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Chapter 20

Non Compartmental Analysis


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Student Objectives for this Chapter

To understand and use the non compartmental approach to parameter estimation

be able to define, use, and calculate the parameters:


o AUMC (area under the first moment curve)
o MRT (mean residence time)
o MAT (mean absorption time)
o MDT (mean dissolution time)

Non Compartmental Analysis


Non compartmental methods can be used to determine certain pharmacokinetic parameters
without deciding on a particular compartmental model. The basic calculations are based on the
area under the plasma concentration versus times curve (zero moment) and the first moment
curve (AUMC). The AUC can be calculated as before using the trapezoidal rule. The first
moment is calculated as concentration times time (Cp t). The AUMC is the area under the
concentration times time versus time curve. Maybe best covered with an example. Consider a
drug given both by IV and oral administration. Both the AUC and AUMC were calculated using
the trapezoidal rule without making any assumption concerning the number of compartments.
The final segment of the AUC curve is calculated as Cp(last)/k', where k' is the last exponential
term (the slowest) calculated from the Cp versus time graph. The last segment for the AUMC
curve is:

Equation 20.1.1 Equation of the last segment AUMC

Table 20.1.1 Typical Cp versus Time Data after 100 mg IV


Bolus Administration
Time
Cp
Cp t
AUC
AUMC
(hr) (mg/L) (mg.hr/L)
(mg.hr/L)
(mg.hr2/L)
0
8
0
0
0
1
7.09
7.09
7.55
3.55
2
6.29
12.58
14.24
13.39
3
5.58
16.74
20.18
28.05
4
4.95
19.80
25.45
46.32
6
3.89
23.34
34.29
89.46
9
2.71
24.39
44.19
161.06
12
1.89
22.68
51.09
231.67
18
0.92
16.56
59.52
349.39
24
0.44
10.56
63.60
430.75

67.27
549.31

These data, Cp versus time and Cp x time versus time, can be plotted on linear graph.

Figure 20.1.1 Plot of Cp versus Time (IV)

Figure 20.1.2 Plot of Cp x Time versus Time (IV)

and various parameters can be calculated as:

Equation 20.1.2 Equation for Mean Residence Time (MRT)

Equation 20.1.3 Equation for Apparent Elimination Rate constant (kel')

Equation 20.1.4 Equation for Total Body Clearance (TBC)

Equation 20.1.5 Equation for Apparent Volume of Distribution, Steady State (Vss)
From the AUC and AUMC values we can calculate the mean residence time, MRT. This is the
average time that the drug stays in the body (or plasma as measured here). It can be related to the
average elimination rate constant as 1/MRT. The values from the above data are
MRT = 549.31/67.27 = 8.17 hr
and
kel' = 1/8.17 = 0.12 hr-1
Remember we can also calculate the clearance,
CL = Dose/AUC = 100/67.27 = 1.49 L.hr-1
Finally a steady state volume can be calculated as

Vss = CL MRT = 1.49 x 8.17 = 12.14 L

Oral data can be analyzed by these methods as well.


Table 20.1.2 Typical Cp versus Time Data after 250 mg Oral Administration
Time (hr) Cp (mg/L)
Cp t (mg.hr/L)
AUC (mg.hr/L)
AUMC (mg.hr2/L)
0
0
0
0
0
1
12.18
12.2
6.09
6.09
2
14.12
28.24
19.24
26.30
3
13.43
40.29
33.02
60.57
4
12.16
48.64
45.82
105.04
6
9.64
57.84
67.62
211.52
9
6.73
60.57
92.18
389.14
12
4.69
56.24
109.31
564.42
18
2.28
41.22
130.25
856.92
24
1.11
26.64
140.45
1060.50

149.70
1359.58
These data, Cp versus time and Cp x time versus time, can be plotted on linear graph.

Figure 20.1.3 Plot of Cp versus Time (PO)

Figure 20.1.4 Plot of Cp x Time versus Time (PO)


and additional parameters can be calculated (NOTE: We don't calculate Clearance or Vss using
oral data).

Equation 20.1.6 Equation for Mean Absorption Time (MAT)

Equation 20.1.7 Equation for Apparent Absorption Rate Constant (ka')

Equation 20.1.8 Equation for Oral Bioavailability (F)


The data were calculated after a 250 mg oral dose of the same drug. From these data a MRT was
calculated as
MRT = AUMC/AUC = 1361/149.8 = 9.08 hr
We can subtract from this MRT(PO) the MRT(IV) to get an idea of the absorption process, the
mean absorption time (MAT). That is
MAT = MRT(PO) - MRT(IV) = 9.08 - 8.17 = 0.92 hr

From this we can calculate an average absorption rate constant


ka' = 1/MAT = 1/0.92 = 1.09 hr-1
Of course we can calculate the bioavailability of the oral dosage form using the dose adjusted
AUC ratio. Thus
F = (149.70/67.27) x (100/250) = 0.89

Another Example
using Data from Bevill et al. 1977
Pharmacokinetics of Sulfamethazine in Cattle following IV and Three Oral Dosage Forms
Dosage Forms

IV Bolus 107 mg/Kg

Oral Solution 107 mg/Kg

Oral Rapid Release Tablet 105 mg/Kg

Oral Sustained Release Tablet 249 mg/Kg

Figure 20.1.5 The Average Data from Each Dosage Form

IV
Solution
Tablet
Slow Tablet

Table 20.1.6 Non Compartmental Analysis Results


AUC
AUMC
MRT (hr)
MAT (hr)
437
6393
14.6
431
9454
21.9
7.3
450
11303
25.1
10.5
765
45484
59.5
44.9

MDT (hr)
3.2
37.6

Table 20.1.7 Comparison with Non Linear Regression Analysis (SAAM)


Rate Constant (hr-1) Non Linear Regression Analysis
Non Compartmental Analysis
kel'
0.077
0.068
ka'
0.11
0.14
kd' (fast)
0.41
0.31
kd' (slow)
0.026
0.027
Non compartmental analysis:
kel' = 1/MRT
ka' = 1/MAT
kd' = 1/MDT
where MDT is the mean dissolution time
Want more practice with this type of problem!
References

Bevill, R.F., Dittert, L.W. and Bourne, D.W.A. 1977 Pharmacokinetics of Sulfamethazine
in Cattle following IV and Three Oral Dosage Forms, J. Pharm. Sci., 66, 619-23

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2015 at 09:21 PM
Non compartment Analysis IV Administration

A drug follows first order (i.e. linear) pharmacokinetics. A 200 mg dose was given by
rapid IV administration to a patient and a number of plasma drug concentration
were determined. The results are shown in the table below. A non compartmental
analysis was completed and AUC and AUMC values calculated. As you can see some
of these values are missing from the table. Complete the table and estimate MRT,
CL, and Vss from these data.

Time
hr

Cp
mg/L

AUC
mg.hr/L

AUC
mg.hr/L

Cp t
mg.hr/L

AUMC
mg.hr2/L

AUMC
mg.hr2/L

3.23

0.25

1.96

0.649

0.649

0.49

0.0613

0.0613

0.5

1.44

0.425

1.07

0.72

0.151

0.213

0.75

1.22

0.333

1.41

0.915

0.204

0.417

1.12

1.12

0.254

0.671

1.25

1.07

1.97

1.34

0.307

0.978

1.5

1.03

0.263

2.24

1.55

0.982

0.503

2.74

1.96

2.22

0.82

1.8

4.54

3.28

5.24

7.46

0.686

1.51

6.05

4.12

7.4

14.9

0.525

1.82

7.86

4.73

13.3

28.1

12

0.402

1.39

9.25

4.82

14.3

42.4

24

0.137

3.23

12.5

3.29

48.7

91.1

Infinity

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Some Equations:

Equation 30.4.1 AUC for the segment from i-1 to i

Equation 30.4.2 AUC for the last segment from tlast to infinity
where k' is the slowest rate constant. k' can be calculated from the terminal slope of Cp versus
time on semi-log graph paper.

Equation 30.4.3 AUMC for the last segment from tlast to infinity
where k' is the slowest rate constant. k' can be calculated from the terminal slope of Cp versus
time on semi-log graph paper.

Equation 30.4.4 Mean Resident Time (MRT)

Equation 30.4.5 Clearance (CL)

Equation 30.4.6 Steady State Apparent Volume of Distribution, Vss

Last update: Thu 19 Jan 2012 09:10:00 am