1

2
The rate of a chemical reaction of process is
the velocity with which the reaction occurs.
drug A  drug B

The rate of a reaction is determined experimentally

by measuring the disappearance of drug A at given
time intervals.
3
ORDER OF A REACTION

= is the way in which the concentration of a drug

or reactant in a chemical reaction affects the rate.

A.) Zero-order kinetics

B.) First-order kinetics

4
• If the amount of drug (A) is decreasing at a constant time interval,
then it follows zero-order kinetics.

• The drug concentration changes with respect to time at a constant

rate.

•The rate of a reaction does not depend on the substrate

concentration.

dA/dt = -ko Extrapolation: A = -kot + Ao

C = -kot + Co

5
- the half-life for a zero-order is not constant.
- It is proportional to the initial amount or
concentration of the drug and is inversely
proportional to the zero-order rate constant, ko.

t1/2 = 0.5Ao
ko

6
If the amount of drug A is decreasing at a rate that is
proportional to the drug remaining, then it follows the
first-order kinetics.
dA/dt = -kA Extrapolation method:

C = Coe-kt

In C = - kt + ln Co

log Cp = -kt + log CpO

2.3 7
-the amount of drug administered during a
dosing interval exactly replaces the amount of
drug excreted.

When this equilibrium occurs (rate in = rate out),

steady-state is reached.

8
-is the time it takes for plasma drug concentration to
be reduced or increased by 50%
-is constant for a drug that follows first-order kinetics.
- half-life for a first-order kinetics is:

t1/2 = 0.693 t1/2 = 0.693 Vd

k Clearance

k = first-order rate constant

9
No matter what the initial amount or concentration of drug is,
the time required for the amount to decrease by one-half is a
constant.

Example:

Initial Drug Conc. After 1 hr.

100 mg/mL 50 mg/mL
50 mg/mL 25 mg/mL
25 mg/mL 12.5 mg/mL
10
Half-life
- is a major determinant :

a.) the duration of action after a single dose

b.) the time required to reach steady-state

c.) the dosing frequency

11
 PRACTICE PROBLEMS

1.) A single 400-mg IV bolus dose of an

antibiotic was administered to a patient. The
amounts of the drug determined at different
times after drug administration were as follows:

12
 PRACTICE PROBLEMS

1.) Does the elimination process (rate of drug decline) follow

zero-order or first-order kinetics?
2.) What is the rate constant for the elimination process?
3.) What is the half-life of the drug immediately after
administration?
4.) What is the rate constant for the elimination process if the dose
was 600 mg?
5.) What is the amount of the drug in the body 20 hr after drug
administration?
6.) What is the amount of the drug in the body 40 hr after drug
administration?
13
 PRACTICE PROBLEMS

1.) Does the elimination process (rate of drug decline) follow

zero-order or first-order kinetics?
Ans. Zero-order kinetics

2.) What is the rate constant for the elimination process?

Ans. A = - kot + Ao
202 = -ko (18) + 400
202 – 400 = ko
- 18
ko = 11 mg/hr
14
 PRACTICE PROBLEMS

3.) What is the half-life of the drug immediately after

administration?
t1/2 = 0.5 (400)
11
= 18.2 hour

4.) What is the rate constant for the elimination process

if the dose was 600 mg?
ko = 11 m mg/hr

15
 PRACTICE PROBLEMS

5.) What is the amount of the drug in the body 20 hr after drug
administration?
A = -kot + Ao
= - 11(20) + 400
= 180 mg

6.) What is the amount of the drug in the body 40 hr after drug
administration?
A = -11 (40) + 400
= - 40 mg
16
 PRACTICE PROBLEMS

2.) If the half-life for decomposition of a drug is 8

hours, how long will it take for 275 mg of the
drug to decompose by 20%? Assume first-order
kinetics and constant temperature.
Ans. Operation:
A = AOe-kt 220/275 = 0.8 press ln
-0.086625(t) = - 0.223143551
220 = 275 e = - 0.223143551
t = 2.58 hours - 0.086625
= 2.576 hours
17
 PRACTICE PROBLEMS

2.) If the half-life for decomposition of a drug is 8 hours, how long

will it take for 275 mg of the drug to decompose by 20%?
Assume first-order kinetics and constant temperature.
Ans.
log A = - kt + log AO
2.3
log 220 = - 0.086625(t) + log 275
2.3
(log 220 – log 275 ) 2.3 = t
- 0.086625
t = 2.573 hours
18
 PRACTICE PROBLEMS

2.) If the half-life for decomposition of a drug is 8 hours, how long

will it take for 275 mg of the drug to decompose by 20%?
Assume first-order kinetics and constant temperature.
Ans.
ln A = - kt + ln AO
ln 220 = - 0.086625(t) + ln 275
ln 220 – ln 275 = t
-0.086625
t = 2.576 hours

19
 PRACTICE PROBLEMS

3.) Two different drugs were administered on different

occasions in different doses to the same subject by IV
administration and the half-lives of the two drugs were
determined.

20
 PRACTICE PROBLEMS

a.) Which one of the two drugs is eliminated by first

order process? Explain.
b.) If 10 mg of the drug that is eliminated by first order
process was administered to the same patient, how
much time (hr) would be required to eliminate 7 mg of
the drug?
c.) What is the rate constant of drug B at 60 mg?

21
 PRACTICE PROBLEMS

a.) Which one of the two drugs is eliminated by first

order process? Explain.

Ans. Drug A because the half-life is constant.

22
 PRACTICE PROBLEMS

b.) If 10 mg of the drug that is eliminated by first order process was

administered to the same patient, how much time (hr) would be
required to eliminate 7 mg of the drug?

log A = - kt + log AO
2.3
log 3 = - 0.144375 (t) + log 10
2.3
t = 8.33 hours

23
 PRACTICE PROBLEMS

c.) What is the rate constant of drug B at 60 mg?

Ans. A = - kot + Ao
30 = - ko(15 hrs) + 60
- 30 = ko
- 15
ko = 2 mg/hr

24
 PRACTICE PROBLEMS

4.) After rapid intravenous bolus administration of 250

mg dose of a drug at 6am, the concentrations of drug in
plasma at 10 am and 1 pm were 290 and 195 μg/mL
respectively. If the drug is eliminated according to first-
order kinetics, what will be the concentration of drug in
plasma at 6 am the following morning?

25
 PRACTICE PROBLEMS

4.) After rapid intravenous bolus administration of 250 mg dose of

a drug at 6am, the concentrations of drug in plasma at 10 am and 1
pm were 290 and 195 μg/mL respectively. If the drug is eliminated
according to first-order kinetics, what will be the concentration of
drug in plasma at 6 am the following morning?

Ans. Cp = Cpoe-kt
= 195e-0.132145 (17)
Cp = 20.6 μg/mL

26
 PRACTICE PROBLEMS

5.) A product is ineffective after it has decomposed

30%. At the time of preparation, the concentration of
active ingredient was 5 µg/teaspoonful. After 3 months
concentration of active ingredient was reduced to 4.5
µg/teaspoonful. What should be the expiration date on
the label if degradation follows zero-order kinetics?

27
 PRACTICE PROBLEMS

5.) A product is ineffective after it has decomposed 30%. At the time of

preparation, the concentration of active ingredient was 5 µg/teaspoonful.
After 3 months concentration of active ingredient was reduced to 4.5
µg/teaspoonful. What should be the expiration date on the label if
degradation follows zero-order kinetics?

Ans. 0 time = 5 µg/5 mL 5 x 30% = 3.5

3 months = 4.5 µg/5 mL

Cp = - kt + Cpo Cp = - kt + Cpo
4.5 = - k(3) + 5 3.5 = - 0.1667(t) + 5
k = 0.1667 µg/month t = 8.99 = 9 months 28
 PRACTICE PROBLEMS

6.) An oral antibiotic suspension should not be used

after the antibiotic has degraded 15%. A hospital
pharmacist reconstituted the suspension and put an
expiration time of 14 days. Calculate the rate constant
of degradation if concentration of antibiotic at
reconstitution time was 125 mg/5mL and degradation
follow zero-order.

29
 PRACTICE PROBLEMS

6.) An oral antibiotic suspension should not be used after the antibiotic
has degraded 15%. A hospital pharmacist reconstituted the suspension
and put an expiration time of 14 days. Calculate the rate constant of
degradation if concentration of antibiotic at reconstitution time was
125 mg/5mL and degradation follow zero-order.

Ans. Cp = -kot + Cpo 15% of 125 = 18.75

106.25 = -ko(14) + 125 125 – 18.75 = 106.25
106.25 - 125 = ko
- 14
ko = 1.34 mg/5mL /day
30
 PRACTICE PROBLEMS

7.) Calculate the half-life of a product if concentrations

on day 10 and day 40 after preparation of the product
were determined to be 28 mg/mL and 16 mg/mL,
respectively. Assume the product undergoes
degradation according to zero-order kinetics.

31
 PRACTICE PROBLEMS
7.) Calculate the half-life of a product if concentrations on day 10 and
day 40 after preparation of the product were determined to be 28
mg/mL and 16 mg/mL, respectively. Assume the product undergoes
degradation according to zero-order kinetics.

Ans. 10 days = 28 mg/mL Cp = - kt + Cpo

40 days = 16 mg/mL 28 = - 0.4 (10) + Cpo
28 + 4 = Cpo
Cp = -kt + Cpo
Cpo = 32 mg/mL
16 = - k (30) + 28
16 – 28 = k
t1/2 = 0.5 (32)
- 30
0.4
k = 0.4
= 40 days 32
33
 OUTLINE:

One-Compartment Model

1.) Intravenous Bolus Injection

a.) Drug Elimination
b.) Apparent Volume of Distribution
2.) Single Oral Dose
3.) Intravenous Infusion
4.) Intermittent Intravenous Infusion
5.) Multiple Doses

34
ONE-COMPARTMENT MODEL

1.) Intravenous Bolus Injection

The entire drug dose enters the body

instantaneously, and the rate of
absorption is therefore assumed to be
negligible in calculations.

35
ONE-COMPARTMENT MODEL

1.) Intravenous Bolus Injection

The entire body acts as a single

compartment, and the drug rapidly
equilibrates with all of the
tissues in the body.

36
37
PHARMACOKINETIC PARAMETERS
1.) Elimination Rate Constant
log Cp = - kt + Cpo k = - slope
2.3 = - ln Y2 - ln Y1
2.) Biologic Half-life X2 - X1
t1/2 = 0.693/k

3.) Apparent VD 5.) Cl = kVD

VD = DB/Cpo

4.) = Co/k

= Dose/Cl
38
INTRAVENOUS BOLUS INJECTION

1.a) Drug Elimination

= is generally a first-order kinetic process.

The first-order elimination rate constant (k or kel) is

the sum of the rate constants for removal of drug
from the body, including the rate constants for renal
excretion and metabolism as described by
the following equation:

k = ke + km
39
INTRAVENOUS BOLUS INJECTION

Where:
ke = rate constant for renal excretion
km = rate constant for metabolism.

This equation assumes that all rates are

first-order processes.

40
INTRAVENOUS BOLUS INJECTION

1.a) Drug Elimination

The elimination half-life is given by the

following equation:
t1/2 = 0.693
k
Rate of elimination = Cl x Cp

41
INTRAVENOUS BOLUS INJECTION

1.b) Apparent Volume of Distribution (VD)

= is the hypothetical volume of body

fluid in which the drug is dissolved.
This value is not a true anatomic or
physical volume.

42
INTRAVENOUS BOLUS INJECTION

1.b) Apparent Volume of Distribution (VD)

VD is needed to estimate the amount

of drug in the body relative to the
concentration of drug in the plasma,
as shown in the following:
VD x CP = DB

43
 PRACTICE PROBLEMS

1.) Four hours following intravenous

administration of a drug, a patient weighing
70 kg was found to have a drug blood level
concentration of 10 µg/mL. Assuming the
apparent volume of distribution is 10% of
body weight; calculate the total amount of
drug in mg that is present in body fluids 4
hours after the drug was administered.
44
 PRACTICE PROBLEMS
1.) Four hours following intravenous administration of a drug, a
patient weighing 70 kg was found to have a drug blood level
concentration of 10 µg/mL. Assuming the apparent volume of
distribution is 10% of body weight; calculate the total amount
of drug in mg that is present in body fluids 4 hours after the
drug was administered.

Given: wt = 70 kg
Cp = 10 µg/mL after 4 hours
VD = 70 x 10% = 7 kg = 7 L
DB = 4 after the drug was administered

45
 PRACTICE PROBLEMS
Given: wt = 70 kg
Cp = 10 µg/mL after 4 hours
VD = 70 x 10% = 7 kg = 7 L
DB = 4 after the drug was administered

C = Coe-kt k = 0.693/4
10 = Coe-0.17325(4) = 0.17325/hr
10 = Co 0.500073595
Cpo = 19.99705661 µg/mL

DB = VD Cpo
DB = 7000 mL (19.99705661 µg/mL)
DB = 139,979.3964 µg
DB = 140 mg 46
 PRACTICE PROBLEMS

2.) The plasma concentration as a function of

time after 250 mg intravenous bolus dose of
an antibiotic is given below. Data below has
been plotted as presented.
Time (hr) 1 2 3 4 5 6 7
Conc. (μg/mL) 8 6.3 4.9 4.0 3.2 2.5 1.9

47
 PRACTICE PROBLEMS

Calculate the following:

1.) Elimination rate constant
2.) Biologic half-life
3.) Volume of Distribution
4.) Total Area Under the Curve

48
PRACTICE PROBLEMS
Calculate the following:

1.) Elimination rate constant

log Cp = - kt + log Cpo
2.3
log 2 = - k (7) + log 10
2.3
k = 0.2297/hr

49
 PRACTICE PROBLEMS

2.) Biologic half-life 4.) Total Area Under the Curve

t1/2 = 0.693
0.2297 = = Cpo
= 3.02 hr k
= 10 µg/mL
3.) Volume of Distribution
0.2297/hr
VD = DB = 43.5 µg · hr/mL
Cpo
= 250 mg
10 µg/mL
= 25 L
50
 PRACTICE PROBLEMS

3.) The plasma profile of a drug following

intravenous administration of a single 300
mg bolus dose of a drug can be described
by the equation:

C = 92 (e-0.35t)

51
 PRACTICE PROBLEMS

If concentration is in mg/L and time is in hours,

calculate the following parameters:

a.) Biological half-life of the drug

b.) Apparent volume of distribution of the drug
c.) Concentration of drug at 6 hour

52
 PRACTICE PROBLEMS

a.) Biological half-life of the drug

t1/2 = 0.693
k
= 0.693
0.35
= 1.98 hr

53
 PRACTICE PROBLEMS

b.) Apparent volume of distribution of the drug

VD = DB = 300 mg = 3.2609 L
Cpo 92 mg/mL

54
 PRACTICE PROBLEMS

c.) Concentration of drug at 6 hour

o -kt
C
Cp = p e
= 92 e-0.35(6)
= 11.27 mg/L

55
 PRACTICE PROBLEMS
4.) A general anesthetic has a VD of 4L/kg,
k of 0.7 hr-1 and MEC of 3.5 mg/L. The drug is
effective as long as the plasma concentration
is above 3.5 mg/L.
a.) What is the expected duration of effect after
administration of a single IV dose of
100 mg/kg?
b.) What CPO needs to be reached in order to
have a duration of effect of 8 hrs?

56
 PRACTICE PROBLEMS
a.) What is the expected duration of effect after
administration of a single IV dose of
100 mg/kg?
log Cp = - kt + log Cp o Cpo = DB/VD
2.3 = 100 mg/kg
log 3.5 = - 0.7(t) + log 25 4 L/kg
= 25 mg/L
2.3
t = 2.81 hr

57
 PRACTICE PROBLEMS
b.) What CPO needs to be reached in order to
have a duration of effect of 8 hrs?

Cp = Cpoe-kt
3.5 = Cpoe-0.7(8)
3.5 = Cpo (0.003697863)
3.5 = Cpo
0.003697863

Cpo = 946.49 mg
58
 PRACTICE PROBLEMS

5. A 10-mg dose of Diazepam is injected

intravenously into a patient with status
epilepticus. The half-life and volume of
distribution of the drug are 48 hr and 80 L,
respectively, in the patient. Calculate your
expectation for each of the following:

59
 PRACTICE PROBLEMS

a.) Elimination rate constant

b.) Plasma Diazepam concentration at 12 hours after
giving the dose.
c.) What percent of the dose remains in the body 34
hours after the dose is given.
d.) Clearance of Diazepam
e.) AUC from 0 to infinity
f.) Amount of drug in the body 1 week after
giving the dose.

60
 PRACTICE PROBLEMS
a.) Elimination rate constant
k = 0.693/48 hr = 0.0144375/hr
b.) Plasma Diazepam concentration at 12 hours after
giving the dose.
log Cp = - kt + log Cpo
2.3
= - 0.0144375 (12) + log 0.125
2.3
Cp = 0.1051 mg/L

61
 PRACTICE PROBLEMS
c.) What percent of the dose remains in the body 48
hours after the dose is given.
Ans. 50% since 48 hr is half-life
d.) Clearance of Diazepam

Ans. Cl = k(VD)
= 0.0144375 (80L)
= 1.155 L/hr

62
 PRACTICE PROBLEMS
e.) AUC from 0 to infinity

= Dose/Cl
= 10 mg
1.15 L/hr
= 8.70 mg-hr/L

63
 PRACTICE PROBLEMS
f.) Amount of drug in the body 1 week after
giving the dose.

A = Aoe-kt
A = 10e-0.0144375(168)
A = 0.8843 mg

1 week = 7 days x 24 hrs

= 168 hrs

64
 SINGLE ORAL DOSE
If the drug is given in an oral dosage form (e.g.,
tablet, capsule), the drug is generally absorbed
by first-order kinetics. Elimination of the drug
also follows the principles of first-order kinetics

65
 SINGLE ORAL DOSE

Barriers to
Gastrointestinal
Absorption

66
 SINGLE ORAL DOSE
a.) The following equation describes the
pharmacokinetics of first-order absorption and
elimination:

kA = first-order absorption rate constant

F = fraction of drug bioavailable.
Changes in F, D0, VD, kA, and k affect the plasma drug concentration.
67
 SINGLE ORAL DOSE
b.) The time for maximum, or peak, drug
absorption is given by the following equations:

tmax depends only on the rate constants kA and k, not

on F, D0, or VD.

68
 SINGLE ORAL DOSE
Significance of peak time:
The peak time can be used:

- to determine comparative bioavailability and/or

bioequivalence
- to determine the preferred route of drug
administration and the desired dosage form for
the patient
- to assess the onset of action.
69
 SINGLE ORAL DOSE
Significance of peak time:
The peak time can be used:

- to determine comparative bioavailability and/ or

bioequivalence
- to determine the preferred route of drug
administration and the desired dosage form for the
patient
- to assess the onset of action.
70
 SINGLE ORAL DOSE
c.) After tmax is obtained, the peak drug
concentration (Cmax) is calculated as:

F D0 ka
Cmax =
VD (ka – k) (e - k tmax - e - ka tmax)

71
 SINGLE ORAL DOSE
Significance of peak plasma concentration:
The peak plasma concentration:

- is one of the parameters used to determine the

comparative bioavailability and/or the bioequivalence
between two products (same and or different dosage
forms) but containing the same chemical entity or
therapeutic agent
- may be used to determine the superiority between two
different dosage forms or two different routes of
administration
- may correlate with the pharmacological effect of a drug.
72
 SINGLE ORAL DOSE

Rectilinear plots of plasma concentration (Cp) against time following the administration
of an identical dose of a drug via the oral or intramuscular (IM) extravascular routes to
show variation in time to peak concentration (tmax) and in onset of action.
73
 SINGLE ORAL DOSE
d.) The area under the curve (AUC) may be
determined the following equation:

changes in F, D0, k, and VD affect the AUC. Minor changes

in kA do not affect the AUC.

74
 SINGLE ORAL DOSE
d.) The apparent volume of distribution maybe
calculated by this formula:

Intercept = FDoka
VD (ka - k)
If F value is not given:
V = kaDo 1
F (ka – k) Intercept

75
 PRACTICE PROBLEMS

1.) A patient received a single 500-mg oral dose of a

bronchodilator that is completely absorbed after oral
administration and with an absorption rate constant of 0.693
hr-1, t1/2 of 4 hrs and VD of 0.185 L. The following plasma
concentration-time data were obtained:

76
 PRACTICE PROBLEMS

a.) Calculate the tmax after administration of a single

500-mg dose.
b.) Calculate the Cmax after administration of a single
500-mg dose.
c.) Calculate the ClT of this drug in mL/hr.

77
 PRACTICE PROBLEMS

a.) Calculate the tmax after administration of a single 500-mg

dose.

k = 0.693/4 = 0.17325/hr

tmax = 2.3 log (0.693/0.17325)

0.693 - 0.17325
tmax = 2.6677 hrs

78
 PRACTICE PROBLEMS

b.) Calculate the Cmax after administration of a single 500-mg

dose. F D0 ka
Cmax =
VD (ka – k) (e - k tmax - e - ka tmax)

Cmax = 225 (e-0.17325(2.6677) - e-0.693(2.6677))

Cmax = 106.32 mg/mL

79
 PRACTICE PROBLEMS

c.) Calculate the ClT of this drug in mL/hr.

ClT = kVD
= 0.17325/hr (185 mL)
= 32.05125 mL/hr

80
 INTRAVENOUS INFUSION
IV infusion allows precise control of plasma drug
concentrations to fit the individual needs of the
patient.

81
 INTRAVENOUS INFUSION

a.) Intravenous infusion is an example of zero-order

absorption and first-order elimination

82
 INTRAVENOUS INFUSION
b.) A few oral controlled-release drug products
release the drug by zero-order kinetics and have
zero-order systemic absorption.
c.) The plasma drug concentration at any time after
the start of an intravenous infusion is given by the
following equation:

R = is the zero-order rate of infusion given in units as

milligrams per hour or milligrams per minute.
83
 INTRAVENOUS INFUSION
d.) If the intravenous infusion is discontinued, the
plasma drug concentration declines by a first-order
process. The elimination half-life or elimination
rate constant, k, may be obtained from the
declining plasma drug concentration versus time
curve.

84
 INTRAVENOUS INFUSION
e.) As the drug is infused, the plasma drug
concentration increases to a plateau, or steady-
state concentration (Css).
1.) Under steady-state conditions, the fraction
of drug absorbed equals the fraction of
drug eliminated from the body.
2.) The plasma concentration at steady state
(Css) is given by the following equation:

85
INTRAVENOUS INFUSION
3.) The rate of drug infusion (R) may be
calculated from a rearrangement of the
equation if the desired Css, the VD, and the
k are known. These values can often be
obtained from the drug literature. To calculate
the rate of infusion, the following equation is
used:

Css is the desired (target) plasma drug concentration and ClT is

total body clearance. 86
 INTRAVENOUS INFUSION
f.) A loading dose (DL) is given as an initial
intravenous bolus dose to produce the Css as
rapidly as possible. The intravenous infusion is
started at the same time as the DL.
1.) The time to reach Css depends on the
elimination half-life of the drug.
t99%Css = ln 1%
-k

87
INTRAVENOUS INFUSION
2.) The DL is the amount of drug that, when
dissolved in the apparent VD, produces the
desired Css. Thus, DL is calculated by the
following equation:

88
 INTRAVENOUS INFUSION
g.) An intravenous infusion provides a relatively
constant plasma drug concentration and is
particularly useful for drugs that have a narrow
therapeutic range. The IV infusion keeps the
plasma drug concentration between the minimum
toxic concentration (MTC) and the minimum
effective concentration (MEC).

89
 PRACTICE PROBLEMS
1. An anticonvulsant drug was given as
(a) a single IV dose
(b) a constant IV infusion.
The serum drug concentrations are as
presented in:

90
PRACTICE PROBLEMS

91
 PRACTICE PROBLEMS
a.What is the steady-state plasma drug level?

The steady state level can be found by plotting

the IV infusion data. The plasma drug-time
curves plateau at 10 mcg/mL.

Half-life of 10 mcg/mL = 3.5 hr

92
 PRACTICE PROBLEMS
b. What is the time for 95% steady-state plasma
drug level?

t95%Css = ln 5%
-k
t95%Css = ln 0.05
- 0.2

t95%Css = - 2.9957
- 0.2

t95%Css = 15 hr
93
 PRACTICE PROBLEMS

c. What is the drug clearance?

ClT = VD k

VD = DB/CPO
= 1000 mcg
10 mcg/mL = 100 mL/kg

ClT = VD k
= 100 mL/kg x 0.2 hr-1
ClT = 20 mL/kg hr
94
 PRACTICE PROBLEMS
d. What is the plasma concentration of the drug
4 hours after stopping infusion? (Infusion was
stopped after 24 hours.)

CP = 9.9 e – (0.2) (4)

CP = 4.45 mcg/mL

95
 PRACTICE PROBLEMS
e. What is the infusion rate for a patient weighing 75 kg to
maintain a steady-state drug level of 10 mcg/mL?

The infusion rate to produce a CSS of 10 mcg/mL is

0.2 mg/kg per hour. Therefore, the infusion rate needed
for this patient is

R = CSS VD k = 10 mcg/mL (100 mL/kg) (0.2 hr-1)

= 200 mcg/kg/hr
= 0.2 mg/kg/hr
R = 0.2 mg/kg hr x 75 kg
R = 15 mg/hr
96
 PRACTICE PROBLEMS
f. What is the plasma drug concentration 4 hours after an IV
dose of 1 mg/kg followed by a constant infusion of 0.2
mg/kg per hour?

From the data shown, at 4 hours after the start of the IV

infusion, the drug concentration is 5.5 mcg/mL; the drug
concentration after an IV bolus of 1 mg/kg is 4.5 mcg/mL.
Therefore, if a 1-mg dose was given and the drug is then
infused at 0.2 mg/kg per hour, the plasma drug
concentration will be 4.5 + 5.5 = 10 mcg/mL.

97
 PRACTICE PROBLEMS
2.) A female patient (35 years old, 65 kg) with normal renal
function is to be given a drug by IV infusion.

According to the literature, the elimination half-life of this

drug is 7 hours and the apparent V D is 23.1% of body weight.
The pharmacokinetics of this drug assumes a first-order
process. The desired steady-state plasma level for this
antibiotic is 10 mcg/mL.

98
 PRACTICE PROBLEMS
b. What is the proper loading dose for this antibiotic in mg?
VD = 23.1% of 65 kg = 15 L
= (10 mcg/mL) (15,000 mL) = 150,000 mcg
= 150 mg
c. What is the proper infusion rate for this drug in mg/hr?
R = Css VD k
k = 0.693 / 7 hr = 0.099 hr-1
R = (10 mcg/mL) (15,000 mL) (0.099 hr-1)
= 14,850 mcg/hr
= 14.85 mg/hr
99
 PRACTICE PROBLEMS
d. What is the total body clearance?
ClT = VD k
= (15,000 mL) (0.099 hr-1)
= 1,485 mL/hr
e. If the patient suddenly develops partial renal failure,
how long would it take for a new steady-state plasma
level to be established (assume that 95% of the
CSS is a reasonable approximation)?
To establish a new Css will still take 4.32 t1/2.
However, the t1/2 will be longer in renal failure.
100
 PRACTICE PROBLEMS
f. If the total body clearance declined 50% due to
partial renal failure, what new infusion rate in mg/hr
would you recommend to maintain the desired
steady-state plasma level of 10 mcg/mL?
If ClT is decreased by 50%, then the infusion rate (R)
should be decreased proportionately:
R = CSS VD k ClT = VD k
R = [10 mcg/mL (0.50)] [(1,485 mL/hr)]
= 7425 mcg/hr
= 7.425 mg/hr
101
 PRACTICE PROBLEMS
3.) A patient received an anticancer drug by a constant-rate IV
infusion of 20 mg/hr. The IV infusion continued for 3 days,
and after termination of the infusion, the half-life was 6 hr,
and the volume of distribution was 35 L.
a.) What is the elimination rate of this drug during the
infusion at steady-state?
At steady-state, RE = RA = 20 mg/hr
b.) What is the steady-state conc. during the infusion?
CSS = R = 20 mg/hr
k VD (0.1155 hr-1) (35 L)
CSS = 4.95 mg/L
102
 PRACTICE PROBLEMS
c.) What is the elimination rate constant of this drug?
k = 0.693 / t1/2
k = 0.1155 hr-1

d.) What is the steady-state concentration if a loading dose

of 200 mg was administered followed by the 20-mg/hr
infusion?

CSS is not affected by a change in loading dose. So, a

loading dose of 200 mg will still have a CSS of 4.95 mg/L.

103
 PRACTICE PROBLEMS
e.) What is the time required to reach 97% steady state if the
loading dose was not administered?
t97%Css = ln 3%
-k
t97%Css = ln 0.03
- 0.1155

t97%Css = - 3.506558
- 0.1155
t97%Css = 30 hr
104
 PRACTICE PROBLEMS
f.) What is the steady-state concentration if the infusion rate
rate was 40 mg/hr?

CSS = R = 40 mg/hr
k VD (0.1155 hr-1) (35 L)

CSS = 9.9 mg/L

105
 INTERMITTENT INTRAVENOUS
INFUSIONS
a.) Intermittent intravenous infusions are infusions
in which the drug is infused for short periods to
prevent accumulation and toxicity

106
 INTERMITTENT INTRAVENOUS
INFUSIONS
b.) Intermittent intravenous infusions are used for
a few drugs, such as the aminoglycosides. For
example, gentamicin may be given as a 1-hr
infusion every 12 hrs. In this case, steady-state
drug concentrations are not achieved.

107
 INTERMITTENT INTRAVENOUS
INFUSIONS
c.) The peak drug concentration in the plasma for a
drug given by intermittent intravenous infusion
may be calculated by the following equation:

Cp,n = peak drug concentration k = dosage interval

R = rate of drug infusion n = number of infusions
Cl = total body clearance t = time for the infusion, and
Ƭ = is the dosage interval. 108
 INTERMITTENT INTRAVENOUS
INFUSIONS
Administering of One Dose for Continuous IV infusion:

Administering of More and Short IV Infusions:

109
 INTERMITTENT INTRAVENOUS
INFUSIONS
After the IV infusion is stopped:

Cstop = concentration when infusion stops

t = time elapsed since infusion stopped

110
 INTERMITTENT INTRAVENOUS
INFUSIONS
Practice Problem:

1.) Gentamicin sulfate was given to an adult male patient

(57 years old, 70 kg) by intermittent IV infusions. One-hour IV
infusions of 90 mg of gentamicin was given at 8-hour
intervals. Gentamicin clearance is similar to creatinine
clearance and was estimated as 7.2 L/hr with an elimination
half-life of 3 hours.

111
 INTERMITTENT INTRAVENOUS
INFUSIONS
a.) What is the plasma drug concentration after the
first IV Infusion?

b.) What is the peak plasma drug concentration, ,

and the trough plasma drug concentration, , at
steady state?

112
 INTERMITTENT INTRAVENOUS
INFUSIONS
a.) What is the plasma drug concentration after the
first IV Infusion?

Cp = 90 mg/hr( 1 – e-0.23(1)) = 2.58 mg/L

7.2 L/hr

113
 INTERMITTENT INTRAVENOUS
INFUSIONS
b.) What is the peak plasma drug concentration, Cpk ( ),
and the trough plasma drug concentration, , at steady
state?

Cpk = 90 (1 – e-0.231(1)) 1
7.2 (1 – e-0.231(8))
Cpk = 3.06 mg/L

114
 INTERMITTENT INTRAVENOUS
INFUSIONS
b.) What is the peak plasma drug concentration, Cpk ( ),
and the trough plasma drug concentration,
, at steady state?
= R (1 – e-ktinf) e-kƬ
Cl (1 – e-kƬ)
= 90 (1 – e-0.231(1)) e-0.231(8)
7.2 (1 – e-0.231(8))
Cmin = 0.48 mg/L
115
 MULTIPLE DOSES
Many drugs are given intermittently in a multiple-
dose regimen for continuous or prolonged
therapeutic activity. This regimen is often used to
treat chronic disease.
a.) If drug doses are given frequently before
the previous dose is completely eliminated,
then plasma drug concentrations
accumulate and increase to a steady-state
level.
116
 MULTIPLE DOSES
b.) At steady state, plasma drug concentration
fluctuates between a maximum
and a minimum value.
As repetitive equal doses are given at a
constant frequency, the plasma level-time
curve plateaus and a steady-state is
obtained. Once steady-state is reached,
and are constant and remain
unchanged from dose to dose. Also, the
AUC is constant during a dosing interval at
steady-state.
117
MULTIPLE DOSES

118
 MULTIPLE DOSES

c.) When a multiple-dose regimen is

calculated, the superposition principle
assumes that previous drug doses have no
effect on subsequent doses. Thus, the
predicted plasma drug concentration is the
total plasma drug concentration obtained
by adding the residual drug concentrations
found after each previous dose.

119
 MULTIPLE DOSES

d.) When a multiple-dose regimen is designed,

only the dosing rate (D0/Ƭ) can be adjusted
easily.
1.) The dosing rate is based on the size of
the dose (D0) and the interval (Ƭ)
between doses, or the frequency of
dosing.

120
 MULTIPLE DOSES

2.) The dosing rate is given by the

following equation:

3.) As long as the dosing rate is the same,

the expected average drug
concentration at steady state ( )
is the same.
121
 MULTIPLE DOSES
3.)
a.) For example, if a 600-mg dose is given
every 12 hrs, the dosing rate is
600 mg/12 hrs, or 50 mg/hr.
b.) A dose of 300 mg every 6 hrs or 200 mg
every 4 hrs also gives the same dosing rate
(50 mg/hr), with the same expected
. However, the and
values will be different.
122
 MULTIPLE DOSES
3.)
c.) For a larger dose given over a longer
interval (e.g., 600 mg every 12 hrs), the
is higher and the is lower
compared with a smaller dose given more
frequently (e.g., 200 mg every 4 hrs).

123
 MULTIPLE DOSES

e.) Certain antibiotics are given by multiple

rapid intravenous bolus injections.
1.) The peak, or maximum, serum drug
concentration at steady state may be
estimated by the following equation:

124
 MULTIPLE DOSES

2.) The minimum serum drug

concentration ( ) at steady state is
the drug concentration after the drug
declines one dosage interval. Thus,
is determined by the following
equation:

125
 MULTIPLE DOSES

3.) The average drug concentration ( )

at steady state is estimated with the
equation used for multiple oral doses:

For intravenous bolus injections, F = 1

126
 MULTIPLE DOSES

f.) Orally administered drugs given in

immediate-release dosage forms
(e.g., solutions, conventional tablets,
capsules) by multiple oral doses are usually
rapidly absorbed (kA > k) and slowly
eliminated. and for these
drugs are approximated by the equations:

127
 MULTIPLE DOSES

f.)
1.) For more exact calculations of and
after multiple oral doses, the following
equations are used:

128
 MULTIPLE DOSES

f.)
2.) The calculation of is the same as for
multiple intravenous bolus injections,
using the equation below:

129
 MULTIPLE DOSES

f.)
3.) The term 1/(1 – e–kƬ ) is known as the
accumulation rate.

4.) The fraction of drug remaining in the body

( f ) after a dosage interval is given by the
following equation:

130
 MULTIPLE DOSES

g.) Loading dose. An initial loading dose (DL) is

given to obtain a therapeutic steady-state drug
level quickly.
1.) For multiple oral doses, DL is calculated by:

DM = Maintenance Dose
131
 MULTIPLE DOSES

2.) If DM is given at a dosage interval equal to

the elimination half-life of the drug, then
DL equals twice the maintenance dose.

DL = 2(DM)

DM = Cl (Ƭ)
(S)(F)
132
 MULTIPLE DOSES
Practice Problems:
1.) The elimination half-life of an antibiotic is 3
hours and the apparent volume of distribution is
20% of the body weight. The therapeutic window
for this drug is from 2 to 10 µg/mL. Adverse toxicity
is often observed at drug concentrations above
15 µg/mL. The drug will be given by multiple IV
bolus injections.

133
 MULTIPLE DOSES
a.) Calculate the dose for an adult male patient
(68 yrs old, 82 kg) with normal renal function to
be given every 8 hours.
b.) Calculate the anticipated and
values.
c.) Calculate the value.
d.) Comment on the adequacy of your dosage
regimen.

134
 MULTIPLE DOSES
a.) Calculate the dose for an adult male patient (68 yrs old, 82 kg)
with normal renal function to be given every 8 hours.

Do = (1 – e-kƬ) VD = 20% of 82 = 16.4 L

VD
k = 0.693/3 = 0.231 hr-1
Do = VD (1 – e-kƬ)

Do = 16.4 L (10) (1 – e-0.231(8))

Do = 138.16 mg q8hrs
135
 MULTIPLE DOSES
b.) Calculate the anticipated and values.

(10) (e –( 0.231)(8))

1.58 mg/L

136
 MULTIPLE DOSES
c.) Calculate the value.

= 138.16
(0.231) (16.4) (8)

= 4.56 mg/L

137
 MULTIPLE DOSES
d.) In the above dosage regimen, the of 1.58 mg/L is below
the desired of 2 mg/L.

Suggestion: Change the dosage interval to 6 hours.

Do = VD (1 – e-kƬ)

Do = 16.4 L (10) (1 – e-0.231(6))

Do = 123 mg q6hrs

138
 MULTIPLE DOSES

(10) (e –( 0.231)(6)) = 138.16

2.5 mg/L (0.231)(16.4)(6)
= 5.41 mg/L

139
 MULTIPLE DOSES
2.) Tetracycline HCl (Achromycin), 500 mg, is prescribed for a
young adult male patient 28 yrs old, 78 kg) suffering from
gonorrhea. According to the literature, Tetracycline HCl is 77%
orally absorbed, is 65% bound to plasma proteins, has an
average steady-state concentration of 27.5 mg/L, apparent
volume of distribution of 0.5 L/kg, has an elimination half-life
of 10.6 hours, and is 58% excreted unchanged in the urine.
The minimum inhibitory drug concentration (MIC) for
gonorrhea is 25 to 30 µg/mL.

140
 MULTIPLE DOSES
a.) Calculate the exact maintenance dose for this patient to
be given every 6 hours around the clock.

b.) Achromycin is available in 250-mg and 500-mg capsules.

How many capsules (state dose) should the patient take
every 6 hours?

c.) What loading dose using the above capsules would you
recommend for this patient?

141
 MULTIPLE DOSES
a.) Calculate the exact maintenance dose for this patient to
be given every 6 hours around the clock.

b.) Achromycin is available in 250-mg and 500-mg capsules.

How many capsules (state dose) should the patient take
every 6 hours?

c.) What loading dose using the above capsules would you
recommend for this patient?

142
 MULTIPLE DOSES
a.) Calculate the exact maintenance dose for this patient to
be given every 6 hours around the clock.

Cl = k VD
= 0.0654/hr (39 L)
DM = 2.5497 L/hr (27.5 mg/L) (6 hr) = 2.5497 L/hr
0.77 VD = 0.5 L/kg (78 kg)
DM = 546 mg q6hr = 39 L
k = 0.693
10.6 hrs
= 0.0654/hr
143
 Aminophylline

Theophylline + EDTA
80% 20%

144
 MULTIPLE DOSES
b.) Achromycin is available in 250-mg and 500-mg capsules.
How many capsules (state dose) should the patient take
every 6 hours?

For 250 mg = 2 capsules q6hr

For 500 mg = 1 capsule q6hr

145
 MULTIPLE DOSES
c.) What loading dose using the above capsules would you
recommend for this patient?

1
DL = 500
1 – e-0.0654(6)

DL = 1540 mg

DL = 3 x 500 mg cap = 1500 mg

146
 MULTIPLE DOSES
3.) What is the loading dose for an antibiotic (k = 0.23 hr-1)
with a maintenance dose of 200 mg every 3 hours?
DL = DM
or 1 – e-kƬ

DL = 200
1 – e-0.23(3)
DL = 401 mg = 400 mg

147
THANK YOU FOR
LISTENING!

148