SIXTH EDITION
`
`' ••■;;--0i5'''--:rg-^&k.
`- ■:<
`
`CONCEPTS IN CLINICAL
`PHARMACOKINETICS
`
`\i 'P-
`
`•'**''
`
`William J. Spruil
`William E. Wade
`Joseph T. DiPiro
`Robert A. Blouin
`Jane M. Prueme
`
`asimnubpublkatfons
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 1
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`Concepts in Clinical Pharmacokinetics
`
`14
`
`natural log function, the abbreviation e is used. Also,
`instead of writing natural logarithm of 8.0, we shall
`use the abbreviation In 8.0.
`Natural logarithms can be related to common
`logarithms (base 10 logarithms) as follows:
`
`estimated data. These are the In key and the f!'" key.
`Certain calculators do not have the ex key. Instead,
`they will have an In key and an !NV key or a 2nd key.
`Pressing the !NV key or the 2nd key and then the In
`key will give f? values.
`
`log base e
`1 0
`I b
`og ase = ---=-2-.3-0-3-
`
`Using the Calculator with Natural Log
`and Exponential Keys
`
`There are two major keys that will be used to calcu(cid:173)
`late pharmacokinetic values from either known or
`
`Clinically Important Equations
`Identified in This Chapter
`
`1. C=XI V
`
`2. V=XIC
`
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`IPR2019-00685
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`Concepts in Clinical Pharmacokinetics
`
`16
`
`•.
`
`1-11. For a drug with a narrow therapeutic index,
`the plasma concentration required for ther(cid:173)
`apeutic effects is near the concentration
`that produces toxic effects.
`A. True
`B. False
`
`1-12. Highly perfused organs and blood comprise
`what is usually known as the peripheral
`compartment.
`A. True
`B. False
`
`1-13. The most commonly used model in clinical
`pharmacokinetic situations is the:
`A. one-compartment model.
`B.
`two-compartment model.
`C. multicompartment model.
`
`1-14.
`
`Instantaneous distribution to most body
`tissues and fluids is assumed in which of the
`following models?
`A. one-compartment model
`B.
`two-compartment model
`C. multicompartment model
`
`1-15. The amount of drug per unit of volume is
`defined as the:
`A. volume of distribution.
`B. concentration.
`C.
`rate.
`
`1-16.
`
`If 3 g of a drug are added and distributed
`throughout a tank and the resulting concen(cid:173)
`tration is 0.15 gjL, calculate the volume of
`the tank
`A. 10 L
`B. 20 L
`C. 30 L
`D. 200 L
`
`1-17. For a drug that has first-order elimination
`and follows a one-compartment model,
`which of the following plots would result in
`a curved line?
`A. plasma concentration versus time
`B. natural log of plasma concentration
`versus time
`
`1-18. A drug that follows a one-compartment
`model is given as an intravenous injection,
`and the following plasma concentrations
`are determined at the times indicated:
`
`Plasma Concentration
`(mg/L)
`81
`67
`55
`
`Time after Dose
`(hours)
`1
`2
`3
`
`Using semilog graph paper, determine the
`approximate concentration in plasma at
`6 hours after the dose.
`A. 18 mg/L
`B. 30 mg/L
`C. < 1 mg/L
`
`ANSWERS
`
`1-1.
`
`A.
`
`B.
`
`Incorrect answer. Pharmacodynamics
`deals with the relationship between the
`drug concentration at the site of action
`and the resulting effect.
`Incorrect answer. Drug concentrations
`in plasma and tissues result from phar(cid:173)
`macokinetic processes.
`C. CORRECT ANSWER
`D.
`Incorrect answer. Kinetic homogeneity
`describes
`the
`relationship between
`plasma drug concentration and concen(cid:173)
`tration at a receptor or site of action.
`
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`IPR2019-00685
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`Concepts in Clinical Pharmacokinetics
`
`18
`
`1-14. A. CORRECT ANSWER
`B.
`Incorrect answer. In a two-compartment
`model, it is assumed that drug distribu(cid:173)
`tion to some tissues proceeds at a lower
`rate than for other tissues.
`Incorrect answer. In a multicompart(cid:173)
`ment model, it is also assumed that drug
`distribution to some tissues proceeds at
`a lower rate than for other tissues.
`
`C.
`
`1-15. A
`
`Incorrect answer. The volume of distri(cid:173)
`bution refers to the dose over the
`resulting concentration.
`B. CORRECT ANSWER
`Incorrect answer. The amount per unit
`C.
`of volume is a static value and would not
`change over time; therefore, it would
`not be considered a rate.
`
`'·
`
`1-16. A, C, D. Incorrect answers. A math error must
`have been made. The answer can be
`found by dividing 3 g by 0.15 g/L.
`B. CORRECT ANSWER
`
`1-17. A. CORRECT ANSWER
`B.
`Incorrect answer. This plot would be a
`straight line (see Figure 1-29).
`
`1-18. A, C. Incorrect answers. These results might
`have been determined if linear graph
`paper was used or if the points were
`plotted incorrectly.
`B. CORRECT ANSWER
`
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`IPR2019-00685
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`IPR2019-00685
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`Lesson 2
`
`I Basic Pharmacokinetics
`
`23
`
`Clinical Correlate
`
`Most drug concentrations are measured using
`plasma or serum that usually generate similar
`values. It is more relevant to use plasma or
`serum than whole blood measurements to
`estimate drug concentrations at the site of effect.
`However, some drugs, such as antimalarials, are
`extensively taken up by red blood cel ls. In these
`situations, whole blood concentrations would be
`more relevant, although they are not commonly
`used in clinical practice.
`
`Clearance
`
`Another important parameter in pharmacokinetics
`is clearance. Clearance is a measure of the removal of
`drug from the body. Plasma drug concentrations are
`affected by the rate at which drug is administered,
`the volume in which it distributes, and its clearance.
`A drug's clearance and the volume of distribution
`determine its half-life. The concept of half-life and its
`relevant equations are discussed in Lesson 3.
`Clearance
`(expressed
`as
`volume/time)
`describes the removal of drug from a volume of
`plasma in a given unit of time (drug loss from the
`body). Clearance does not indicate the amount
`of drug being removed. It indicates the volume
`of plasma (or blood) from which the drug is
`completely removed, or cleared, in a given time
`period. Figures 2-4 and 2-5 represent two ways
`of thinking about drug clearance. In Figure 2-4, the
`amount of drug (the number of dots) decreases but
`fills the same volume, resulting in a lower concen(cid:173)
`tration. Another way of viewing the same decrease
`would be to calculate the volume that would be
`drug-free if the concentration were held constant.
`
`Initial
`concentration
`• • • •
`• • • •
`• • • •
`• • • •
`• • • •
`• •
`
`Elimination
`over time
`
`Resulting
`concentration
`• •
`• • •
`••
`•
`•
`• • •
`
`FIGURE 2-4.
`Decrease in drug concentration due to drug clearance.
`
`Initial
`concentration
`• • • •
`• •
`• •
`• • • •
`• •
`
`• • . : . :
`
`Resulting
`concentration
`
`: •
`Elimination
`•
`over time
`- - - - - -+ :·
`• :. t
`7
`Volume from
`which drug is
`removed over time
`
`FIGURE 2-5.
`Clearance may be viewed as the volume of plasma from which
`drug is totally removed over a specified period.
`
`Drugs can be cleared from the body by many
`different mechanisms, pathways, or organs, including
`hepatic biotransformation and renal and biliary
`excretion. Total body clearance of a drug is the sum of
`all the clearances by various mechanisms.
`
`q = Cl, + Clm + Clb + Clother
`
`where
`
`Cl1 =
`
`total body clearance (from all
`mechanisms, where t refers to total);
`Cl,. = renal clearance (through renal
`excretion);
`Clm = clearance by liver metabolism or
`biotransformation;
`Clb = biliary clearance (through biliary
`excretion); and
`Cl other = clearance by all other routes (gastro(cid:173)
`intestinal tract, pulmonary, etc.).
`
`For an agent removed primarily by the kidneys,
`renal clearance (CIJ makes up most of the total body
`clearance. For a drug primarily metabolized by the
`liver, hepatic clearance (Clm) is most important.
`A good way to understand clearance is to
`consider a single well-perfused organ that elimi(cid:173)
`nates drug. Blood flow through the organ is referred
`to as Q (mL/minute) as seen in Figure 2-6, where
`C;n is the drug concentration in the blood entering
`the organ and cout is the drug concentration in the
`exiting blood. If the organ eliminates some of the
`drug, C;n is greater than C out·
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 31
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`Concepts in Clinical Pharmacokinetics
`
`28
`
`REVIEW QUESTIONS
`
`2-1.
`
`The volume of distribution equals _ _ _
`divided by initial drug concentration:
`A. clearance
`B.
`initial drug concentration
`C. half-life
`D. dose
`
`2-2.
`
`A dose of 1000 mg of a drug is administered
`to a patient, and the following concentrations
`result at the indicated times below. Assume a
`one-compartment model.
`
`Plasma Concentration
`(mg/L)
`
`100
`67
`45
`
`Time after Dose
`(hours)
`2
`4
`6
`
`An estimate of the volume of distribution
`would be:
`A. 10 L.
`B. 22.2 L.
`c. 6.7L.
`D. 5 L.
`
`If a drug is poorly distributed to tissues, its
`apparent volume of distribution is probably:
`A.
`large.
`B. small.
`
`For the body fluid compartments below,
`rank them from the lowest volume to the
`highest, in a typical 70-kg person.
`A. Plasma < extracellular fluid < intracel(cid:173)
`lular fluid < total body water
`B. Extracellular fluid < intracellular fluid <
`plasma < total body water
`Intracellular fluid < extracellular fluid <
`plasma < total body water
`D. Total body water < plasma < intracel(cid:173)
`lular fluid < extracellular fluid
`
`C.
`
`2-3.
`
`2-4.
`
`2-5.
`
`2-6.
`
`2-7.
`
`2-8.
`
`Plasma refers only to the fluid portion of
`blood, including soluble proteins but not
`formed elements.
`A. True
`B. False
`
`The units for clearance are:
`A. concentration/half-life.
`B. dosejvolume.
`C. half-life/ dose.
`D. volume/time.
`
`Total body clearance is the sum of clearance
`by the kidneys, liver, and other routes of
`elimination.
`A. True
`B. False
`
`To determine drug clearance, we must first
`determine whether a drug best fits a one- or
`two-compartment model.
`A. True
`B. False
`
`2-9. With a drug that follows first-order elimina(cid:173)
`tion, the amount of drug eliminated per unit
`time:
`A.
`remains constant while the fraction of
`drug eliminated decreases.
`B. decreases while the fraction of drug
`eliminated remains constant.
`
`ANSWERS
`
`2-1.
`
`A, B, C. Incorrect answers
`D. CORRECT ANSWER. You can determine
`the correct answer from the units in
`the numerator and denominator. They
`should cancel to yield a volume unit.
`Grams divided by grams per liter would
`leave you with liter as the unit. The
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 36
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`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 56
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`Concepts in Clinical Pharmacokinetics
`
`58
`
`So, dosej(Cl x -r) has the following units:
`
`amount
`
`(volume/time) x time
`
`Then, as both hour terms cancel out, we see that
`amount per volume (concentration) is left.
`
`Predicting Steady-State Concentration
`
`The equation for Cpea k[steacty stateJ derived above (and
`shown below) is valuable because it allows us to
`predict the peak plasma concentration achieved
`when a drug is given in a specified dose (X0) at a
`consistent and repeated interval (-r). To predict
`peak concentration at steady state, however, we also
`must have an estimate of the elimination rate (K)
`and the volume of distribution (V); therefore, the
`following equation is used only for IV bolus dosing:
`
`_ Xo [
`1
`C
`peak(steady state) - v (1- e -KT)
`
`:
`
`It is possible to estimate a patient's K and V from
`published reports of similar patients. For example,
`most patients with normal renal function will
`have a gentamicin V of 0.20-0.30 L/kg and a K of
`0.035-0.2 hr-1. In a clinical setting in which a drug
`is administered and plasma concentrations are then
`determined, it is possible to calculate a patient's
`actual K and V using plasma concentrations. Such
`calculations can be performed as follows.
`
`Example 1
`A patient receives 500 mg of drug X intra(cid:173)
`venously every 6 hours until steady state is
`reached. Just after the dose is administered,
`a blood sample is drawn to determine a peak
`plasma concentration. Then, 5 hours later, a
`second plasma concentration is determined.
`Using the two plasma concentrations, we first
`calculate K, as described previously:
`
`K = _ln_C::..:.pea::c.k_-_l_n_C....:.5"'-hr
`5 hr
`
`Then we insert the known Cpeak• K, X0, and -r
`values in the equation for Cpeak· By rearranging the
`equation to isolate the only remaining unknown
`variable, we can then use it to calculate V:
`
`V =
`Xo
`cpeak(steady state)
`
`[
`]
`1
`(1- e - KT )
`
`Now we know the values of all the variables in
`the equation (V, K, Cpeak• X0, and -r) and can use
`this information to calculate a new cpeak if we
`change the dose (e.g., if the previous c peak is too
`high or too low). For example, if we want the
`peak level to be higher and wish to calculate the
`required dose to reach this new peak level, we
`can rearrange our equation:
`Xo = v X c peak(steady state) (1- e - KT )
`
`and substitute our calculated V and K and the
`desired Cpeak· Or we can choose a new dose (X0) and
`calculate the resulting Cpeak by inserting the calcu(cid:173)
`lated K and Vwith -r into the original equation:
`
`_ Xo [
`1
`C
`peak(steady state) - v (1- e - KT)
`
`]
`
`Remember that each time we calculate a peak
`plasma level (Cpeak), the trough plasma level also
`can be calculated if we know K and -r:
`- c e -KT
`
`f'
`Lltrough -
`
`peak
`
`If the dosing interval is not changed, new doses
`and concentrations are directly proportional if
`nothing else changes (i.e., K or V).
`So,
`
`= cpeak(steady state)new X X
`X
`0 (new) C
`0 (old)
`peak(steady state)old
`
`and,
`
`Xo (new) C
`cpeak(steady state) new =-X-- X steady state( old)
`0 (old)
`
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`Lesson 4
`
`I IV Bolus Administration, Multiple Drug Administration, & Steady-State Average Concentrations
`
`61
`
`4-9. Which of the following dosage techniques
`results in the greatest difference between
`maximum (peak) and minimum (trough)
`concentrations after a dose?
`A. Small doses given at a short dosing
`interval
`B. Large doses given at a long dosing
`interval
`
`4-10. What is the peak drug X concentration
`attained at steady state if 100 mg is given
`by IV injection every 6 hours, the patient's
`K = 0.35 hr-1, and V = 20 L? (Assume a one(cid:173)
`compartment distribution.)
`A. 3.4 mg/L
`B. 5.7 mg/L
`C. 16.3 mg/L
`D. 41 mg/L
`
`4-11. What would be the trough level for the
`example in question 4-10?
`A. 0.41 mg/L
`B. 0.7 mg/L
`C. 2 mg/L
`D. 5 mg/L
`
`4-12. A 500-mg dose of drug X is given every 6
`hours until steady-state levels are reached.
`At steady state, the AUC for one dosing
`interval is 42 (mg/L) x hour. What is the
`average concentration over that dosing
`interval?
`A. 3.1 mg/L
`B. 7 mg/L
`c. 12.5 mg/L
`D. 22 mg/L
`
`4-13. A patient receives an antimicrobial dose of
`400 mg IV every 8 hours. After steady state
`is reached, a peak level of 15 mg/L is determined;
`the level4 hours after the peak is 4.5 mgjL. What
`dose is required to attain a peak plasma
`level of 35 mg/L? (Assume IV bolus drug
`administration.)
`A. 400 mg
`B. BOO mg
`C. 933 mg
`D. 3108 mg
`
`4-14. For the example given in the last question,
`when the peak plasma level is 35 mg/L.
`what will the trough plasma level be?
`A. 2.3 mg/L
`B. 3.2 mg/L
`C. 4.8 mg/L
`D. 32 mg/L
`
`ANSWERS
`
`4-1.
`
`A. CORRECT ANSWER
`the
`B.
`Incorrect answer. This value is
`minimum concentration after the first
`dose. Remember to add the value of
`cmaxll which was 100 mg/L.
`Incorrect answer. This is the value of
`cmaxl ' cmax2 is calculated as the sum of
`cmax l and c minl ·
`Incorrect answer. This is close to the
`cmax2 but is actually the steady-state cmax•
`c max2 is calculated as the sum of cmaxl and
`
`D.
`
`C.
`
`cminl'
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 69
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`Concepts in Clinical Pharmacokinetics
`
`76
`
`REVIEW QUESTIONS
`
`5-1.
`
`S-2.
`
`S-3.
`
`S-4.
`
`5-S.
`
`S-6.
`
`For a drug regimen, if the elimination rate
`(K) of a drug is reduced while V, X0, and
`T remain constant, the peak and trough
`concentrations will:
`A.
`increase.
`B. decrease.
`
`A decrease in drug dose will result in lower
`plasma concentrations at steady state but
`will not change the time to reach steady
`state.
`A. True
`B. False
`
`Which of the following dosing techniques
`results in smaller fluctuations between peak
`and trough plasma levels?
`A. small doses very frequently
`B.
`large doses relatively less frequently
`
`When the volume of distribution increases
`(and clearance remains the same), steady(cid:173)
`state plasma concentrations will have more
`peak-to-trough variation.
`A. True
`B. False
`
`When drug clearance decreases (while
`volume of distribution remains unchanged),
`steady-state plasma concentrations will:
`A.
`increase.
`B. decrease.
`
`is
`concentration
`plasma
`Steady-state
`approximately reached when the contin(cid:173)
`uous infusion has been given for at least
`how many half-lives of the drug?
`A.
`two
`B.
`three
`C.
`five
`D.
`ten
`
`5-7.
`
`S-8.
`
`S-9.
`
`5-10.
`
`If you double the infusion rate of a drug,
`you should expect to see a twofold increase
`in the drug's steady-state concentration.
`Assume that clearance remains constant.
`A. True
`B. False
`
`Theophylline is administered to a patient
`at 35 mgjhour via a constant IV infusion.
`If the patient has a total body clearance for
`theophylline of 40 mLjminute, what should
`this patient's steady-state plasma concen(cid:173)
`tration be?
`A. 14.6 mg/L
`B. 0.875 mg/L
`C. 0.1 mg/L
`
`With a continuous IV infusion of drug,
`the steady-state plasma concentration is
`directly proportional to:
`A. clearance.
`B. volume of distribution.
`C. drug infusion rate.
`D. K
`
`If a drug is given by continuous IV infu(cid:173)
`sion at a rate of 20 mgjhour and produces
`a steady-state plasma concentration of
`10 mgjL, what infusion rate will result in a
`new Css of 15 mg/L?
`A. 30 mgjhour
`B. 35 mgjhour
`C. 50 mgjhour
`D. 75 mgjhour
`
`5-11. For a continuous infusion, given the equa(cid:173)
`tion C = K0(1 - e-Kt)jClt, at steady state
`the value for t approaches infinity and e-Kt
`approaches infinity.
`A. True
`B. False
`
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`Concepts in Clinical Pharmacokinetics
`
`78
`
`5-4.
`
`5-5.
`
`5-6.
`
`5-7.
`
`5-8.
`
`A
`Incorrect answer
`B. CORRECT ANSWER. A larger volume
`of distribution will result in the same
`amount of drug distributing in a greater
`volume, which would result in a lower
`peak-to-trough variation.
`
`A CORRECT ANSWER. When clearance
`decreases, plasma concentrations will
`increase because drug is administered at
`the same rate (dose and dosing interval)
`but is being removed at a lower rate.
`Incorrect answer
`
`B.
`
`A
`
`B.
`
`Incorrect answer. Only 75% of the
`steady-state concentration would be
`reached by two half-lives.
`Incorrect answer. Only 87.5% of the
`steady-state concentration would be
`reached by three half-lives.
`C. CORRECT ANSWER. At five half-lives,
`approximately 97% of the steady-state
`concentration has been reached.
`Incorrect answer. This is much longer
`than necessary.
`
`D.
`
`A CORRECT ANSWER. The changes in the
`infusion rate will directly affect plasma
`concentrations, if other factors remain
`constant.
`Incorrect answer
`
`B.
`
`A CORRECT ANSWER. The equation Css =
`K0/Clt should be used. The value for K0
`is 35 mgjhour. The value for Cit must
`be converted from 40 mL/minute to
`2.4 L/hour.
`B, C. Incorrect answers
`
`5-9. A B, D. Incorrect answers
`C. CORRECT ANSWER. The steady-state
`concentration is directly proportional to
`the drug infusion rate.
`
`5-10. A CORRECT ANSWER
`B, C, D. Incorrect answers
`
`5-11. A
`
`Incorrect answer. As t becomes larger,
`the term e-Kt becomes smaller, and the
`term 1 - e-Kt approaches 1.
`
`B. CORRECT ANSWER
`
`5-12. A, B, D. Incorrect answers
`C. CORRECT ANSWER. The loading dose is
`determined by multiplying the desired
`concentration (12 mg/L) by the volume
`of distribution:
`css(desired) X v = 12 mg/L X 28 L = 336 mg.
`Note that the units cancel out to yield
`milligrams.
`
`5-13. A C. Incorrect answers
`B. CORRECT ANSWER. The infusion rate is
`related to Cit and Css as follows:
`Css = KofC!t.
`Cit can be determined by multiplying
`V x K = 1 .12 L/hour.
`So, rearranging,
`K0= Css x Cl 1 = 12 mg/L x 1.12 L/hour =
`13.4 mg/hour.
`
`5-14. A, B, C. Incorrect answers
`D. CORRECT ANSWER. One half-life
`calculated as follows:
`TY2 = 0.693/K.
`Steady state is reached by five half-lives,
`or 23 hours.
`
`is
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`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 86
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`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 100
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`fifth dose, a peak plasma
`the
`PS2-8. After
`concentration (drawn at the end of the
`infusion) is 5 mg/L and the trough concen(cid:173)
`tration (drawn right before the sixth dose) is
`0.9 mg/L. What is the patient's actual genta(cid:173)
`micin half-life?
`
`A. 1 hour
`B. 2 hours
`C. 4 hours
`D. 8 hours
`
`PS2-9. What would be the volume of distribution?
`[hint, rearrange Equation 5-1]
`
`A. 7.6 L
`B. 10.2 L
`C. 15.5 L
`D. 22.0 L
`
`PS2-10. For this patient, what dose should be admin(cid:173)
`istered to reach a new steady-state peak
`gentamicin concentration of 8 mg/L?
`
`A. 64 mg
`B. 82 mg
`C. 95 mg
`D. 128 mg
`
`Concepts in Clinical Pharmacokinetics
`
`94
`
`PS2-4. If the infusion is continued for 3 days and
`then discontinued, what would the plasma
`concentration be 12 hours after stopping
`the infusion?
`
`A. 1.2 mg/L
`B. 3.2 mg/L
`C. 7.6 mg/L
`D. 8.1 mg/L
`
`PS2-5. If the infusion is continued for 3 days at
`40 mgjhour and the steady-state plasma
`concentration is 12 mg/L, what rate of drug
`infusion would likely result in a concentra(cid:173)
`tion of 15 mg/L?
`
`A. 46 mgjhour
`B. 50 mgjhour
`C. 60 mgjhour
`D. 80 mg/hour
`
`PS2-6. After the increased infusion rate above is
`begun, how long would it take to reach a
`plasma concentration of 15 mg/L?
`
`A. 6.3 hours
`B. 12.6 hours
`C. 18.9 hours
`D. 31.5 hours
`
`The following pertains to Questions PSZ-7 to
`PSZ-10: A 60-kg patient is started on 80 mg of
`gentamicin every 6 hours given as 1-hour infusions.
`
`PS2-7. If this patient is assumed to have an average
`V of 15 Land a normal gentamicin half-life
`of 3 hours, what will be the peak plasma
`concentration at steady state?
`
`A. 6.3 mg/L
`B. 8.9 mg/L
`C. 12.2 mg/L
`D. 15.4 mg/L
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 102
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`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 106
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`lesson 8
`
`I Drug Distribution and Protein Binding
`
`123
`
`REVIEW QUESTIONS
`
`8-1.
`
`8-2.
`
`8-3.
`
`8-4.
`
`8-5.
`
`8-6.
`
`Drugs that are very lipid soluble tend to
`distribute poorly into body tissues.
`A. True
`B. False
`
`Drugs that are predominantly un-ionized at
`physiologic pH (7.4) have a limited distri(cid:173)
`bution when compared to drugs that are
`primarily ionized.
`A. True
`B. False
`
`Drugs are generally less well distributed
`to highly perfused tissues (compared with
`poorly perfused tissues).
`A. True
`B. False
`
`Estimate the volume of distribution for a
`drug when the volume of plasma and tissue
`are 5 and 20 L, respectively, and the fraction
`of drug unbound in plasma and tissue are
`both 0.7.
`A. 18.5 L
`B. 100 L
`C. 30 L
`D. 25 L
`
`The portion of drug that is bound to plasma
`protein is pharmacologically active.
`A. True
`B. False
`
`Penetration of drug into tissues is not related
`to the extent bound to plasma proteins.
`A. True
`B. False
`
`8-7.
`
`8-8.
`
`8-9.
`
`Cationic drugs and weak bases are more
`likely to bind to:
`A. globulin.
`B. alpha-1-acid glycoprotein.
`C.
`lipoprotein.
`D. A and C.
`
`Anionic drugs and weak acids are more
`likely to bind to:
`A. albumin.
`B. globulin.
`C. alpha-1-acid glycoprotein.
`D.
`lipoprotein.
`
`Predict how the volume of distribution (V)
`would change if the unbound fraction of
`phenytoin in plasma decreased from 90%
`to 85%. Assume that unbound fraction in
`tissues (Ft) and volumes of plasma (~) and
`tissues (Vc) are unchanged.
`increase
`A.
`B. no change
`C. decrease
`D. cannot be predicted with the
`information provided
`
`8-10. A new drug has a tissue volume (Vc) of 15 L,
`an unbound fraction in plasma (Fp) of 5%,
`and an unbound fraction in tissues (F;J of
`5%. What will be the resulting volume of
`distribution if the plasma volume (~) is
`reduced from 5 to 4 L?
`A. 13 L
`B. 19 L
`C. 18 L
`D. 5 L
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 131
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`Concepts in Clinical Pharmacokinetics
`
`144
`
`9-13. Heart failure reduces cardiac output and
`hepatic blood flow. Consequently, the total
`daily dose of lidocaine may need to be
`decreased in a patient with heart failure
`who has a myocardial infarction.
`A True
`B. False
`
`9-14. Which of the following types of metabo(cid:173)
`lism do drugs with a high extraction ratio
`undergo to a significant extent?
`A
`first-pass
`B. zero-order
`C.
`intraluminal
`D. nonlinear
`
`9-15. Significant first-pass metabolism means
`that much of the drug's metabolism occurs
`before its arrival at the:
`A hepatocyte.
`B. systemic circulation.
`C. portal blood.
`D.
`liver lobule.
`
`9-16. The liver receives blood supply from the GI
`tract via the:
`A portal vein.
`B. hepatic artery.
`c. hepatic vein.
`D. portal artery.
`
`9-17. For a drug that is totally absorbed without
`any presystemic metabolism and
`then
`undergoes hepatic extraction, which of the
`following is the correct equation for F?
`A F= 1- Ka
`B. F= 1- FP
`C. F=1-E
`D. F = 1 -the fraction of the drug absorbed
`
`9-18. Route of administration, extraction ratio,
`and protein binding are all factors that
`should be considered when trying to assess
`the effect of disease states on plasma
`concentrations of drugs eliminated by the
`liver.
`A True
`B. False
`
`9-19. Will drugs that inhibit the hepatic cyto(cid:173)
`chrome P450 system likely increase or
`decrease the plasma clearance of theo(cid:173)
`phylline?
`A
`increase
`B. decrease
`
`9-20. Disease states may increase or decrease
`drug protein binding.
`A True
`B. False
`
`9-21. Drug elimination encompasses both:
`A metabolism and excretion.
`B. metabolism and biotransformation.
`C. absorption and metabolism.
`D. metabolism and distribution.
`
`9-22. Two important routes of drug excretion are:
`A hepatic and tubular secretion.
`B. biliary and metabolic.
`renal and biliary.
`C.
`D.
`renal and metabolic.
`
`9-23. Fluid is filtered across the glomerulus
`through active transport.
`A True
`B. False
`
`9-24. Tubular secretion most often occurs with
`weak organic acids.
`A True
`B. False
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 152
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`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 156
`
`