CHAPTER 5 I.V.

Infusion

Author: Michael Makoid and John Cobby

Reviewer: Phillip Vuchetich

OBJECTIVES
1. Given patient drug concentration and/or amount vs. time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters available ( V d , K, k m , k r ,
AUC , Clearance, MRT) from IV infusion data.
2. I.V. Infusion dosing for parent compounds
3. Plasma concentration vs. time profile analysis
4. Rate vs. time profile analysis
5. Professional communication of IV Infusion information
6. Computer aided instruction and simulation
7. Metabolite (active vs. inactive)

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I.V. Infusion

5.1 Parent compound

5.1.1 PLASMA
Valid equations:

Q – Kt
C p = -------------- ( 1 – e ) or (EQ 5-1)
K ⋅ Vd

Dose – Kt
-( 1 – e )
C p = -------------------------------------- (EQ 5-2)
K ⋅ Vd ⋅ T infusion
at any time during the infusion

Q
( C p )ss = -------------- (EQ 5-3)
K ⋅ Vd
at steady state (t is long)

– Kt
C p = C p( term ) ⋅ e (EQ 5-4)

after termination of infusion

Where C p is the plasma concentration

Dose is the infusion rate shown in equation 5-1 and equation 5-2.
Q = -------------------
T infusion

Q – Kt infusion
C p( term ) = -------------- ( 1 – e ) is the plasma concentration when the
K ⋅ Vd
infusion is stopped.

Rewriting equation 5-4 to an equation which may be used by a computer results in:

Q - ( e – K ⋅ T∗ – e – K ⋅ T )
Cp = ----------- (EQ 5-5)
K⋅V

where T∗ = ( T – T i v ) for ( T > T iv )

and T∗ = 0 for ( T < T iv ) .

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I.V. Infusion

Using The Scientist@‘s Unit function makes the change in T∗ straight forward. In
The Scientist@, Unit(+) = 1 and Unit(-) = 0, so defining T∗ = ( T – T iv ) ⋅ UNIT ( T – Ti v )
meets these needs.

This equation is utilized in The Scientist@’s companion product PKAnalyst@ also

by MicroMath. Since the route of administration is an infusion and we would
know how much we gave (Dose), how fast we gave it (Q), and over how long the
infusion lasted (Tiv), the only other variables in the equation are K and Vd. PKAn-

alyst asks for Tiv and yields DoverV ( Dose

------------- ) and K as parameters resulting from
Vd

non-linear regression analysis. Dividing Dose by Dose

------------- yields Vd.
Vd

Utilization: You should be able to determine the infusion rate necessary to obtain a desired
plasma concentration. Rearranging equation 5-3 results in:

K ⋅ V d ⋅ ( C p )ss = Q (EQ 5-6)

You should be able to determine how long it would take to get to a desired plasma
concentration. Using equation 5-1 and equation 5-3, it looks like it will take for-
ever to get exactly to steady state because in order for
Q = --------------
Q ( 1 – e – Kt ) , e – Kt → 0 which occurs when t = ∞ . So,
( C p )ss = --------------
K ⋅ Vd K ⋅ Vd
how close is close enough? If ( C p ) = 0.95 ⋅ ( C p )ss , that’s good enough in most
people’s estimation. So in order to find out how long it will take we use equation
5-1, setting ( C p ) = 0.95 ⋅ ( C p )ss and solve for time. Thus:

Q ( 1 – e – Kt ) which results in
( C p ) = 0.95 ⋅ ( C p )ss = --------------
K ⋅ Vd

– Kt
0.95 = ( 1 – e )

– Kt
0.95 – 1 = – e

ln ( 0.05 ) = – Kt

– 2.996 = – Kt

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I.V. Infusion

–----------------
2.996 = t
–K

2.996
-------------t 1--- = 4.32t 1--- = t , (EQ 5-7)
0.693 2 2

or about 4.32 half lives to get to 95% of steady state. Generalizing, then, the num-
ber of half-lives it takes to get to steady-state is equal to the logarithm of the
inverse of how close is close (in this case, 5% or 0.05 = 20) devided by the loga-
rithm of two.
Changing infusion rates: Occasionally, it is necessary to change infusion rates to stabilize the patient. If a
patient were started on an infusion rate, Q1, and then at some subsequent time,
T>T*, the infusion rate was changed to Q2, the equation for the concentration after
the change would be:

Q1 – ( K ⋅ T∗ ) – ( k ⋅ ( T – T∗ ) ) Q2 - ⋅ ( 1 – e – ( k ⋅ ( T – T∗ ) ) )
Cp = ------------ ⋅ ( 1 – e )⋅e + ----------- (EQ 5-8)
K⋅V K⋅V

Assuming equilibrium was reached at infusion rate Q1, we could simplify equation
5-8 by setting T = 0 at the time of the rate change (thus we would be interested in
the time after the change) resulting in:

Q1 –k ⋅ T Q2 –k ⋅ T
-⋅e
Cp = ----------- + ------------ ⋅ ( 1 – e ) (EQ 5-9)
K⋅V K⋅V

Under these conditions, it would be useful to determine the time to reach the new
equilibrium. As before, within 5% is close enough. Thus if we are coming down
Q2- and if we were
(lowering the Cp, i.e. Q2 < Q1), we would want Cp = 1.05 -----------
K⋅V
Q2 . Taking
going up (raising the Cp, i.e. Q2 > Q1), we would want Cp = 0.95 -----------
-
K⋅V
the first condition we find:

Q2 Q1 –k ⋅ T Q2 - ⋅ ( 1 – e – k ⋅ T )
Cp = 1.05 ------------ = ------------ ⋅ e + ----------- (EQ 5-10)
K⋅V K⋅V K⋅V

Rearranging and solving for T results in:

⋅ Q2
ln  0.05
----------------------
Q1 – Q2 
T = ---------------------------------- (EQ 5-11)
–K

Similarly, under the second condition, we would find:

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I.V. Infusion

0.05 ⋅ Q2
ln  –-------------------------
Q1 – Q2 
T = ------------------------------------- (EQ 5-12)
–K
Combining equation 5-11 and equation 5-12 and rearranging results in:

ln  -----------------------
Q1 – Q2- ⋅ 20 ln  ----------------------- Q1 – Q2- ⋅ 20
Q2   Q2 
T = ---------------------------------------------- = ---------------------------------------------- ⋅ t 1 ⁄ 2 (EQ 5-13)
K 0.693
Thus it is the absolute value of the difference of the two rates and the elimination
rate constant which determine the length of time needed to establish a new equilib-
rium. Under the conditions of Q1 = 0 , that is no previous infusion, and the dif-
ference is maximal equation 5-13 simplifies to equation 5-7. Under the conditions
of Q1 = Q2 , the equation is undifined and has no utility (as well as makes no
sense, because the equation was designed to be used when there was a change in
rate.) However, lim T = 0 , thus no change results in zero time to get to the new
Q2 → Q1
equilibium. Similar to equation 5-7 as before, the generalization for the number of
half-lives it takes to obtain the new steady-state is the logarithm of (the fractional
difference of the rates (or the steady-state concentrations) times the inverse of how
close is close) devided by the logarithm of two.
As pharmacokinetic equations are additive, you should be able to determine a
loading dose (by I.V. bolus, for example) and a maintenance dose (infusion rate)
for a patient to extablish an equilibrium. If, for example, you want to give a load-
ing dose followed by an IV infusion, the generalization for the number of half-
lives it takes to obtain the new steady-state is the logarithm of (the fractional dif-
ference of the concentrations, Cp0 and Cpss, times the inverse of how close is
close) devided by the logarithm of two.

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I.V. Infusion

Discussion: IV infusion is a controlled way to get drug into your patient. Using patient popula-
tion average pharmacokinetic parameters (K, Vd) available in the drug mono-
graphs, you are able to make a professional judgement about:
1. the plasma concentration that you would like to achieve (from therapeutic range) and the time in
which you would like to get there.
2. the infusion rate necessary to get to the target concentration, and
3. the time necessary to to get there.

Example: Using As an example, theophylline is a bronchodilator used in asthma with a therapeutic

population average range of 10 to 20 mg/L, a volume of distribution of 0.45 (0.3 - 0.7) L/kg and a half
pharmacokinetic life of about 8 (6 - 13) hours for a non-smoking adult. Your patient weighs 200
parameters to make
pounds and meets these these criteria. The physician decides to maintain him at 15
professional judgements.
mg/L. What do you do?

Using population average parameters for K and Vd, equation 5-6 results in:

 0.693 - ⋅  0.45 ----- kg - ⋅ 200 lb ⋅  15 mg

L- ⋅ -------------  = 53.2mg
 ------------   ------- ------- .
8 hr   kg 2.2 lb L hr

For an eight hour IV infusion, you would need

53.2 mg
------- ⋅ 8 hr = 425 mg of theophylline.
hr

IV Theophylline comes as aminophylline which is theophylline compound con-

taining 85% theophylline and 15% ethylenediamine. So in order to get 425 mg of
theophylline we have to give
100 mg aminophylline
425 mg theophylline ⋅ ------------------------------------------------------ = 500 mg aminophylline . So we
85 mg theophylline
prepare our IV infusion using Aminophylline U.S.P. for injection (500 mg amino-
phylline in 20 mL) by placing the contents of the ampule in 1000 mL of D5W and
calculate the drip rate using an adult IV administration set which regulates the drip
to 10 gtts/mL. Thus the drip rate is:

1020 ml- ⋅ ----------------

hr - ⋅ 10 gtts- ∼ 21 --------
gtts- ∼ --------------
7 gtts-
------------------- ---------------
8 hr 60 min ml min 20 sec

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I.V. Infusion

How long to get to steady After setting up the infusion, the doctor asks, “How long to steady state?
state?
Using equation 5-7, our patient who has an eight hour half life, will take about
4.32 ⋅ 8 hr = 34.6 hr to get to 95% of steady state. The patient doesn’t want
relief in a day and a half. He needs to breathe NOW. What would you suggest?
Infusion takes too long. It might be possible to give him an IV Bolus dose stat which would get him to
How do we get relief Dose-
now? IV Bolus stat. ( C p )ss right away. This is done by converting ( C p )ss = ------------ to
Vd
V d ⋅ ( C p ) ss = Dose .

 0.45 ----- kg - ⋅ 200 lb ⋅  15 mg

L- ⋅ ------------- ------- = 613.6 mg Theophylline
 kg 2.2 lb   L

Converting to aminophylline yields:

613.6 mg Theophylline ⋅ 100 mg aminophylline ∼ 725 mg aminophylline . Thus,
------------------------------------------------------
85 mg theophylline
if we gave a 725 mg IV bolus dose of aminophylline followed by a concomitant
IV infusion of 500 mg aminophylline over 8 hours, our patient should get to
steady state right away and stay there.
Some protocols require Sometimes the physician might want to just increase the infusion rate (say double
starting with faster it for a short time, 2Q) to get to the target concentration faster and then just back
infusion, then changing the infusion down. If that is the protocol, the question becomes, “ How long do
to a slower one to get to
steady state faster.
you run the infusion in at the faster rate?” Thus:

Q 2Q – Kt – Kt
( C p )ss = -------------- = -------------- ( 1 – e ) which yields 1 = 2 ( 1 – e ) and so
K ⋅ Vd K ⋅ Vd
1 – Kt 1 – Kt
--- = 1 – e . Thus --- – 1 = – e . Taking the ln of both sides ln ( 0.5 ) = –Kt
2 2

ln ( 0.5 ) = 0.693
------------------ ------------- t 1--- = t 1--- = t or that it will take one half-life to get to the target
–K 0.693 2 2
plasma concentration (which is the Cpss obtained by the infusion rate of 1Q) if you
run the infusion at a faster rate, 2Q. So for your patient, you might suggest an
infusion of 1000 mg over 8 hours (2Q for one half life) to get to steady state
quickly and then back off to 500 mg over 8 hours for the second 8 hours.

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I.V. Infusion

Clearance: New Clearance ( Cl = K ⋅ Vd ) is a pharmacokinetic parameter which relates the fraction

pharmacokinetic
of the volume of distribution which is cleared of the drug per unit time. The vol-
parameter
ume of distribution is a mathematical construct which relates two knowns, the
Dose of the drug and the resultant Concentration. In linear kinetics, the Dose is
proportional to the Concentration. C ∝ D . The units of concentration are
Mass - while the units of dose are Mass. So the units of the proportionality con-
-------------------
Volume
stant must be volume in order for the equation to balance. Thus, the volume of dis-
tribution is a hypothetical volume and not necessarily a real volume or
physiological space. Consequently, clearance is the hypothetical volume of fluid
from which the drug is irreversibly removed per unit time. So equation 5-3 can be
rewritten:

Q-
( C p )ss = ----- (EQ 5-14)
Cl
How do we calculate and equation 5-14 can be rewritten to:
Clearance from IV infu-
sion data? Q -
Cl = -------------- (EQ 5-15)
( C p )ss

Thus, assuming steady state, the clearance can be calculated by dividing the infu-
sion rate by the resultant steady state plasma concentration.
How do we separate K Graphing equation 5-4 which relates the decline in plasma concentration after ces-
and Vd out of Clear- sation of the infusion, the resultant slope of the line yields - K, the elimination rate
ance? constant. Dividing the elimination rate constant, - K, obtained by equation 5-4 into
the clearance obtained by equation 5-15 results in the other necessary pharmacoki-
netic parameter, Vd.
How can we utilize the From our original model
rate of change of
plasma concentration to d
determine the pharma- X = Q – (K ⋅ X ) (EQ 5-16)
dt
cokinetic parameters, K
and Vd?
X- . Thus , V ⋅ C p = X . Rewriting equation 5-16 yields:
and Cp = ----- d
Vd

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I.V. Infusion

dCp Q- – K ⋅ C and rearranging and incorporating equation 5-1 yields

= ----- p
dt Vd
dCp Q- – K ⋅  --------------
Q  ( 1 – e – Kt ) which can be simplified to
= -----
dt Vd  K ⋅ Vd
dCp Q- – ----- Q- e – Kt or
Q- + -----
= -----
dt V d V d Vd

dC p Q- e – Kt
= ----- (EQ 5-17)
dt Vd

vs. t ( actually, ∇
dCp Cp
Thus a plot of ----------- vs. tmid exactly like we did in urinary
dt ∇t
rate graphs) of the ascending portion of the plasma profile would result in a
straight line with a slope of -K and an intercept of ----- Q- .
Vd

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I.V. Infusion

5.2 Problems
Equations needed for solving the problems:
1. k from the slope of the terminal portion of the graph of Cp vs. T

0.693
2. t 1 ⁄ 2 = ------------
-
k

3.
Q
Volume of distribution from Cp = -------------- ( 1 – e
– Kt
)
K ⋅ Vd

4. Clearance Cl = K ⋅ V d

5. You wish to maintain a plasma concentration of Cpss.

a. Calculate the infusion rate necessary to maintain

Cpss. Q = Cp ss ⋅ K ⋅ V d

b. Suggest a loading dose which would give you Cpss immediately.

Dose loading = Cp ss ⋅ V d
c. How long will it take to reach steady state?

T 95 = 4.32 ⋅ T 1 ⁄ 2
d. Find the plasma concentration if the infusion is discontinued at time = Tdc hours.

Q ( 1 – e – ( K ⋅ Tdc ) ) .
Cp dc = --------------
K ⋅ Vd
e. Find the plasma concentration Tpost hours after infusion is discontinued at time = Tdc hours.
– ( K ⋅ T post )
Cp post = Cp dc ⋅ e

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I.V. Infusion

Acyclovir (Problem 5 - 1)

Problem Submitted By: Maya Leicht AHFS 08:18.00 Antivirals

Problem Reviewed By: Vicki Long GPI: 1200001000 Antivirals
Laskin, O., "Clinical pharmacokinetics of acyclovir", Clinical Pharmacokinetics (1983), p. 187 - 201.

Acyclovir (225.21 g/Mole) is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppres-
sive therapy. In this study, patients were given varying doses of acyclovir over one hour by infusion. Acyclovir distrib-
utes uniformly into the plasma and tissues such that the plasma concentration is representative of tissue concentration.
Acyclovir is 30% metabolized and 70% renally excreted. The following data was obtained from an intravenous infu-
sion dose of 2.5 mg/kg over one hour where the patient weighed 70 kg.
PROBLEM TABLE 5 - 1. Acyclovir

 umol -
Plasma concentration
 ------------
L
Time (hours)
0 0
0.25 7
0.5 12
0.75 17
1 20
2 10
3 5
5 1

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Volume of distribution
4. Clearance

5. You wish to maintain a plasma concentration of 25 umol ⁄ L .

a. Calculate the infusion rate necessary to maintain a plasma concentration of 25 umol ⁄ L

b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.

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I.V. Infusion

“Acyclovir” on page 11

102
Concentration

101

100
0 1 2 3 4 5
Time

1. k = 0.751 hr-1 (from slope of graph).

2. t 1 ⁄ 2 = 0.923 hr (from slope of graph).

3. Volume of distribution = 26.2 L
4. Clearance = 19.67 l/hr

5. You wish to maintain a plasma concentration of 25 umol ⁄ L .

a. Calculate the infusion rate necessary to maintain a plasma concentration of 25 umol ⁄ L = 111 mg/hr
b. Suggest a loading dose for the patient which would give you Cpss immediately. 148 mg
c. How long will it take to reach steady state? 4 hr

d. Find the plasma concentration if the infusion is discontinued at time = 5 hours. = 25 umol ⁄ L

e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours. = 5.6 umol ⁄ L

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I.V. Infusion

Aminophylline (Problem 5 - 2)

Problem Submitted By: Maya Leicht AHFS 12:12.00 Sympathomimetics

Problem Reviewed By: Vicki Long GPI: 4430001000 Xanthine Sympathomimetic
Gilman, T., et al., "Estimation of theophylline clearance during intravenous aminophylline infusions", Journal of Pharmaceutical
Sciences (May 1985), p. 508 - 514.

Aminophylline is used in the treatment of bronchospasm. In this study, aminophylline was given by intravenous infu-
sion to patients with a mean weight of 75.7 kg. The doses given were chosen to maintain a between 10 -20 mg/L based
on desirable body weight. The doses were given at a rate of 0.5 mg/kg/hour (Theophylline) for 84 hr. The following
set of data was collected.
PROBLEM TABLE 5 - 2. Aminophylline

 mg 
Plasma concentration
 -------
L
Time (hours)
0 0.
6 5
12 8
24 11
30 11.6
36 12.0
48 12.4
54 12.5
66 12.6
72 12.8
84 12.8
88 9
92 6.4
96 4.6
100 3.2

From this data determine the following:

1. k 2. t1 ⁄ 2
3. Volume of distribution 4. Clearance
5. 6. You wish to maintain a plasma concentration of 15 mg/L in your patient.
a. Calculate the infusion rate necessary to maintain a plasma concentration of 15 mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.

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I.V. Infusion

“Aminophylline” on page 13
102
CONCENTRATION

101

0
10
0 20 40 60 80 100
Time

1. k = 0.085 hr-1
2. t 1 ⁄ 2 = 8.15 hr
3. Vd = 35.3 L
4. Cl = 3 L/hr

5a. Q = 45 mg/hr
5b. D L = 530 mg

ss
5c. t = 35 hr
95%
5d. C p = 5.2 mg/L

5e. C p = 4.4 mg/L

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I.V. Infusion

Carmustine (Problem 5 - 3)

Problem Submitted By: Maya Leicht AHFS 10:00.00 Antineoplastics

Problem Reviewed By: Vicki Long GPI: 2110201000 Antineoplastics, Nitrosoureas
Henner, W., et al., "Pharmacokinetics and immediate effects of high-dose carmustine in man", Cancer Treatment Reports vol.70
(1986), p. 877 - 880.

Carmustine (BCNU) is an antineoplastic agent with a molecular weight of 214.04 g.

2
In this study a 70 kg, 1.8 M2 patient was given 600 mg ⁄ m by intravenous infusion over 2 hours. The following data
was obtained.
PROBLEM TABLE 5 - 3. Carmustine

mg
Plasma concentration -------
Time (minutes) L
15 .3
30 .5
60 .7
90 .75
120 .8
135 .5
142.5 .4
150 .3

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4 Cl
2
5. A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma

concentration of 2 uM . Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 2 uM .

b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 10 minutes.
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 minutes.

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I.V. Infusion

“Carmustine” on page 15

0
10
CONCENTRATION

-1
10
0 50 100 150

TIME

1. k = 0.031 min-1

2. t 1 ⁄ 2 = 22 min

3. Vd = 198 L/M2

4 Cl = 6.15 L/M2/hr
2
5. A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma

concentration of 2 uM . Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 2 uM .

Q = Cp ss ⋅ V d ⋅ K = 2µmole 214µg- ⋅ ------------------

mg - ⋅ ------------
198L ⋅ 1.8M 2 ⋅ 0.031min– 1 = 4.73mg
------------------- ⋅ --------------- ------------------ ∼ 285mg
-----------------
L µmole 1000µg M2 min hr

b. Suggest a loading dose for the patient which would give you Cpss immediately.
Dose = Cp ss ⋅ Vd = 2µmole 214µg- ⋅ ------------------
mg - ⋅ ------------
198L ⋅ 1.8M 2 = 150mg
------------------- ⋅ ---------------
L µmole 1000µg M 2

c. How long will it take to reach steady state? 4.32 * T 1/2 = 97 min.
d. Find the plasma concentration if the infusion is discontinued at time = 10 min. = 0.1197 mg/L
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 min. = 0.017 mg/L

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I.V. Infusion

Cefotaxime (Problem 5 - 4)

Problem Submitted By: Maya Leicht AHFS 08:12.06 Cephalosporins

Problem Reviewed By: Vicki Long GPI: 0230007510 Cephalosporins - 3rd Generation
Kearns, G., Young, R., and Jacobs, R., "Cefotaxime dosage in infants and children--pharmacokinetic and clinical rationale for an
extended dosage interval", Clinical Pharmacokinetics (1992), p. 284 - 297.

Cefotaxime is a third generation cephalosporin which is widely used as an antimicrobial in neonates, infants, and chil-
dren. In this study, infants and children were given a 50 mg/kg dose of cefotaxime intravenously over 0.25 hour. The
following data was collected:
PROBLEM TABLE 5 - 4. Cefotaxime

 mg 
Plasma concentration
 -------
L
Time (hours)
0.00 0
0.05 35
0.10 70
0.20 140
0.35 155
0.60 130
0.85 110
1.20 80
1.30 75
2.00 45
2.40 35
3.40 15
4.50 8
6.50 1.7

From this data, assuming that the patient weighs 30 kg, determine the following:
1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. You wish to maintain a plasma concentration of 80 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 80mg/L
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 0.25 hours.

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I.V. Infusion

e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.25 hours.
“Cefotaxime” on page 17
103
CONCENTRATION

102

101

100
0 1 2 3 4 5 6 7
TIME

1. k = 0.733 hr-1
2. t 1 ⁄ 2 = 0.945 hr
3. Vd = 0.276 L/kg
4. Cl = 0.202 L/kg/hr

4a. Q = 16.2 mg/kg/hr

4b. D L = 22.1 mg/kg

ss
4c. t = 4.1 hr
95%
4d. C p = 13.35 mg/L

4e. C p = 3.09 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-18

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I.V. Infusion

Ganciclovir (Problem 5 - 5)

Problem Submitted By: Maya Leicht AHFS 08:18.00 Antivirals

Problem Reviewed By: Vicki Long GPI: 1200002010 Antivirals
Trang, J., et al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections",
Clinical Pharmacology and Therapeutics (1993), p. 15 - 21.

Ganciclovir is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus infections of the
gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given 4 mg/kg of ganci-
clovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in the following
table:
PROBLEM TABLE 5 - 5. Ganciclovir

Plasma concentration  --------

ug
 mL
Time (hours)
0.5 3.10
1.5 4.50
2.0 3.80
3.0 2.90
4.0 2.30
6.0 1.50
8.0 0.88

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
4. A patient is to be given ganciclovir by IV infusion to an infant weighing 6.1 kg. You wish
to maintain a plasma concentration of 5.5 mcg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.5mcg/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.

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I.V. Infusion

“Ganciclovir” on page 19
10 1
CONCENTRATION

10 0

10-1
0 2 4 6 8
Time

1. k = 0.255 hr-1
2. t 1 ⁄ 2 = 2.72 hr
3. Vd = 0.687 L/kg
4. Cl = 0.175 L/kg/hr

1000ml ⋅  0.687L
Q = Cp ss ⋅ V d ⋅ K = 5.5µg - ⋅ 6.1kg ⋅ 0.255
mg - ⋅ ------------------
-------------- ⋅ ------------------ ------------- = 5.9mg
 ----------------
5a. ---------------
ml 1000µg L kg hr hr

1000ml ⋅  0.687L
D L = Cp ss ⋅ Vd = 5.5µg ----------------- ⋅ 6.1kg = 23mg
mg - ⋅ ------------------
5b. -------------- ⋅ ------------------
ml 1000µg L  kg 

ss
5c. T = 4.32 ⋅ t1 ⁄ 2 = 11.75hr
95%
5.9mg
---------------
Q hr – K ⋅ 1hr
) = 1.24mg
– Kt
5d. C p term = -------------- ( 1 – e ) = -----------------------------------------------------
- (1 – e ------------------
K ⋅ Vd 0.255
------------- ⋅ 0.687L L
----------------- ⋅ 6.1kg
hr kg
– K ⋅ 2hr
5e. C p = C p term ⋅ e = 1.24mg
------------------ ⋅ 0.6 = 0.74mg
------------------
L L

Basic Pharmacokinetics REV. 99.4.25 5-20

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I.V. Infusion

Gentamicin (Problem 5 - 6)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0700002010 Aminoglycosodes
Kaojarern, S., et al., "Dosing regimen of gentamicin during intermittent peritoneal dialysis", Journal of Clinical Pharmacology
(1989), p. 140 - 143.

Gentamicin is an aminoglycoside antibiotic which is frequently used in the treatment of gram-negative bacilli infec-
tions. Since it has a low therapeutic index, it is important to determine proper dosage regimens. In this study, patients
on peritoneal dialysis received a 30 minute intravenous infusion of 80 mg gentamicin in 100 mL of 5% dextrose in
water. The following data was collected:
PROBLEM TABLE 5 - 6. Gentamicin

 -------
ug 
Plasma concentration
 mL-
Time (hours)
0.50 5.68
1.50 5.15
3.70 4.80
7.35 3.99
11.30 3.35
24.00 2.02

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given gentamicin by IV infusion. You wish to maintain a plasma concentration
of 5.2 ug ⁄ mL . Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.2 ug ⁄ mL

b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 0.5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.5 hours.

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I.V. Infusion

“Gentamicin” on page 21
101
CONCENTRATION

100
0 5 10 15 20 25

Time

1. k = 0.0431 hr-1
2. t 1 ⁄ 2 = 16.1 hr

3. V d = 14.5 L
4. Cl =0.625 L/hr

5a. Q = 3.25 mg/hr

5b. D L = 75 mg

ss
5c. t = 69.6 hr
95%
5d. C p = 0.11 mg/L

5e. C p = 0.10 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-22

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I.V. Infusion

Human Monoclonal Anti-lipid A antibody (HA-1A) (Problem 5 - 7)

Problem Submitted By: Maya Leicht AHFS 24:06.00 Antilepemics

Problem Reviewed By: Vicki Long GPI: 3900000000 Antihyperlipidemic
Fisher, C., et al., "Initial evaluation of human monoclonal anti-lipid A antibody (HA-1A) in patients with sepsis syndrome", Criti-
cal Care Medicine (1990), Vol.18, No. 12, p. 1311 - 1315.

HA-1A is an immunoglobulin antibody. In this study, patients received a 250 mg intravenous infusion of HA-1A over
15 minutes. Serum levels were measured before and after infusion and the following data was collected:
PROBLEM TABLE 5 - 7. Human Monoclonal Anti-lipid A antibody (HA-1A)

Plasma concentration  -------

ug-
 mL
Time (hours)
0.00 0
0.75 80
1.00 75
2.00 74
5.00 65
15.00 50
25.00 40
48.00 21
72.00 10

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given HA-1A by IV infusion. You wish to maintain a plasma concentration of 100 µg/mL.
Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 100 ug ⁄ mL .

b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 3 hours after infusion is discontinued at time = 1 hour.

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I.V. Infusion

“Human Monoclonal Anti-lipid A antibody (HA-1A)” on page 23

102
CONCENTRATION

101
0 20 40 60 80
Time
1. k = 0.0282 hr-1
2. t 1 ⁄ 2 = 24.4 hr

3. V d = 3.2 L

4. Cl = 0.09 L/hr
5a. Q = 9 mg/hr
5b. D L = 320 mg

ss
5c. t = 105 hr
95%
5d. C p = 2.78 mg/L

5e. C p = 2.56 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-24

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I.V. Infusion

Ifosfamide (Problem 5 - 8)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Lewis, L., "The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients", British Journal
of Clinical Pharmacology Vol. 31 (1991), p. 77 - 82.

Ifosfamide is an agent which has shown some pharmacological response in the treatment of cancer. In this study, a 5
2 2
g⁄m dose of ifosfamide was infused over 30 minutes. The median BSA for the subjects was 1.8 m . The
following data was obtained:
PROBLEM TABLE 5 - 8. Ifosfamide

 -------
ug 
Plasma concentration
 mL-
Time (hours)
0 0.0
0.5 285.0
1 260.0
2 220.0
4 160.0
6 112.0
8 80.0
10 60.0
24 5

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl

5. A patient is to be given ifosfamide by IV infusion. The patient has a BSA 1.8 M2. You wish to maintain a
plasma concentration of 336 µg/mL. Determine the following:

a. Calculate the infusion rate necessary to maintain a plasma concentration of 336 ug ⁄ mL

b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 20 min.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 20min.

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I.V. Infusion

“Ifosfamide” on page 25
103

102
CONCENTRATION

101

100
0 5 10 15 20 25
Time

1. k = 0.1716 hr-1
2. t 1 ⁄ 2 = 4.04 hr

3. V d = 16.6 L/M2

4. Cl = 2.85 L/hr/M2
5a. Q = 1.725 g/hr
5b. D L = 10 g

ss
5c. t = 17.5
95%
5d. C p = 18.7 mg/L

5e. C p = 13.25 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-26

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I.V. Infusion

Isosorbide 5-mononitrate (Problem 5 - 9)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Major, R., et al., "Isosorbide 5-mononitrate kinetics" (1983), p. 653- 660.

Isosorbide 5-mononitrate (5-ISMN) is a metabolite of isosorbide dinitrate. In this study, the kinetics of isosorbide 5-
mononitrate were looked at in 12 healthy patients after an intravenous infusion of 20 mg at 8 mg/hour for 2.5 hours.
This drug follows one-compartment, open model kinetics. The following data was collected:
PROBLEM TABLE 5 - 9. Isosorbide 5-mononitrate

Time (hours) Plasma concentration (ng/mL)

0.25 40
0.50 91
0.75 141
1.00 181
1.50 239
2.00 305
2.50 351
3.00 335
3.50 303
4.50 257
5.50 216
7.50 162
9.50 117
11.50 77
14.50 47
18.50 24
26.50 7

From this data determine the following:

1. k 2. t1 ⁄ 2
3. Vd 4. Cl
5. A patient is to be given 5-ISMN by IV infusion. You wish to maintain a plasma concentration
of 300 ng/mL. If the volume of distribution of 5-ISMN is 44.5, determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 300 ng/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.

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I.V. Infusion

“Isosorbide 5-mononitrate” on page 27

103
CONCENTRATION

102

101

100
0 5 10 15 20 25 30

Time

1. k = 0.168 hr-1
2. t 1 ⁄ 2 = 4.125 hr

3. V d = 44.6 L

4. Cl = 7.5 L/hr
5a. Q = 2.25 mg/hr
5b. D L = 13.4 mg

ss
5c. t = 17.8 hr
95%
5d. C p = 46.4 ng/mL

5e. C p = 33.2 ng/mL

Basic Pharmacokinetics REV. 99.4.25 5-28

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I.V. Infusion

Moclobemide (Problem 5 - 10)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Schoerlin, M., et al., "Disposition kinetics of moclobemide a new MAO-A inhibitor, in subjects with impaired renal function", Jour-
nal of Clinical Pharmacology Vol 30 (1990), p. 272 - 284.

Moclobemide is reversibly inhibits the A-isozyme of the monoamine oxidase enzyme system. In this study, twelve
patients received a 96.7 mg dose as an intravenous infusion over 20 minutes. Blood samples were obtained during the
infusion and after the infusion was ended and the following data was obtained:
PROBLEM TABLE 5 - 10. Moclobemide

Time (hours) Plasma concentration (mg/L)

0.0 0.000
0.2 0.6
0.4 1
0.7 0.85
0.9 0.750
1.2 0.70
1.6 0.60
1.9 0.50
2.4 0.40
3.4 0.25
4.5 0.15
5.5 0.10
6.4 0.070

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given moclobemide by IV infusion. You wish to maintain a plasma concentration
of 1mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 1mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 15 min.

Basic Pharmacokinetics REV. 99.4.25 5-29

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I.V. Infusion

e. Find the plasma concentration 3 hours after infusion is discontinued at time = 15 mins.
“Moclobemide” on page 29
10 0
CONCENTRATION

10-1

10-2
0 1 2 3 4 5 6 7
Time

1. k = 0.44 hr-1
2. t 1 ⁄ 2 = 1.6 hr.

3. V d = 90.4 L

4. Cl = 39.8 L/hr
5a. Q = 40 mg/hr
5b. D L = 90 mg

ss
5c. t = 6.8 hr
95%
5d. C p = 0.1 mg/L

5e. C p = 0.028 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-30

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I.V. Infusion

Obidoxime (Problem 5 - 11)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Bentur, Y., et al., "Pharmacokinetics of obidoxime in organophosphate poisoning associated with renal failure", Clinical Toxicol-
ogy (1993), Vol. 31, p. 315 - 322.

Obidoxime is an agent which is used as an antidote in organophosphate poisoning. In this study, the pharmacokinetics
of obidoxime were studied in a 20 year old patient who attempted to commit suicide by ingesting Tamaron (60% meth-
amidophos, an organophosphate, in ethylene glycol monethyl ether). She was given 4 mg/kg Obidoxime by intrave-
nous infusion over 10 minutes and the following data was collected:
PROBLEM TABLE 5 - 11. Obidoxime

Time (minutes) Plasma concentration µg ⁄ mL

5 9
10 18
15 17
30 16
45 15
60 14
90 12
120 11
150 9.3
180 8
240 6.1
300 4.6

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given obidoxime by IV infusion. The patient has a body weight of 60 kg.
You wish to maintain a plasma concentration of 10 µg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 10 ug ⁄ mL .
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 30 minutes.

Basic Pharmacokinetics REV. 99.4.25 5-31

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I.V. Infusion

e. Find the plasma concentration 1 hour after infusion is discontinued at time = 30 minutes.
“Obidoxime” on page 31
102
CONCENTRATION

101

100
0 50 100 150 200 250 300
Time

1. k = 0.00463 min-1
2. t 1 ⁄ 2 = 150 min

3. V d = 0.22L/kg

4. Cl = 1 mL/min
5a. Q = 0.61 mg/min
5b. D L = 132 mg

ss
5c. t = 10.8 hr
95%
5d. C p = 1.3 mg/L

5e. C p = 0.98 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-32

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I.V. Infusion

Perindoprilat (Problem 5 - 12)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Macfadyen, R., Lees, K., and Reid, J., "Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normo-
tensive male volunteers", Journal of Pharmaceutical Sciences (1991), p. 115 - 121.

Perindoprilat and other ACE inhibitors are used in the management of hypertension and chronic congestive heart fail-
ure. In this study, a 1 mg dose was infused over a one hour period. The following data was collected:
PROBLEM TABLE 5 - 12. Perindoprilat

Time (minutes) Plasma concentration ng ⁄ mL

5 4.0
10 9.0
20 16.0
30 24.0
40 30.0
50 36.0
60 42.0
65 40.0
70 38.0
80 35.0
90 32.0
100 29.0
110 27.0
120 24.0

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given perindoprilat by IV infusion. You wish to maintain a plasma concentration
of 30 ng/ml. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 30 ng/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.

Basic Pharmacokinetics REV. 99.4.25 5-33

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I.V. Infusion

e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.
“Perindoprilat” on page 33

102
CONCENTRATION

101

100
0 20 40 60 80 100 120
Time

1. k = 0.0087 min-1
2. t 1 ⁄ 2 = 79.6 min

3. V d = 18.9 L

4. Cl =164 mL/min
5a. Q = 5 µg/min
5b. D L = 0.57 mg

ss
5c. t = 5.73 hr
95%
5d. C p = 27.8 ng/mL

5e. C p = 9.8 ng/mL

Basic Pharmacokinetics REV. 99.4.25 5-34

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I.V. Infusion

Sulfonamides (Problem 5 - 13)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Boddy, A., Edwards, P., and Rowland, M., "Binding of sulfonamides to carbonic anhydrase: influence on distribution within blood
and on pharmacokinetics", Pharmaceutical Research (1989), p. 203- 209

This study looks at the affinity of sulfonamides for carbonic anhydrase. Doses of 8 micromoles/kg were administered
via the jugular vein cannula in approximately 0.5 mL of PEG 400 over 5 minutes at a constant rate. Samples were col-
lected during the infusion period and for 30 minutes afterward. The following set of data was collected:
PROBLEM TABLE 5 - 13. Sulfonamides

Time (minutes) Plasma concentration ( µM )

2.0 17.0
4.0 31.0
5.0 37.0
7.5 32.0
9.0 28.0
12.0 22.5
15.0 18.0
18.0 14.0
23.0 11.0
30.0 6.5
35.0 4.5

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A 70-kg patient is to be given a sulfonamide by IV infusion. You wish to maintain a plasma
concentration of 30 µM. Determine the following:
a. Calculate the infusion rate which would be necessary to maintain the plasma concentra-
tion of 30 µM.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 4 hours.

Basic Pharmacokinetics REV. 99.4.25 5-35

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I.V. Infusion

e. Find the plasma concentration 30 minutes after stopping infusion at time = 4 hours.
“Sulfonamides” on page 35

102
CONCENTRATION

101

100
0 5 10 15 20 25 30 35

Time

1. k = 0.0705 min-1
2. t 1 ⁄ 2 = 9.8 min

3. V d = 0.18 L/kg

4. Cl = 12.7 mL/min/kg
5a. Q = 26.9 µmole/min
5b. D L = 380 µmole

ss
5c. t = 42 min
95%
5d. C p = 30 µmole/L

5e. C p = 3.6 µmole/L

Basic Pharmacokinetics REV. 99.4.25 5-36

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I.V. Infusion

Terodiline (Problem 5 - 14)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Hallen, B. ,et al., "Bioavailability and disposition of terodiline in man", Journal of Pharmaceutical Sciences (1994), p. 1241 -
1246.

Terodiline is an agent which works as an anticholinergic and a calcium antagonist. It is used to treat incontinence. It
is metabolized into p-Hydroxyterodiline, which is further metabolized to 3,4-dihydroxyterodiline. The parent drug and
all of its metabolites are excreted into the urine as well as the feces. A patient is given 12.5 mg of Terodiline by IV
infusion at a rate of 1 mL/ minute for 5 minutes. The following data is collected:
PROBLEM TABLE 5 - 14. Terodiline

Time (hours) Plasma concentration µg ⁄ L

25.000 31
50.000 23
75.000 15
100.000 12
125.000 8
150.000 6
175.000 4
200.000 3
225.000 2

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given terodiline by IV infusion. You wish to maintain a plasma concentration
of 40 mcg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of40 mcg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion ended at
time = 5 hours.

Basic Pharmacokinetics REV. 99.4.25 5-37

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I.V. Infusion

“Terodiline” on page 37

102
CONCENTRATION

101

100
0 50 100 150 200 250

Time

1. k = 0.0136 hr-1
2. t 1 ⁄ 2 = 50.9 hr

3. V d = 283 L

4. Cl =3.85 L/hr
5a. Q = 0.154 mg / hr
5b. D L = 11.32 mg

ss
5c. t = 220 hr
95%
5d. C p = 2.63 µg/L

5e. C p = 2.56 µg/L

Basic Pharmacokinetics REV. 99.4.25 5-38

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Tinidazole (Problem 5 - 15)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Robson, R., Bailey, R., and Sharman, J., "Tinidazole pharmacokinetics in severe renal failure", Clinical Pharmacokinetics (1984),
p. 88 - 94.

Tinidazole is an antimicrobial similar to metronidazole which is used in the treatment of trichomoniasis, giardiasis,
amoebiasis, and anaerobic infections. This study focuses on the pharmacokinetics of tinidazole in patients suffering
from severe renal failure. Twelve patients received 800 mg of tinidazole dissolved in 400 mL of dextrose monohydrate
solution as an intravenous infusion at a rate of 60 mg/min. Blood samples were taken and the following data was
obtained:
PROBLEM TABLE 5 - 15. Tinidazole

Time (hours) Plasma concentration (mg/L)

1 14.9
3 13.1
6 11.2
12 8.9
24 5.1
48 2.1

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given tinidazole by IV infusion. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 25 mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion was stopped
at time = 1 hour.

Basic Pharmacokinetics REV. 99.4.25 5-39

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I.V. Infusion

“Tinidazole” on page 39

102
CONCENTRATION

101

100
0 10 20 30 40 50
Time

1. k = 0.04136 hr-1
2. t 1 ⁄ 2 = 16.75 hr

3. V d = 54.7 L

4. Cl = 2.26 L/hr
5a. Q = 56.6 mg/hr
5b. D L = 1.37 g

ss
5c. t = 72.4 hr
95%
5d. C p = 1 mg/L

5e. C p = 0.93 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-40

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

Tobramycin (Problem 5 - 16)

Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0000000000
Cooney, G., et al., "Absolute bioavailability and absorption characteristics of aerosolized tobramycin in adults with cystic fibro-
sis", Journal of Clinical Pharmacology Vol. 34, (1994), p. 255- 259.

Most persons with cystic fibrosis (CF) become colonized with Pseudomonas aeruginosa in their bronchial secretions
within their second decade of life. These patients require frequent treatment with potent anti-pseudomonal antibiotics
such as Tobramycin. In this study, an intravenous infusion of 2.5 mg/kg tobramycin was given over 35 minutes. The
following data was collected:
PROBLEM TABLE 5 - 16. Tobramycin

 mg 
 -------
L
Plasma concentration
Time (minutes)
35 8.00
60 6.00
90 4.50
150 2.50
270 0.75

From this data determine the following:

1. k

2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given tobramycin by IV infusion. The patient has a body weight of 70 kg. You wish
to maintain a plasma concentration of 10 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 10 mg/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 30 minutes.
e. Find the plasma concentration 1 hour after stopping infusion if the infusion wasstopped at
time = 30 minutes.

Basic Pharmacokinetics REV. 99.4.25 5-41

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion

“Tobramycin” on page 41
101
CONCENTRATION

100

10-1
0 50 100 150 200 250 300

Time
1. k = 0.01 min-1
2. t 1 ⁄ 2 = 69.3 min

3. V d = 0.269 L/kg

4. Cl = 2.7 mL/min
5a. Q = 0.027mg/kg/min = 1.62 mg/kg/hr
5b. D L = 2.7 mg/kg

ss
5c. t = 300 min = 5 hr
95%
5d. C p = 2.6 mg/L

5e. C p = 1.43 mg/L

Basic Pharmacokinetics REV. 99.4.25 5-42

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/