116 E&Hh►t II.

II. CLINICAL PHARMACOKINETICS

A. Definition
I. Clinical pharmacokinetics is the application of pharmacokinetic principles for the rational design
of an individualized dosage regimen. The two main objectives are maintenance of an optimum
drug concentration at the receptor site to produce the desired therapeutic response for a specific
period and minimization of any adverse or toxic effects of the drug.

Ill. TOXICOKINETICS
A. Definitions
I. Toxicokinetics is the application of pharmacokinetic principles to the design, conduct, and inter-
pretation of drug safety evaluation studies.
2. Toxicokinetics is also used to validate dose-related exposure in animals. Toxicokinetic studies are
performed in animals during preclinical drug development to aid in prediction of human drug
toxicity. Toxicokinetic (nonclinical) studies may continue after the drug has been tested in humans.
3. Clinical toxicology is the study of adverse effects of drugs and toxic substances (poisons) in the
human body. The pharmacokinetics of a drug in an overmedicated (intoxicated) patient may
be very different from the pharmacokinetics of the same drug given in therapeutic doses. For
example, a very high toxic dose may show nonlinear pharmacokinetics due to saturation kinetics
compared to the drug given at lower therapeutic doses in which the drug levels follow linear
pharmacokinetics.

IV. POPULATION PHARMACOKINETICS

A. Definition
I. Population pharmacokinetics is the study of sources and correlates of variability in drug concen-
trations among individuals who are the target patient population. Population pharmacokinetics
is most often applied to the clinical patient who is receiving relevant doses of a drug of inter-
est. Both pharmacokinetic and nonpharmacokinetic data may be considered, including gender,
age, weight, creatinine clearance, and concomitant disease. Population pharmacokinetics can
be used to assist with therapeutic drug monitoring and the principles of dosage adjustments
(see Chapter 26).

Directions: Each question, statement, or incomplete For questions 2-5: A new cephalosporin antibiotic was
statement in this section can be correctly answered or given at a dose of 5 mg/kg by a single intravenous bolus
completed by one of the suggested answers or phrases. injection to a 58-year-old man who weighed 75 kg.
Choose the best answer. The antibiotic follows the pharmacokinetics of a one-
compartment model and has an elimination half-life of
1. Creatinine clearance is used as a measurement of
2 hrs. The apparent volume of distribution is 0.28 L/kg, and
(A) renal excretion rate. the drug is 35% bound to plasma proteins.
(B) glomerular filtration rate (GFR).
(C) active renal secretion. 2. What is the initial plasma drug concentration ( cg) in
(D) passive renal absorption. this patient?
(E) drug metabolism rate. (A) 0.24 mg/L
(B) 1.80 mg/L
(C) 17.9 mg/L
(D) 56.0 mg/L
(E) 1339 mg/L
 Basic Pharmacokinetics 117

3. What is the predicted plasma drug concentration ( Cp) 9. To infuse the antibiotic as a solution containing 10-g
at 8 hr after the dose? drug in 500 mL 5% dextrose, how many milliliters per
(A) 0.73 mg/L hour of the solution would be infused into the patient?
(B) 1.11 mg/L (A) 10.0 mL/hr
(C) 2.64 mg/L (B) 46.8 mL/hr
(D) 4.02 mg/L (C) 100.0 mL/hr
(E) 15.10 mg/L (D) 936.0 mL/hr
(E) 1141.0 mL/hr
4. How much drug remains in the patient's body (DB)
8 hrs after the dose? 10. What is the total body clearance rate for carbenicillin
(A) 15.3 mg in this patient?
(B) 23.3 mg (A) 100 mL/hr
(C) 84.4 mg (B) 936 mL/hr
(D) 100.0 mg (C) 4862 mL/hr
(E) 112.0 mg (D) 6237 mL/hr
(E) 9000 mL/hr
5. How long after the dose is exactly 75% of the drug
eliminated from the patient's body? I I. If the patient's renal clearance for carbenicillin is 86 mL/
min, what is the hepatic clearance for carbenicillin?
(A) 2 hrs
(B) 4 hrs (A) 108 mL/hr
(C) 6 hrs (B) 1077 mL/hr
(D) 8 hrs (C) 3840 mL/hr
(E) 10 hrs (D) 5160 mL/hr
(E) 6844 mL/hr
For questions 6-11: A 35-year-old man who weighs
70 kg and has normal renal function needs an intravenous 12. The earliest evidence that a drug is stored in tissue is
infusion of the antibiotic carbenicillin. The desired steady- (A) an increase in plasma protein binding.
state plasma drug concentration is 15 mg/ dL. The physician (B) a large apparent volume of distribution (V0 ) .
wants the antibiotic to be infused into the patient for 10 hrs. (C) a decrease in the rate of formation of metabolites
Carbenicillin has an elimination half-life (t½) of 1 hr and an by the liver.
apparent volume distribution (V0 ) of9 Lin this patient. (D) an increase in the number of side effects
produced by the drug.
6. Assuming that no loading dose was given, what rate of (E) a decrease in the amount of free drug excreted in
intravenous infusion is recommended for this patient? the urine.
(A) 93.6 mg/hr
13. The intensity of the pharmacologic action of a drug is
(B) 135.0 mg/hr
most dependent on the
(C) 468.0 mg/hr
(D) 936.0 mg/hr (A) concentration of the drug at the receptor site.
(E) 1350.0 mg/hr (B) elimination half-life (t½) of the drug.
(C) onset time of the drug after oral administration.
7. Assuming that no loading intravenous dose was (D) minimum toxic concentration (MTC) of the drug
given, how long after the initiation of the intravenous in plasma.
infusion would the plasma drug concentration reach (E) minimum effective concentration (MEC) of the
95% of the theoretic steady-state drug concentration? drug in the body.
(A) 1.0 hrs 14. Drugs that show nonlinear pharmacokinetics have
(B) 3.3 hrs which property?
(C) 4.3 hrs
(D) 6.6 hrs (A) A constant ratio of drug metabolites is formed as
(E) 10.0 hrs the administered dose increases.
(B) The elimination half-life (t½) increases as the
8. What is the recommended loading dose? administered dose increases.
(A) 93.6 mg (C) The area under the plasma drug concentration
(B) 135.0 mg versus time curve (AUC) increases in direct
(C) 468.0 mg proportion to an increase in the administered dose.
(D) 936.0 mg (D) Both low and high doses follow first-order
(E) 1350.0 mg elimination kinetics.
(E) The steady-state drug concentration increases in
direct proportion to the dosing rate.
11 a e&Hh►t

15. The loading dose (Dd of a drug is usually based on the 21. The principle of superposition in designing multiple-
(A) total body clearance ( Clr) of the drug. dose regimens assumes that
(B) percentage of drug bound to plasma proteins. (A) each dose affects the next subsequent dose,
(C) fraction of drug excreted unchanged in the urine. causing nonlinear elimination.
(D) apparent volume of distribution ( V 0) and desired (B) each dose of drug is eliminated by zero-order
drug concentration in plasma. elimination.
(E) area under the plasma drug concentration versus (C) steady-state plasma drug concentrations are
time curve (AUC) . reached at approximately 10 half-lives.
(D) early doses of drug do not affect subsequent doses.
16. The renal clearance of inulin is used as a
(E) the fraction of drug absorbed is equal to the
measurement of
fraction of drug eliminated.
(A) effective renal blood flow.
(B) rate ofrenal drug excretion. For questions 22-24: A new cardiac glycoside is developed
(C) intrinsic enzyme activity. for oral and intravenous administration. The drug has
(D) active renal secretion. an elimination half-life (t½) of24 hrs and an apparent
(E) GFR. volume of distribution ( V0) of 3 L/kg. The effective drug
concentration is 1.5 ng/mL. Toxic effects of the drug are
17. All of the following statements about plasma protein observed at drug concentrations > 4 ng/mL. The drug is
binding of a drug are true except which one? bound to plasma proteins at approximately 25%. The drug
(A) Displacement of a drug from plasma protein is 75% bioavailable after an oral dose.
binding sites results in a transient increased
22. What is the oral maintenance dose, if given once a day, for
volume of distribution (V0 ).
a 68-year-old man who weighs 65 kg and has congestive
(B) Displacement of a drug from plasma protein
heart failure (CHF) and normal renal function?
binding sites makes more free drug available for
glomerular filtration. (A) 0.125 mg
(C) Displacement of a potent drug that is normally (B) 0.180 mg
> 95% bound may cause toxicity. (C) 0.203 mg
(D) Albumin is the major protein involved in protein (D) 0.270 mg
binding of drugs. (E) 0.333 mg
(E) Drugs that are highly bound to plasma proteins 23. What is the loading dose (Dd for this patient?
generally have a greater VO compared with drugs
(A) 0.270mg
that are highly bound to tissue proteins.
(B) 0.293 mg
18. The onset time for a drug given orally is the time for (C) 0.450 mg
the drug to (D) 0.498 mg
(A) reach the peak plasma drug concentration. (E) 0.540 mg
(B) reach the MEC. 24. If the drug is available in tablets of 0.125 mg and
(C) reach the MTC. 0.250 mg, what is the patient's plasma drug concentration
(D) begin to be eliminated from the body. ifhe has a dosage regimen of0.125 mg every 12 hrs?
(E) begin to be absorbed from the small intestine.
(A) 1.39 ng/mL
19. The initial distribution of a drug into tissue is (B) 1.85 ng/mL
determined chiefly by the (C) 2.78 ng/mL
(A) rate of blood flow to tissue. (D) 3.18 ng/mL
(B) GFR. (E) 6.94 ng/mL
(C) stomach emptying time. 25. If digoxin has a half-life of 35 hrs how long will it take for
(D) affinity of the drug for tissue. a toxic plasma concentration of8 ng/mL to decline to a
(E) plasma protein binding of the drug. therapeutic plasma concentration of2 ng/mL?
20. Which tissue has the greatest capacity to biotransform (A) 17.5 hrs
drugs? (B) 35 hrs
(A) brain (C) 70 hrs
(B) kidney (D) 105 hrs
(C) liver (E) 140 hrs
(D) lung
(E) skin
 Basic Pharmacokinetics 119

Directions for question 26: The question in this section 26. Which equation is true for a zero-order reaction rate
can be correctly answered by one or more of the suggested of a drug?
answers. Choose the correct answer, A-E.
A ifl only is correct I. t= -k
B iflll only is correct II. t½ = o.t;:3
C if I and II are correct
D if II and III are correct III. A = A 0e - kt
E if I, II, and III are correct

Answers and Explanations

I. The answer is B [see I.E.2.a]. 6. The answer is D [see I.B.3.e.(3)}.
A substance that is used to measure the GFR must be
7. The answer is C [see I.B.3.c}.
filtered but not reabsorbed or actively secreted. Al-
though inulin clearance gives an accurate measure- 8. The answer is E [see I.B.3j(2)].
ment of GFR, creatinine clearance is generally used
9. The answer is B [see I.B.3.e.(3)}.
because no exogenous drug must be given. However,
creatinine formation depends on muscle mass and 10. The answer is D [see I.B.3.e.(3); I.E.l .a].
muscle metabolism, which may change with age and
11. The answer is B [see I.EA.a].
various disease conditions.
The equation for the plasma concentration at steady
2. The answer is C [see I.B.l .b.(2)]. state ( C,,) provides the formula for calculating the rate
of an intravenous infusion (R). The equation is
3. The answer is B [see I.A.3.b.(1); I.B.l].
4. The answer is B [see I.B.1 .a.(2)]. C - R
ss - kVo
5. The answer is B [see I.B.1 .a.(2)] . where k is the first-order elimination rate constant and
Substituting the data for this patient in the equation for V0 is the apparent volume of distribution. Rearranging
the initial plasma drug concentration (G) gives the equation and substituting the data for this patient
0 _Do_ 5mg _ give the following calculations:
C P - Vo - 0.28 L/kg - 17.9 mg/L
15 mg 0.693
R = C,,kV0 = lO0 mL X 1hr X 9000 mL
To obtain the patient's plasma drug concentration
(Ci,) 8 hrs after the dose, the following calculation is R = 936 mg/hr
performed:
The time it takes for an infused drug to reach the
Cp = cop e-kt C,, depends on the elimination half-life of the drug.
k = 0.f3 = o.~63 = 0.347 hr-I The time required to reach 95% of the C,, is equal to
4.3 times the half-life, whereas the time required to
CP = l 7.9e-(o.347J(sJ reach 99% of the C,, is equal to 6.6 times the half-life.
Because the half-life in the current case is 1 hr, the time
CP = (17.9)(0.0623) = l.ll mg/L to reach 95% of the Css is 4.3 X 1 hr or 4.3 hrs.
The amount of drug in the patient's body at 8 hrs is The loading dose (Dd is calculated as follows:
calculated as follows: 15mg
D1 = C,,V 0 = lO0 mL X 9000 mL = 1350 mg
D8 = CP V 0 = (1.11)(0.28)(75) = 23.3 mg
For any first-order elimination process, 50% of the The answer to question 6 shows that the infusion rate
initial amount of drug is eliminated at the end of the should be 936 mg/hr. Therefore, if a drug solution con-
first half-life, and 50% of the remaining drug (i.e., 75% taining 10 g in 500 mL is used, the required infusion
of the original amount) is eliminated at the end of the rate is
second half-life. Because the drug in the current case 936 mg X 500 mL 46 _8 mL/hrs
has an elimination half-life (t½) of 2 hrs, 75% of the 1 hr 10000 mg
dose is eliminated in two half-lives or 4 hrs.
120 e&Hh►t

The patient's total body clearance (CIT) is calculated as 17. The answer is E [see I.A.5.d].
follows: Drugs that are highly bound to plasma proteins diffuse
poorly into tissue and have a low apparent volume of
CIT= kVo
distribution (V0 ).
CIT = 0 -693 X 9000 mL = 6237 mL/hr
1 18. The answer is B [see I.B.3.g].
The onset time is the time from the administration
The hepatic clearance (Cltt) is the difference between
of the drug to the time when absorbed drug reaches
total clearance (Ch) and renal clearance (CIR):
the MEC. The MEC is the drug concentration in the
CIH = CIT - CIR plasma that is proportional, but not necessarily equal,
Cltt = 6237 - (86 mL/min X 60 min/hr) to the minimum drug concentration at the receptor
= 1077 mL/hr site that elicits a pharmacologic response.

12. The answer is B [see I.B.l.b.(1)]. 19. The answer is A [see I.A.5.a}.
A large apparent volume of distribution (V0 ) is an early The initial distribution of a drug is chiefly determined
sign that a drug is not concentrated in the plasma but by blood flow, whereas the affinity of the drug for tis-
is distributed widely in tissue. An increase in plasma sue determines whether the drug concentrates at that
protein binding suggests that the drug is located in the site. The GFR affects the renal clearance of a drug, not
plasma rather than in tissue. A decrease in hepatic me- its initial distribution. The gastric emptying time and
tabolism, an increase in side effects, or a decrease in uri- degree of plasma protein binding affect drug distribu-
nary excretion of free drug is caused by a decrease in drug tion but are less important than the rate of blood flow
elimination. to tissue.

13. The answer is A [see I.A.5.d.(3)]. 20. The answer is C [see l.E.4.b.(2)].
As more drug is concentrated at the receptor site, more The kidney, lung, skin, and intestine all have some
receptors interact with the drug to produce a pharma- capacity to biotransform, or metabolize, drugs; but the
cologic effect. The intensity of the response increases brain has little capacity for drug metabolism. The liver
until it reaches a maximum. When all of the available has the highest capacity for drug metabolism.
receptors are occupied by drug molecules, additional
21. The answer is D [see l.B.5.c}.
drug does not produce a more intense response.
The superposition principle, which underlies the
14. The answer is B [see I.DJ. design of multiple-dose regimens, assumes that ear-
Nonlinear pharmacokinetics is a term used to indicate lier drug doses do not affect subsequent doses. If the
that first-order elimination of a drug does not occur elimination rate constant or total body clearance of the
at all drug concentrations. With some drugs, such drug changes during multiple dosing, then the super-
as phenytoin, as the plasma drug concentration in- position principle is no longer valid. Changes in the
creases, the elimination pathway for metabolism of total body clearance (CIT) may be caused by enzyme
the drug becomes saturated and the half-life increases. induction, enzyme inhibition, or saturation of an elim-
The area under the plasma drug concentration versus ination pathway. Any of these changes would cause
time curve (AUC) of the drug is not proportional to nonlinear pharmacokinetics.
the dose, neither is the rate of metabolite formation.
22. The answer is D [see l.B.5.e.(3)}.
The metabolic rate is related to the effects of the drug.
23. The answer is E [see l.B.5.g.(1)].
15. The answer is D [see I.B.l.b.(2); I.B.5.g.(l)J.
A loading dose (DL) of a drug is given to obtain a thera- 24. The answer is A [see l.B.5.d.(2); l.B.5.e.(3)}.
peutic plasma drug level as rapidly as possible. The DL The oral maintenance dose (D0 ) should maintain the
is calculated based on the apparent volume of distribu- patient's average drug concentration at the effective
tion (V0 ) and the desired plasma level of the drug. drug concentration. The bioavailability of the drug (F),
the apparent volume of distribution ( V 0), the dosage
16. The answer is E [see I.E.3.c].
interval (-r), and the excretion rate constant (k) must
Inulin is neither reabsorbed nor actively secreted.
be considered in calculating the dose. The equation
Therefore, it is excreted by glomerular filtration only.
used is
The inulin clearance rate is used as a standard measure
of the GFR, a test that is useful both in a clinical situa- C~v = FD0 I kV0 -r
tion and in the development of new drugs.
 Basic Pharmacokinetics 121

For this drug, F = 0.75, k = 0.693/24 hrs, V0 = 3 L/kg 25. The answer is C [see l.A.3.b].
X 65 kg, T = 24 hrs, and c:v = 1.5 ng/mL, or 1.5 µg/L. For first-order elimination, it takes two half-lives for
Therefore, by substitution, D0 = 270 µg, or 0.270 mg. plasma drug concentration of8 ng/mL to decline to 2 ng/
When the maintenance dose is given at a dosage mL. The first half-life, the plasma drug concentration
frequency equal to the half-life, then the loading dose is declines to 4 ng/mL, and the next half-life, the plasma
equal to twice the maintenance dose, in this case 540 µg, drug concentration declines to 2 ng/mL.
or 0.540 mg. To determine the plasma drug concentra-
26. The answer is A (I) [see l.A.3.a].
tion for a dosage regimen of 0.125 mg every 12 hrs, the
The first equation in the question describes a zero-order
c:Jormulais used. Thistime,F = 0.75,D0 = 0.125 mg,
reaction (dA/dt) in which the reaction rate increases or
k = 0.693/24 hrs, V 0 = 3 L/kg X 65 kg, and -r = 12 hrs.
decreases at a constant rate (k). A zero-order reaction
Therefore, c:v = 1.39 ng/mL. For cardiac glycosides,
produces a graph of a straight line with the equation of
the peak (CmaJ and trough (Cmm) concentrations are
A = -kt+ A 0 when A is plotted against time (t). The
calculated, and plasma drug concentrations are moni-
other equations in the question represent first-order
tored after dosing. The loading dose (DL) may be given
reactions.
in small increments over a specified period, according
to the dosage regimen suggested by the manufacturer.