Mathematical Fundamentals in Pharmacokinetics

* Mathematical fundamentals are summarized here for review purposes only.

* Most of the mathematics needed for pharmacokinetics may be performed with pencil, graph paper
(ordinary and semi logarthmic), calculator and ruler.

Exponents and Logarithms

Exponents
x
In the expression N = b

x is the exponent, b is the base, and N represents the number when b is raised to the xth power, ie, b x.

For example,

1000 = 103

Where:

3 is the exponent,

10 is the base, and

103 is the third power of the base, 10.

Logarithms
a. Common logarithm (log)

The logarithm of a positive number N to a given base b is the exponent (or the power) x to which the
base must be raised to equal the number N. Therefore, if

In the expression

N = bx

then  

For example, with common logarithms (log), or logarithms using base 10,

Antilogb x = N

Antilog10 2 = 100
N.B.

• A logarithm does not have units.

• A logarithm is dimensionless and is considered a real number.

• The logarithm of 1 is zero.

• The logarithm of a number less than 1 is a negative number.

• The logarithm of a number greater than 1 is a positive number.

b. Natural logarithm (ln)

 Natural logarithms (ln) use the base e, whose value is 2.718282.

 To relate natural logarithms to common logarithms, the following equation is

used:

Ln N = 2.303 log N

The following table represents some rules of exponential and logarithmic

expressions and their corresponding examples:
Graphs
* The values of the independent variable (x) are placed on the horizontal line in a plane, or
on the abscissa (x axis),

* The values of the dependent variable are placed on the vertical line in the plane, or on
the ordinate (y axis), as demonstrated in .

* The values are usually arranged so that they increase from left to right and from bottom
to top.

* In pharmacokinetics, time is the independent variable and is plotted on the abscissa (x

axis), whereas drug concentration is the dependent variable and is plotted on the
ordinate (y axis).

* Two types of graph paper are usually uspered in pharmacokinetics: Rectangular

coordinate graph paper (Ordinary paper) and Semilog graph paper.
Rectangular coordinate graph paper
Semi-log graph paper
Determination of the Slope

Rectangular coordinate paper Semi-log graph paper

y = slope x + intercept Log y = slope x + intercept

Slope = Y1 – Y2 / X1 – X2 Slope = ln Y1 – ln Y2 / X1 – X2
= 2.303 (log Y1 – logY2 / X1 – X2)

Curve Fitting

Fitting a curve to the points on a graph implies that there is some sort of
relationship between the variables x and y, such as dose of drug versus
pharmacologic effect (eg, lowering of blood pressure).

The relationship is not confined to isolated points but is a continuous function of x

and y.

 Calculation of AUC by trapezoidal rule

The trapezoidal rule is a numerical method frequently used in
pharmacokinetics to calculate the area under the plasma drug
concentration-versus-time curve, called the area under the curve (AUC).
For example, the following figure shows a curve depicting the elimination of a drug
from the plasma after a single intravenous injection. The drug plasma levels and the
corresponding time intervals plotted in this figure are as follows:

The area between time intervals is the area of a trapezoid and can be calculated with
the following formula:
 Where [AUC] = area under the curve, tn = time of observation of drug
concentration Cn, and tn–1 = time of prior observation of drug
concentration corresponding to Cn–1.
To obtain the AUC from 1 to 4 hours, each portion of this area must be summed. The AUC
between 1 and 2 hours is calculated by proper substitution into the Previous equation:

Similarly, the AUC between 2 and 3 hours is calculated as 14.75 mg·h/mL, and the
AUC between 3 and 4 hours is calculated as 8.94 mg·h/mL. The total AUC between 1
and 4 hours is obtained by adding the three smaller AUC values together .

• The total area under the plasma drug level–time curve from time zero
to infinity is obtained by summation of each individual area between
each pair of consecutive data points using the trapezoidal rule.

• The value on the y axis when time equals 0 is estimated by back

extrapolation of the data points using a log linear plot (ie, log y vs x).
The last plasma level–time curve is extrapolated to t = ∞. In this case
t∞
the residual area [ AUC ]tn is calculated as follows:
 where C pn = last observed plasma concentration at tn and k =
slope obtained from the terminal portion of the curve
Total AUC

The trapezoidal rule written in its full form to calculate the AUC from t = 0 to t = ∞

Example

A curve depicting the elimination of a drug from the plasma after a single intravenous injection.
The drug plasma levels and the corresponding time intervals plotted in are as follows:

A) Draw the previous data on both ordinary and semilog paper

B) Calculate the total AUC between 1 and 4 hours and what is its unit ?

(30.3+18.4) (18.4+ 11.1) (11.1+6.77) µ g . hr

AUC = (2-1) + (3-2) + (4-3)= 48.04
2 2 2 ml

The unit of AUC = Concentraion× Time

Single IV dose of an antibiotic was given to a patient and blood samples ware removed
periodically and assayed for parent drug. The following data were obtained :

Time (hr) Concentration ( µg/ml)

0.25 4.2
0.5 3.5
1.0 2.5
2.0 1.25
4.0 0.31
6.0 0.08

A) Represent the above data on both rectangular coordinate paper and

semilogarithmic papers
B) Calculate the AUC between 0.5 and 6 and mention its unit
C) Calculate AUC and mention its unit

Answer:

µ g . hr
B) 5.325
ml

µ g . hr
c) 7.53
ml

Consider the following graph (Figure 2a in the original article) presented in Schilling et al
(2013):

The equation in the graph is that for the standard curve generated for
progesterone using a high-performance liquid chromatography method.
In the equation, y is the area under the curve of progesterone peak and
x represents the concentration of the drug in ml ( μg )
1- Using this equation, predict the AUC for a drug concentration of 35
mg/mL.

Answer: 57.9

2-predict the concentration of progesterone (mg/L) for a peak area (AUC) of

145.
Answer: 87.4 mg/L

Consider the following function dc/dt = 0.98 with c and t being the
concentration of the drug and time, respectively. This equation can also be
written as ______.
a. x = x0 − 0.98 t
b. x = 0.98 − t
c. x = x0 + 0.98 t
d. x = t/0.98
 The above figure (from Basu Sarkar et al, 2013) shows
the plasma concentration–time profile of DMAA (1,3-
dimethylamylamine) in eight men following a single oral
dose of the DMAA (25 mg).
1-What type of graph paper is the above graph?
(Semilogarithmic or rectangular?)
2-What are the Cmax and Tmax values for subject #1?
(subject #1) occurred at Tmax of ____ hour.
3-What is the average Cmax value for all eight subjects?
Please use the correct units for your answer.
4-What are the units for AUC obtained from the graph?
5-For subject #3, the Cmax value is approximately 105 ng/mL.
Express this concentration in %w/v.
Answer:

1- A rectangular coordinate graph.

2- According to the figure, the highest plasma concentration for

subject #1 occurred at 24 hours

3- From the graph, the average Cmax was between 50 and 100
ng/mL.

4- It is (concentration units) × (time) = (ng/mL) × (hours) =

ng·h r
(ng·h/mL) or ml

5- 105 ng/mL = 10,500 ng/100 mL = 10.5 μg/100 mL

= 0.0105 mg/100 mL = 0.0000105 g/100 mL.

Cunha (2013) reported the following: “…CSF levels following 2 g of

ceftriaxone are approximately 257 mcg/mL, which is well above the
minimal inhibitory concentration (MIC) of even highly resistant (PRSP)
in CSF…”
1-What is the value of 257 mcg/mL in mg/mL?

2-Express the value 257 mcg/mL in mcg/dL.

Answer
1-Since 1 mg = 1000 μg, then (257 μg/mL)/1000 =0.257 mg/mL
2-Since 1 dL = 100 mL, then (257 μg/mL) × 100 = 25,700 μ
g/dL.