PHR 921 Block 1

Select the concentration-time profiles for the same drug shown in the graph (rectilinear coordinates) for the control condition (black solid line) and a second condition (red interrupted line) when the absorption rate constant ka is 5-fold lower (assumptions: one compartment model, terminal slope is associated with the elimination rate constant K).

2021 Exam 1 #36

Which of the equations below is a linear equation? A) C = Co - ko^t B) lnC = lnCo - kt A B A and B Neither is a linear equation

A and B

Which of the following pharmacokinetic parameters best reflects the bioavailability F? A. AUC B. t1/2 C. Cl D. kelimination E. tmax

A. AUC

After an intravenous injection of a drug, a female patient (43 years, 56 kg) has an initial drug plasma concentration of 32 mg/L. How often does the patient have to take the drug (t1/2 = 9 hours, V = 3.9 L/kg) if the minimum effective concentration is 5 mg/L? A. Once per day B. Twice per day C. Three times per day D. Four times per day

A. Once per day

The concentration-time profiles for the drug products A, B, and C (same active drug) can be explained by differences in: **********graph in 2020 exam 1: #17********** A. Rate of absorption (ka) B. Dose (mg) C. Half-life (t1/2) D. Systemic Clearance (Cl) E. Volume of Distribution (V)

A. Rate of absorption (ka)

Identify all CORRECT statements about systemic bioavailability F: A. The systemic bioavailability F for a drug with FA = 0.5, FG = 0.7, and FH = 0.6 is 21%. B. Bioavailability has additive properties. C. When calculating the absolute bioavailability of a drug, oral administration of the innovator product is often used as the reference standard. D. Systemic bioavailability F is defined as the fraction of a drug that reaches the systemic circulation.

A. The systemic bioavailability F for a drug with FA = 0.5, FG = 0.7, and FH = 0.6 is 21%. D. Systemic bioavailability F is defined as the fraction of a drug that reaches the systemic circulation.

First Order Kinetics

Amount of drug removed over time changes Data plotted on rectilinear paper yield in a curve

Identify all correct statements after ORAL DOSING of a drug: A change in the distribution volume (V) results in a change of the dose (X0). An increase in clearance (Cl) results in a decrease in the area-under-the-curve (AUC). A decrease in the absorption rate constant (ka) results in a lower peak concentration (Cmax) at a later time point. An increase in the absorption rate constant (ka) results in an increase in the area-under-the-curve (AUC).

An increase in clearance (Cl) results in a decrease in the area-under-the-curve (AUC). A decrease in the absorption rate constant (ka) results in a lower peak concentration (Cmax) at a later time point.

Identify all correct statements about half life (t1/2). Changes over time Depends on concentration Appropriate to use only in the context of first order kinetics Defined as the time it takes for a concentration (or amount) of drug to decrease by 50%.

Appropriate to use only in the context of first order kinetics Defined as the time it takes for a concentration (or amount) of drug to decrease by 50%.

Which equation is consistent with a first order elimination describing the rate of change of drug A as a function of time (initially only A is present)? ***********2021 Exam 1: #16************** A, B, C, D, E,

B

The physico-chemical characteristic of a drug molecule that favors passage across a biological membrane is: A. Large molecule size B. High lipophilicity C. Great ionization D. Strong hydrogen bonding E. High hydrophilicity

B. High lipophilicity

Which statement regarding the pharmacokinetics after oral administration of a drug is CORRECT? A. The method of residuals ("curve stripping") allows to estimate if the absorption rate is faster than the elimination rate when using oral administration data alone ✓B. The method of residuals ("curve stripping") allows to estimate ka from oral dosing C. Lag time (tlag) refers to the time it takes for the process of absorption to end D. Doubling the oral dosing rate decreases the steady-state concentration by half

B. The method of residuals ("curve stripping") allows to estimate ka from oral dosing

A patient with a urinary tract infection is treated with 80 mg gentamicin, which results in a gentamicin plasma concentration of 4 μg/ml shortly after initial i.v. administration. What is the distribution volume V of gentamicin? A. 0.2 L B. 2 L C. 20 L D. 200 L E. None of the above

C. 20 L

To ensure that a generic drug product is bioequivalent to the original brand name product, a generic drug company has to demonstrate that their product has the same... A. therapeutic window B. systemic clearance C. rate and extent of absorption D. half-life E. absorption lag time

C. rate and extent of absorption

The rate constant k0 for a drug with zero order elimination kinetics with respect to concentration has the following unit:

( mg ) / ( ml * h )

Identify all correct statements about clearance (Cl). Clearance can severely change in kidney and liver disease. Clearance is a dependent parameter. Clearance is one of two parameters that determines half life (t1/2). Clearance changes with a change in drug dose (Xo).

Clearance can severely change in kidney and liver disease. Clearance is one of two parameters that determines half life (t1/2).

If a drug displays linear, first order kinetics and the dose of the drug given to a patient is doubled, which parameter do you expect to change? A. Systemic Clearance (Cl) B. Volume of Distribution (V) C. Half-life (t½) D. Area under the concentration versus time curve (AUC) E. Absorption rate constant (ka)

D. Area under the concentration versus time curve (AUC)

Nilotinib is a BCR-ABL kinase inhibitor used in cancer chemotherapy. After oral administration with various meals, the following concentration-time profile (figure below) was observed. Although the half-life of the drug is unchanged (t1/2: 21-24 hrs), the AUC is markedly increased by food. This observation is most likely due to meals and fat... *********graph in 2020 exam 1: #19********** A. increasing Nilotinib systemic clearance B. decreasing Nilotinib systemic clearance C. decreasing Nilotinib oral availability D. increasing Nilotinib oral availability E. affecting Nilotinib renal elimination

D. increasing Nilotinib oral availability

Zero Order Kinetics

Data plotted on rectilinear paper yield in a line Amount of drug removed over time is constant

What assumptions need to be made to use the data gained from the analysis of the graph below and to model the behavior of the administered drug? **********graph in 2020 exam 1: #26************* A. Instantaneous drug distribution B. Linearity C. Elimination process follows first order kinetics D. Parameters are stationary E. All of the above

E. All of the above

A decrease in drug clearance will result in: A. An increase in the volume of distribution B. A decrease in the volume of distribution C. An increase in the volume of distribution followed by a decrease in the volume of distribution D. A decrease in the volume of distribution followed by an increase in the volume of distribution E. No change in the volume of distribution

E. No change in the volume of distribution

The change in the concentration-time profile from 1 to 2 (see figure below) is most likely due to: **********graph in 2020 exam 1: #25************* A. an increase in the absorption rate constant ka B. a decrease in the distribution volume V C. an increase in clearance Cl D. a decrease in the elimination rate constant k E. an increase in the dose X0

E. an increase in the dose X0

True or False A compartment in pharmacokinetics represents a real physiologic or anatomic region.

False

True or False The absorption process observed after oral dosing of conventional dosage forms follows zero order kinetics and the elimination process follows first order kinetics.

False

True or False Protein binding of a drug has no effect on the clearance of the drug

False

True or False The fraction unbound (fu) and the concentration unbound (Cu) of a drug are proportional to each other and both drive therapeutic response.

False

True or False Three drugs have a similar half-life of about 20 hours which implies they have a similar systemic clearance.

False

True or False: A compartment in pharmacokinetics represents a real physiologic or anatomic region.

False

True or False: Changing the volume of distribution (V) of a drug affects this drug's half-life (t1/2) and its area under the concentration-time profile (AUC).

False

True or False: Drugs with a similar half life also have to have a similar systemic clearance.

False

True or False: In an extended release formulation that follows flip-flop kinetics, the mathematical relationship between absorption and elimination is ka >K.

False

True or False: It is highly unlikely that the apparent volume of distribution for any drug would exceed total body water (70 L)

False

True or False: Protein binding of a drug has no effect on the clearance of the drug

False

True or False: The area-under-the-curve (AUC) for an orally administered drug with first order elimination kinetics (assume one compartment model) has the unit: ( mg ) / ( ml * h )

False

True or False: The concentration-time profile after oral dosing has two distinct phases, where the first phase consists of drug elimination and the second phase consists of both drug absorption and drug elimination.

False

True or False: The equation AUC = C0/K to calculate the area-under-the-curve can be used after an oral dose of a drug (assuming the drug follows first order kinetics).

False

True or False: The graph below is consistent with a first order process. *** Y=dA/dt; X=A; slope is straight horizontal line ****

False

True or False: The plasma concentration of a drug that follows the kinetic equation C = 42*e-0.045*t will fall below 3 mg/L after about 24 hours.

False

True or False: The unbound fraction of a drug and the unbound concentration of a drug are the same

False

True or False: When we say a drug displays one compartment model behavior, this means the drug distributes rapidly and uniformly throughout the body.

False

Identify all correct statements about what physicochemical and physiological factors influence the volume of distribution (VD) of a drug. Ionization, solubility, and lipophilicity of the drug The volume of distribution of a drug is not influenced by physicochemical and physiological factors Systemic clearance Blood flow to tissue

Ionization, solubility, and lipophilicity of the drug Blood flow to tissue

In a first order process, the units of rate (dC/dt) and rate constant (K) are...

Rate: ( mg ) / ( ml * h ) rate constant (k): 1 / h

Gentamicin is predominantly eliminated by the kidneys. Briefly describe how gentamicin halflife is affected in patients with renal impairment. Explain why.

Renal impairment: renal clearance reduced Reduced clearance means it takes longer to clear drug If clearing drug takes longer, half-life is prolonged

What is the correct definition of "pharmacokinetics"? Study of drug movement in the body Study of drug action in the body Study of bodily structures Study of bodily functions

Study of drug movement in the body

True or False Fruit juices like orange juice and grapefruit juice can interact with drug transporters and metabolizing enzymes, thereby affecting a drug's bioavailability and area-under-the-curve.

True

True or False In residual analysis, data from the concentration-time profile after oral dosing are subtracted from the data of the extrapolated terminal line.

True

True or False Oral clearance (Cl/F, clearance "contaminated" with F) after an oral dose of a drug overestimates systemic clearance because the amount of drug that makes it into the systemic circulation is unknown.

True

True or False Residual analysis can be used to determine the absorption rate constant (ka) after oral dosing.

True

True or False: After residual analysis, the slope of the residual line mresidual = -ka.

True

True or False: Changes in volume of distribution (V) of a drug affect the drug's half-life but not the drug's measured area under the concentration-time profile (AUC).

True

True or False: Disease can affect both systemic clearance and the volume of distribution of a drug.

True

True or False: Ethanol follows zero order kinetics. Thus, the half-life of ethanol elimination increases as ethanol blood concentration increases.

True

True or False: In flip-flop kinetics, the rate limiting kinetic step is associated with drug absorption (ka < K).

True

True or False: In flip-flop kinetics, the rate limiting kinetic step is associated with drug absorption (ka<K).

True

True or False: Protein binding of a drug impacts the volume of distribution of the drug

True

True or False: Protein binding, drug transport, and drug metabolism can be saturated at high drug levels.

True

True or False: Systemic clearance Cl cannot be estimated from an oral dose X0 because the amount of drug that makes it into the systemic circulation is unknown.

True

True or False: The Trapezoidal Method can be used to estimate the AUC after oral administration of a drug that follows first order kinetics and shows pronounced distribution.

True

True or False: The area under the plasma concentration-time curve (AUC) can be determined by integration and by using the trapezoidal method.

True

True or False: The therapeutic window of a drug defines the range of plasma drug concentrations that results in optimal drug therapy and where toxic effects usually do not occur.

True

True or False: The unbound drug concentration drives the therapeutic response

True

True or False: The value of utilizing a model or a mathematical relationship to describe a series of data is that it allows for a more concise approach to convey information and may provide insights into an underlying mechanism.

True

True or False: Transporters such as P-glycoprotein (P-gp) and metabolizing enzymes such as CYP3A4 can play a significant role in drug absorption by limiting drugs from leaving the GI track and entering the body, resulting in reduced bioavailability.

True

A patient is admitted to the ER with a drug overdose after a self-injection 6 hours earlier. The drug's blood level at admission is 114 ng/ml. (Drug t1/2 = 15 h, drug VD = 200L). What was the dose of the drug in mg?

about 30

For a bioavailability study, healthy control individuals are first given an intravenous dose of a drug (X0 = 170 mg; AUC = 148 mg*min/L) and later in the study they are given an oral dose of the same drug (X0 = 300 mg; AUC = 17.5 mg*min/L). What is the oral bioavailability F for this drug in %?

about 6.7

A drug follows the following one compartment kinetics equation: C(t) = 42*e-0.045*t How many hours will it take for the drug concentration to fall below 3 mg/L?

about 60

How many hours will it take for 99.9% of the gentamicin dose to be eliminated from the body?

equation In 2020 exam 1: #39 b

True or False: The rate constant for a drug with XERO ORDER ELIMINATION has units of: 1/time or time^-1

false

In a zero order process, the units of rate (dC/dt) and rate constant (k) are:

for both: ( mg ) / ( ml * h )

This new anti-seizure drug shows a 91% plasma protein binding (mostly albumin). Briefly describe how plasma protein binding of this drug might be affected during disease and what the clinical consequences could be.

in general: disease affects drug plasma protein binding. In this case: disease could reduce albumin levels, which could increase drug plasma concentration of unbound drug which is responsible for the pharmacological/therapeutic effect. if drug plasma concentration of unbound drug increased too much, it could lead to adverse/toxic effects.

The area under the concentration-time curve (AUC) of a drug increases, when... the dose of the drug decreases. the elimination rate constant of the drug increases. the distribution volume of the drug increases. the clearance of the drug decreases.

the clearance of the drug decreases.

List 6 different factors that can affect (negatively or positively) a drug's passage from the intestinal lumen into the systemic circulation.

• Dosage form: dissolution, release profile, solutions, suspensions, gel capsules, tablets, etc • Drug: physicochemical properties, lipophilicity/hydrophilicity, ionization • Physiology: surface area, GI tract pH, GI/liver blood flow, gastric emptying/drugs/food (liquid/solid, fat) • Biological Membranes: lipid bilayer, tight junctions • Biochemical Defense: uptake/efflux transporters & enzymes in enterocytes/hepatocytes • Will also affect fruit juice that inhibit transporters/enzymes, drugs that induce transporters/enzymes

Describe a clinical situation in which a pharmacist takes advantage of "flip-flop" kinetics. Describe why this is advantageous with respect to patient compliance.

• To overcome the problem of frequent dosing for short half-life drugs, sustained release dosage forms take advantage of flip-flop kinetics. • Flip-flop is a phenomenon observed for oral dosage forms where the rate of absorption is slow relative to the rate of elimination (ka<K); the terminal slope is controlled by ka, not K.

For a given drug, the fraction of the dose that leaves the intestinal lumen FA = 0.8, the fraction of the dose that escapes the enterocytes FG = 0.75, and the fraction of the dose that escapes the liver FH = 0.5. What is the systemic bioavailability F for this drug? ✓A. 0.3 B. 0.5 C. 0.75 D. 0.8 E. 2.05

✓A. 0.3

Which of the following pharmacokinetic parameters best reflects the bioavailability F? ✓A. AUC B. t1/2 C. Cl D. K E. tmax

✓A. AUC

Identify all correct statements about what physicochemical and physiological factors influence the volume of distribution (VD) of a drug. ✓A. Blood flow to tissue ✓B. Ionization, solubility, and lipophilicity of the drug C. The volume of distribution of a drug is not influenced by physicochemical and physiological factors D. Systemic clearance

✓A. Blood flow to tissue ✓B. Ionization, solubility, and lipophilicity of the drug

For a drug exhibiting zero order elimination kinetics, how does drug half-life change as drug concentration changes? ✓A. Half-life increases as drug concentration increases B. Half-life decreases as drug concentration increases C. Half-life increases as drug concentration decreases D. Half-life does not change E. None of the above

✓A. Half-life increases as drug concentration increases

Using the Trapezoidal Method to determine the AUC of a concentration-time profile after a single bolus iv injection (one compartment model) will: ✓A. Overestimate the AUC and underestimate the clearance B. Underestimate the AUC and underestimate the clearance C. Overestimate the AUC and overestimate the clearance D. Underestimate the AUC and overestimate the clearance E. None of the above

✓A. Overestimate the AUC and underestimate the clearance

Identify all correct statements about systemic bioavailability F. ✓A. Systemic bioavailability F is defined as the fraction of a drug that reaches the systemic circulation. B. Bioavailability has additive properties. ✓C. Systemic bioavailability is the product of the fraction of the dose absorbed (FA), the fraction of the dose that escapes the enterocytes (FG), and the fraction of the dose that escapes the liver (FH). D. When calculating the absolute bioavailability of a drug, oral administration of the innovator product is often used as the reference standard.

✓A. Systemic bioavailability F is defined as the fraction of a drug that reaches the systemic circulation. ✓C. Systemic bioavailability is the product of the fraction of the dose absorbed (FA), the fraction of the dose that escapes the enterocytes (FG), and the fraction of the dose that escapes the liver (FH).

Select all that apply. In a first order process, half life t1/2... ✓A. is independent of concentration B. is dependent on concentration C. is independent of clearance ✓D. is dependent on clearance

✓A. is independent of concentration ✓D. is dependent on clearance

The slope of a ln(Concentration)-versus-time profile for a drug with first order elimination kinetics is: A. -2.303/K ✓B. -K C. -1/K D. K E. -2.303*K

✓B. -K

The half-life of the drug described by the graph below is numerically consistent with: **********graph in 2020 exam 1: #29************* A. 40 h ✓B. 75 h C. 100 h D. 150 h E. 200 h

✓B. 75 h

Identify all correct statements after oral dosing of a drug. A. A change in the distribution volume (V) results in a change of the dose (X0). ✓B. An increase in clearance (Cl) results in a decrease in the area-under-the-curve (AUC). ✓C. A decrease in the absorption rate constant (ka) results in a lower peak concentration (Cmax) at a later time point. D. An increase in the absorption rate constant (ka) results in an increase in the area-under-the-curve (AUC).

✓B. An increase in clearance (Cl) results in a decrease in the area-under-the-curve (AUC). ✓C. A decrease in the absorption rate constant (ka) results in a lower peak concentration (Cmax) at a later time point.

Identify all correct statements about half life (t1/2). A. Changes over time ✓B. Defined as the time it takes for a concentration (or amount) of drug to decrease by 50%. ✓C. Appropriate to use only in the context of first order kinetics D. Depends on concentration

✓B. Defined as the time it takes for a concentration (or amount) of drug to decrease by 50%. ✓C. Appropriate to use only in the context of first order kinetics

Which statement about kinetic processes and conceptual models is CORRECT? A. If the two variables Y and X are correlated with one another, this shows a causal mechanism, i.e., X causes a response in Y. ✓B. The slope of a ln(Concentration) vs. time-profile for a drug with first order elimination kinetics equals -k. C. In pharmacokinetics, a compartment represents a real anatomic organ or site. D. Half-life is appropriate to use for processes that follow both zero and first order kinetcs. E. In a first order kinetic process, the change in rate (dC/dt) is independent of C.

✓B. The slope of a ln(Concentration) vs. time-profile for a drug with first order elimination kinetics equals -k.

Wellbutrin XL is a sustained release formulation that follows flip-flop kinetics. Which statement is CORRECT? A. The terminal rate is limited by the elimination rate constant (K) ✓B. The terminal rate is limited by the absorption rate constant (ka) C. The terminal rate is neither limited by the elimination rate constant (K) nor the absorption rate constant (ka) D. The elimination rate constant (K) equals the absorption rate constant (ka)

✓B. The terminal rate is limited by the absorption rate constant (ka)

After an intravenous injection of 250 mg of an antibiotic drug, a male patient (48 years, 74 kg) has an initial drug plasma concentration of 0.77 mg/L. How often does the patient have to take the drug (t1/2 = 8 hours, V = 4.3 L/kg, Cl = 0.38 L/h*kg) if the minimum effective concentration is 250 μg/L? A. Once per day ✓B. Twice per day C. Three times per day D. Four times per day

✓B. Twice per day

Which of the three parameters K, V and Cl is/are dependent and which is/are independent of the others? A. V depends on Cl and K according to V = Cl/K B. Cl depends on V and K according to Cl = V*K ✓C. K depends on Cl and V according to K = Cl/V D. Each of these parameters depends on the other two E. They are all independent of one another

✓C. K depends on Cl and V according to K = Cl/V

Which statement about unbound drug fraction (fu) is INCORRECT? Unbound drug fraction (fu)... A. is determined by the ratio of unbound drug concentration (Cu) and total drug concentration (Ctotal) B. can change in disease due to changes in plasma protein levels ✓C. is the driving force for pharmacologic drug response D. can influence the volume of distribution for a drug

✓C. is the driving force for pharmacologic drug response

Which of the following assumptions are required to use the following equation? ***********2021 Exam 1: #12************** A. Drug absorption is a zero order process B. Drug elimination is a zero order process C. Drug bioavailability is 100% ✓D. Both drug absorption and drug elimination follow a first order process

✓D. Both drug absorption and drug elimination follow a first order process

Which of the following statements about the kinetic process after an iv bolus injection (first order, one-compartment) is correct? A. The kinetic process can be described mathematically by C = C0 -kt B. The rate of drug elimination dC/dt is independent of the drug's concentration C C. The dose X0 is inversely proportional to the area-under-the-curve AUC ✓D. The half-life t1/2 of this kinetic process is constant E. None of the above is correct

✓D. The half-life t1/2 of this kinetic process is constant

From the table below, identify which drug(s) would be reasonable candidate(s) for sustained or controlled release oral formulations. ************table in 2021 Exam 1: #2***************** A. Azithromycin B. Citalopram and Valdicoxib C. Glipizide and Valdicoxib D. Valdicoxib ✓E. Zidovadine and Glipizide

✓E. Zidovadine and Glipizide