What is the advantage of the trapezoidal rule?
Compartment-model independent
What is the indirect method for estimating bioavailability?
BA calculation from the drug urinary excretion data
BA can be determined using direct (_______) and indirect (_______) methods
direct (determination of AUC)
indirect (urinary excretion)
For most drugs, AUC is _______ to the dose
Directly proportional
What rule can be used to compute the AUC without PK data?
Trapezoidal
What is the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study
Bioequivalence
What is a special type of relative (comparative) bioavailability?
Bioequivalence
What is when drug’s have the same active ingredient, strength, dosage form, and RoA. That also have the same USP standards (quality, purity, identity) but may differ in shape, color, excipients, release mechanism, packaging, labeling, and expiration date?
Pharmaceutical equivalents
Pharmaceutical equivalence + Bioequivalence =
Therapeutic equivalence
What are drugs that have the same active ingredient, solid state form may vary, DF and strength may differ, product may differ with respect to release rate, and alternatives are NOT interchangeable?
Pharmaceutical alternatives
Bioavailability/Bioequivalence testing subject selection includes?
Minimum of 12 adults
Typically, 18-24 subjects are used
What makes of the procedure of Bioavailability/Bioequivalence testing?
- Subject selection
- Written consent and physical exam to certify healthy
- Subjects fast overnight
- Administration of drug with designated amount of water
- Analysis of blood and/or urine samples
- Tabulating and graphing results
In Bioavailability/Bioequivalence testing what is a standard to minimize individual subject variation?
2x2 Cross-over design
What does it mean if plasma levels show obvious differences in AUC, Cmax, and Tmax?
There is no bioequivalence
If the results are close and bioequivalence is desired, what must be performed?
Statistical analysis (ANOVA)
If selecting optimal formulation, Cmax must be _____ MTC and _____ MEC
and what is usually maximized?
Below
Above
AUC
What is the rule for statistical criteria for bioequivalence? This is the most common criterion to establish BE
80/125 Rule
BE is concluded if the average BA of the test formulation is with _________ that of the reference formulation?
80%, 125%
Determine _____ CI for the test formulation and show that AUC (log-transformed) lies betwen ____ and _____ of the reference AUC
90%
80%
125%
Compare 2 DF of diclofenac sodium, oral tab and IV injection. How would you predict bioavailability of these two DF?
a. Equal
b. Unequal with oral bioavailability being higher
c. Unequal with oral bioavailability being lower
C
What is the key assumption that allows us to estimate bioavailability using blood level equation?
a.AUC is inversely proportional to administered dose
b.AUC is directly proportional to administered dose
c.AUC is independent of administered dose
B
- Consider 2 different tablet formulations. We have a formulation with 100 mg of the same drug. A study shows that the Tmax of the 2 are different, AUC appears to be the same. These are considered
a.Pharmaceutical equivalent
b.Bioavailability
c.Pharmaceutical alternatives
d.Therapeutically equivalent
A
The term biologically available and bioavailability refers to the relative amount of drug that reaches the
a.Small intestine
b.Stomach
c.Systemic circulation
d.Liver
e.Kidney
C
The AUC of a drug can be determined from a graph by using
a.Law of diminishing returns
b.Rule of 9’s
c.Trapezoidal rule
C
Differences in bioavailability are most frequently observed with drugs administered by which of the following routes
a.SubQ
b.IV
c.Oral
d.Sublingual
e.IM
C
Two different oral formulations containing the same dose of the same drug having equal areas under their respective serum concentration time curves
a.Deliver same total amount of drug to bioequivalent in the body but are not necessarily bioequivalent
b.Deliver same total amount of drug in the body are therefore bioequivalent
c.are biorquivalent by definition
A
Requirements for drug products are considered pharmaceutical alternatives including the same
a.Active drug/precursor
b.DF
c.Salt or ester
A
If an oral capsule formation of the drug A produces a serum concentration time curve having the same area under the curve as that produced by an equivalent dose of drug a given IV, it can generally be
a.IV is preferred to oral
b.Capsule formulation is essentially completely absorbed
c.Drug is rapidly absorbed
d.All oral DF of A will be bioequivalent
e.No advantage to IV
B
