PHPS 720 Pharmacokinetics Problem Set #10

Estimation of plasma drug levels after an IV loading dose

followed by a continuous IV infusion

You have seen that after starting a continuous infusion (any drug) steady-state will not

be attained until approximately 5 half-lives have passed (recall the progression: 50, 75,

87.5, 93.7, 96.9). This is a condition associated with any first-order elimination rate

process (although the drug administration is 0 – order, e.g., mg/h.)

As you have seen in the last PS, calculating the Cp value after an infusion is a straight-

forward calculation. In those cases where a loading dose in used, you will need to use

two equations if you want to determine the Cp values. For example, to calculate the

plasma level immediately after the administration of an IV bolus dose you would use

the equation you used in PS 6:

Dose
C p0 =
Vd (1)

Of course, if no other drug was given after the bolus dose, then you could predict the

plasma level at any future time by application of the “master” equation describing first-

order kinetics. Following the loading dose, the plasma level declines in an exponential

function. (You’ve been solving this problem all semester.)

C p,t =C p0 e- kt
(2)

If a continuous infusion is started, the plasma level at any time, t, can be simply

predicted by the following equation used in PS 9.

R0
C p,t =
CL
( 1 - e- kt )
(3)

© William M. Kolling, 2020. All rights reserved.

Now what would you do if asked to predict a future plasma level if the bolus dose was

followed by a continuous IV infusion of the same drug?

The answer to this problem is to consider the two independent processes that are

occurring simultaneously. A peak blood level is decaying via a first-order process

(RED loading dose) and a blood level is increasing as a result of the start of a

continuous infusion (BLUE infusion dose). The sum of the two processes (Black) is the

result.

So, the solution to this problem is to add the two equations together:

© William M. Kolling, 2020. All rights reserved.

 Dose - kt R0
C p,t =
Vd
e +
CL
(
1 - e- kt )
(4)

You can see that an appropriate LD immediately followed by the correct CI will result

in the targeted steady-state plasma concentration.

If a continuous infusion is started following the end of the loading infusion, the plasma

level is the sum of the two processes:

R0
C p,t =(C p,inf )e- kt +
CL
( 1 - e- kt ' )
(5)

Please note that there are three different values of time involved in equation (5). So you

obviously need to keep track of which t goes where. First, there is the value of t for the

length of time the loading dose infusion was administered over (t”). Second, there is

the value of t associated with the period of time that the loading infusion has been

stopped (t). Third, there is the value of t associated with the length of time that the

continuous infusion has been running (t’). We need to keep those parameters straight,

or we’re lost.

The full equation for a loading dose infusion followed by a continuous infusion is:

Dose
C p,t = t " (1- e- kt " )e- kt + R0 ( 1- e- kt ' )
CL CL (6)

Let’s look a little closer at loading doses administered via an infusion. If you calculate

the loading dose based on the target plasma level, then administering that dose with an

© William M. Kolling, 2020. All rights reserved.

infusion (equation (3)) will not result in the target Cp. Why? Because drug is cleared

while the solution is infused. You can use the McPherson graph to adjust the calculated

LD to account for the drug eliminated during the infusion. Dividing the calculated LD

by the y-axis coordinate will result in the new dose to be administered over the selected

infusion time. As a reminder, the x-axis in the McPherson graph is the ratio of the

Loading Dose infusion time

infusion time to the drug’s half life in that patient, Drug half-life .

Review the lecture slides if you need to refresh on how to use the McPherson graph.

Now, try the following problems.

1a) Calculate the bolus loading dose necessary to give a 30 kg patient (V d = 0.3 L/kg,
half-life = 3 h) a peak plasma level of 12 mg/L. (See PS 6) [108 mg]

1b) i) If the LD will be administered as an infusion over 30 minutes, what is the new
calculated dose? ii) 60 minutes? [112, 121 mg]

1c) Calculate the continuous infusion rate necessary to attain a steady-state plasma
level of 12 mg/L for the patient. [25 mg/h]

2a) Calculate the bolus loading dose necessary to give a 25 kg patient (V d = 0.5 L/kg,

ke = 0.099/h) a peak plasma level of 10 mcg/mL. [125 mg]

2b) i) If the LD will be administered as an infusion over 120 minutes, what is the new
calculated dose? ii) 180 minutes? [ 137, 144 mg]

© William M. Kolling, 2020. All rights reserved.

2c) Calculate the continuous infusion rate necessary to attain a steady-state plasma
level of 15 mg/L for the patient. [19 mg/h]

3) What is the benefit of giving a loading dose to a patient prior to the start of a
continuous infusion? [A properly calculated loading dose, given over an appropriate
period of time, will allow the targeted steady-state Cp to be reached immediately with
the start of the CI.]

4) A typical adult oral Azithromycin dosing schedule is 500 mg on day 1, followed by

250 mg on days 2 – 5. Why is the dose doubled on day 1? Look up the necessary PK
data on DailyMed to answer this Q.

5) A 30 kg pediatric patient (Vd = 0.5 L/kg, ke = 0.1/h) is given a 3 mg/kg loading dose
over 30 minutes. Immediately at the end of the loading dose, a continuous infusion of 1
mg/kg/h is started.
i) What Cp value is attained by the LD protocol? [5.8 mg/L]
ii) What steady-state plasma level will be attained on this therapy? [20 mg/L]
iii) After the LD, how long will it take to reach CpSS of 20 mg/L? [~ 35 hrs]
iv) Did the LD make a difference in this case? [No]
v) What LD should have been administered? [300 mg]
vi) If the LD infusion time is 1 h, what dose should be administered? [316 mg]
6) An 80 kg patient (Vd = 130 L, half-life = 95 min) is given a 650 mg loading dose over
30 minutes. Calculate Cp at the end of the LD. [4.5 mg/L]
At the end of the loading dose, a continuous infusion of 4.2 mg/min is started.
Calculate the steady-state plasma level. [4.4 mg/L]
How long would it have taken to reach SS for this patient without the LD? [~ 8 h]

7) A 57 kg patient (Vd = 0.43 L/kg, ke = 0.173/h) is admitted to the ER. The patient has
no drug in their system. Calculate the LD required to target a Cp = 20 mg/L. [490 mg]
If the LD is to be infused over 2 hours, what dose should be given? [580 mg]

© William M. Kolling, 2020. All rights reserved.

Calculate the required CI rate (mg/h). [85 mg/h]

8) An 110 kg patient (Vd = 1.6 L/kg, ke = 0.347/h) is given a 5 mg/kg loading dose over
45 minutes. At the end of the loading dose, a continuous infusion of 3 mg/min is
started. Calculate the plasma levels at steady-state. Did the LD help? [3 mg/L, Yes]

9) An 35 kg patient (Vd = 0.5 L/kg, ke = 0.126/h) is admitted to the ICU. Calculate the
LD required to target a Cp = 15 mg/L. The patient has a Cp = 6 mg/L at the time of
admission. [158 mg]
The LD is to be infused over 1 hour. What dose should be given? [168 mg]
Calculate the required CI rate (mg/h). [33 mg/h]

Let me make some comments on the administration of the loading dose. While it is

possible to administer the loading dose via a rapid IV push (bolus), the more common

scenario is to administer the loading dose via a short infusion. Recall from your

Pharmaceutics course during the discussion of parenteral products that there are

restrictions on vascular access in terms of volume, pH, and osmolarity. Usually, the

volume of the loading dose is not an issue. However, there may be constraints

depending on the pH of the solution. Any significant deviations from normal

physiologic pH will probably cause problems, either immediate pain, or vascular

irritation. More commonly, the problem is osmolarity. Depending on your site of

practice, the upper limit of osmolarity in a peripheral vein will probably be limited to

500 – 600 mOsm/L. It is a good idea at this point to review how to calculate the

osmolarity of an injectable solution.

© William M. Kolling, 2020. All rights reserved.