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 logarithmic), calculator and ruler.

Exponents and Logarithms

Exponents
In the expression bx = n
x is the exponent or the power, b is the base, and n represents the number when b is raised to
the xth power .e.g. bx.
For example,
103 =1000
Where:
3 is the exponent,
10 is the base,
1000 is the number
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
bx = n
then

= x

23 = 8; therefore, 3 is the logarithm of 8 to base 2, or log2 8 = 3.

In the same fashion, since 102 = 100, then log10 100 = 2.
Logarithms of the latter sort (that is, logarithms with base 10) are called common logarithms
and are written simply log n. That is log 100 = 2

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 (but greater than zero) is a negative number.
• The logarithm of a number greater than 1 is a positive number.
• The logarithm of a number ≤ zero is undefined.
The following table represents some rules of exponential and logarithmic expressions and
their corresponding examples:

If = x Then =n

Log 100 = 2 , antilog 2 = 100

Log C = 1.5 , antilog 1.5 = C >>>>> C = 31.6

ln (C0) = 3 , anti ln 3 = C0 >>>>> C0 = 20.08

b. Natural logarithm (ln)

• Natural logarithms (ln) use the base e (Euler's number or natural number ), whose
value is 2.718282 ( infinite number ).
• To relate natural logarithms to common logarithms, the following equation is used:

ln n = 2.303 log n
Examples
Ln 10 = 2.303 log 10
Ln C = 2.303 log C

Same rules above apply on natural logarithms ( ln )

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 used in pharmacokinetics: Rectangular
coordinate graph paper (Ordinary paper) and Semi log graph paper.
Rectangular coordinate graph paper Semi log graph paper
Semi-log graph paper
How to scale a semi-log graph paper ??
https://www.youtube.com/watch?v=TmS1kV30nEI

Determination of the Slope

Rectangular coordinate paper Semi-log graph paper

y = (slope) x + intercept Log y = (slope) x + intercept

log⁡(𝑦1)−log⁡(𝑦2)
Slope =
y1−y2 𝑥1−𝑥2
Slope = x1−x2
ln⁡(𝑦1)−ln⁡(𝑦2)
Slope ×2.303 =
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 (e.g., 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.
1) The AUC between 1 and 2 hours is calculated by proper substitution into the
Previous equation:

2) Similarly, the AUC between 2 and 3 hours is calculated as 14.75 mg·h/mL,

3) And the AUC between 3 and 4 hours is calculated as 8.94 mg·h/mL.
4) 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 [(𝑨𝑼𝑪)𝟎 or AUC ] 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 zero (Cp)0 is estimated by back
extrapolation of the data points using a log linear plot (i.e., log y vs x).
• The last plasma level–time curve is extrapolated to t = ∞.
 In this case the residual area [𝐴𝑈𝐶]𝑡∞
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 = ∞

where C pn = last observed plasma concentration at tn

OR

Example 1
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 semi log 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) µ𝐠.𝐡𝐫

(𝑨𝑼𝑪)𝟒𝟏 = (2-1) + (3-2) + (4-3)= 48.04
𝟐 𝟐 𝟐 𝐦𝐥
The unit of AUC = Concentration × Time

Example 2
Single IV dose of an antibiotic was given to a patient and blood samples were
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:
µ𝐠.𝐡𝐫
B) (𝐀𝐔𝐂)𝟔𝟎.𝟓 = 5.325
𝐦𝐥
µ𝐠.𝐡𝐫
C) AUC or (𝐀𝐔𝐂)∞
𝟎 = 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
𝜇𝑔
drug in ( )
𝑚𝑙
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. C = C0 − 0.98 t
b. C = 0.98 − t
c. C = C0 + 0.98 t
d. C = t/0.98

Answer: C
 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.

ng·hr
4- It is (concentration units) × (time) = (ng/mL) × (hours) = (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 𝜇g/dL.

𝜇g = mcg

x
x
x
 Bioavailability questions
Question (1):
The bioavailability of a new investigational drug was studied in 12 volunteers. Each
volunteer received either a single oral tablet containing 200 mg of the drug, 5 mL of a
pure aqueous solution containing 200 mg of the drug, or a single IV bolus injection
containing 50 mg of the drug. Plasma samples were obtained periodically up to 48
hours after the dose and assayed for drug concentration. The average AUC values (0–
48 hours) are given in the table below. From these data, calculate
(a) The relative bioavailability of the drug from the tablet compared to the oral solution
and
(b) The absolute bioavailability of the drug from the tablet.

Drug Product Dose (mg) AUC (µg hr/mL) Standard Deviation

Oral tablet 200 89.5 19.7
Oral solution 200 86.1 18.1
IV bolus injection 50 37.8 5.7

Answer:
a) 1.039
b) 0.59

2)AUC values of penicillin up on i.v administration of 50 mg and oral administration

of 100 mg tablet were found to be 70 and 90 respectively.
Calculate:
a. Absolute bioavailability of penicillin tablet.
b. Relative bioavailability of penicillin from tablet based on penicillin suspension wh
ose dose is 100 mg and AUC is 95.
Answer:
a) 0.64 b) 0.947
3)Following data are obtained for 4 formulations of pentoxyifylline in volunteers
of average weight 50 kg.
Drug Product Dose (mg/kg) AUC
i.v. solution 1.2 450
oral solution 4.0 822
oral capsule 4.0 736
oral S.R. tablet 8.0 1040

a. What is the absolute bioavailability of the drug from capsule?

0.49
b. What is the absolute bioavailability of the drug from S.R. tablet?
0.35
c. What is the relative bioavailability of capsule against oral solution?
0.90
d. What is the relative bioavailability of S.R. tablet against oral solution?
0.63
e. Which solid formulation shows better bioavailability?
Capsule

4) The total amount excreted into urine as unchanged drug after an oral tablet (A)
of 25 mg was 21.3 mg. After an oral capsule dose (B) of 200 mg the U∞ was 170.4
mg. calculate the relative bioavailability of the tablet A with respect to the capsule
B.

Answer: 1
5) Choose:
1-The absolute bioavailability of a drug can be different when a drug is administered
via different extravascular routes; however, the absolute bioavailability of a drug
cannot be greater than one, regardless of the extravascular route chosen to administer
the drug and the size of the administered dose.
(A) True
(B) False

2)Following the administration of 42.5 mg of theophylline as an intravenous solution

and 170 mg via oral capsule, Tse and Szebo (1982) reported the area under the
plasma concentration–time curve, (𝐴𝑈𝐶)∞ 0 , to be 35.835 𝜇𝑔.ml .hr and 143:343
−1

𝜇𝑔.ml −1.hr, respectively. Determine the absolute bioavailability of theophylline.

(Provide the numerical value.)
(A) 1.00
(B) 0.80
(C) 0.90
(D) 1.25

3- Terbinafine (Lamisil) is a synthetic allylamine antifungal agent. Following the

administration of a 250 mg tablet, Kovarik et al. (Br J Dermatol 1992; 126 (Suppl
39): 8–13) reported the area under the plasma concentration–time
curve (𝐴𝑈𝐶)∞ 0 and the systemic clearance to be 4454 𝑛𝑔.ml .hr and 36.75 L.hr ,
−1 −1

respectively. Determine the absolute bioavailability of terbinafine following the

administration of a 125 mg tablet

(A) 0.065
(B) 0.327
(C) 0.654
(D) 0.500

4- Bumetanide (Bumex) is a sulfonamide diuretic with a short duration of action.

Holazo et al. (J Pharm Sci 1984; 73: 1108–1113) reported on the bioavailability of
bumetanide in a crossover study in normal subjects. Following the administration of 1
mg of bumetanide by oral tablet and intramuscular injection, the area under the
plasma concentration time curves(𝐴𝑈𝐶)∞ 0 , were reported to be 66 𝑛𝑔.ml .hr and 80
−1

𝑛𝑔.ml −1.hr, respectively. Determine the relative bioavailability of bumetanide from

the intramuscular route.
(A) 1.212
(B) 0.825
(C) 0.082
(D) 0.213
Answer: 1- A 2- A 3- C 4- A

6) The data in the following table represent the average findings in antibiotic plasma
samples taken from 10 humans (average weight 70 kg), tabulated in a 4-way
crossover design.

a. Which of the four drug products would be preferred as a reference standard for the
determination of relative bioavailability? Why?
Oral solution
b. From which oral drug product is the drug absorbed more rapidly?
Oral solution
c. What is the absolute bioavailability of the drug from the oral solution?
1.0
d. What is the relative bioavailability of the drug from the oral tablet compared to the
reference standard?
0.8
e. Draw the data of I.V solution on semi-log paper and determine:
(i) Apparent Vd (section 2)
𝑰.𝑽⁡𝒅𝒐𝒔𝒆
Vd= = 2(mg/kg) / 6.7 (𝝁𝒈/𝒎𝒍) = 2000(𝝁𝒈/𝐤𝐠) / 6.7 (𝝁𝒈/𝒎𝒍) =
𝑪𝟎(𝒇𝒓𝒐𝒎⁡𝒈𝒓𝒂𝒑𝒉)
298.5 ml/kg = 0.298(L/kg)
(ii) Elimination t1/2
Method 1: From K
t1/2 = 0.693/k = 0.693/0.229 = 3.026 hours
Method 2: From Graph = 3 hours

(iii) First-order elimination rate constant k

(0.229 hr−1)
(iv) Total body clearance (section 2)
ClT = k.Vd = 0.229 (hr−1) × 0.298 (litre/kg) = 0.0682(litre/kg.hr) = 68(ml/kg.hr)
 Rates and Orders of Reactions
The Rate Of A Chemical Reaction Or Process;
Definition :is the velocity with which the reaction occurs.
Drug (A) Metabolite (B)
❑ If the amount of drug A is decreasing with respect to time (that is, the reaction
is going in a forward direction), then the rate of this reaction can be expressed
as: -dA/dt
❑ Since the amount of metabolite B is increasing with respect to time, the rate of
the reaction can also be expressed as: +dB/dt.
❑ The rate of a reaction is determined experimentally by measuring the
disappearance of drug A at given time intervals.
The Order of Reaction or Process;
❑ refers to the way in which the concentration of drug or reactants influences
the rate of a chemical reaction or process.
We will discuss two types of orders; zero order and first order.
Zero-order Rate Kinetic
If the amount of drug A is decreasing at a constant rate, then the rate of disappearance of
drug A is expressed as:
𝐝𝐀 dc
−⁡ = k0 Or − = k0
𝐝𝐭 dt
𝐝𝐀 dc
= −k0 Or = −k0
𝐝𝐭 dt

By integration:
A = A0 – k0t Or c = c0 − k 0 t
Where:
❖ A 0 is the amount of drug in body at t = 0 ( at time of I.V bolus injection ) (Dose in I.V
bolus)
❖ C0 is the initial concentration of the drug at t = 0
❖ C or Ct or (Cp)t is concentration remaining or present after or at time = t
❖ A or At is amount remaining or present after time = t
❖ k 0 is the zero-order rate constant.
mg
The units for k0 are concentration per unit time (e.g., [ ] or amount per unit time (eg, mg/hr).
ml.hr
The rate of a zero-order process is one that proceeds over time (t) independent from the concentration
the drug (c) or drug amount (A). The negative sign for the rate indicates that the concentration of the
drug decreases over time
Based on this expression, a graph of A versus t yields
Graphical Representation on ordinary paper
A = A0 − k0t
 First-order Rate Kinetics
If the amount of drug A is decreasing at a rate that is proportional to the amount of drug A
remaining, then the rate of disappearance of drug A is expressed as:
−dA/dt = kA −dc/dt = kc
dA/dt =− kA dc/dt =− kc

By integration:
1- ln(A) = ln(A0) – kt ln(c) = ln(c0) − kt
𝐤𝐭 𝐤𝐭
2- log(A) = log(A0) − log(c) = log(c0) −
𝟐.𝟑𝟎𝟑 𝟐.𝟑𝟎𝟑
−kt −kt
3- A = A0 e c = c0 e

Where:
❖ A 0 is the amount of drug in body at t = 0 (( at time of I.V bolus injection )) (( Dose in I.V bolus
❖ C0 is the initial concentration of the drug at t = 0
❖ C or Ct or (Cp)t is concentration remaining or present after or at time = t
❖ A or At is amount remaining or present after time = t
𝟏
❖ k is the first-order rate constant and is expressed in units of ⁡ or time– 1 (e.g., hr– 1).
𝐭𝐢𝐦𝐞⁡
Graphical Representation
1- Exponential equation, on ordinary paper
A = A0 e−kt

2- Natural logarithmic equation, on ordinary paper

ln(A) = ln(A0) – kt

3- logarithmic equation on ordinary paper

 𝒌𝒕
log(A) = log(A0) −
𝟐.𝟑𝟎𝟑

For convenience, A versus t may be plotted on semi-log paper without the need to
convert A to log(A).

Note : all previous graphs could be plotted with C instead of A

Half-life time (t 1/2)

Definition; It expresses the period required for the amount or concentration of a drug to decreas
by one-half.
𝟎.𝟓𝐀𝐨
Zero-Order Half-Life : t1/2⁡=
𝐤𝐨

𝟎.𝟔𝟗𝟑
First-Order Half-Life : t1/2⁡ =
𝐤
Reaction Orders (Comparison)
Order

Zero order First order

Not constant (variable)

Constant Directly proportional to drug amount
rate

𝒅𝑨 𝑑𝑐 or concentration
= −k0 Or = −k0
𝒅𝒕 𝑑𝑡 𝒅𝑨 𝑑𝑐
=− kA or =− kc
𝒅𝒕 𝑑𝑡

lnA = lnA0 – kt
equation

or
𝒌𝒕
A = A0- k0t log(A) = log(A0) −
𝟐.𝟑𝟎𝟑
or
A = A0 e−kt
Not constant (variable)
Directly proportional to Constant
t1/2

drug amount or
concentration t1/2 = 0.693/k
t1/2 = A0/2k0
4 graphs
semi-log graph most applicable
in this course
Graphs
 K unit
Concentration/time 𝟏
or time -1
or amount/time 𝒕𝒊𝒎𝒆

Problem (1):
A solution of a drug was freshly prepared at a concentration of 300 mg/mL. After 30 days at
25°C, the drug concentration in the solution was 75 mg/mL.
a. Assuming first-order kinetics, when will the drug decline to one-half of the original
concentration?

Answer: 15 days

b. Assuming zero-order kinetics, when will the drug decline to one-half of the original
concentration?

Answer: 20 days

Problem (2):

A pharmacist dissolved a few milligrams of a new antibiotic drug into exactly 100 mL of distille
water and placed the solution in a refrigerator (5°C). At various time intervals, the pharmaci
removed a 10-mL aliquot from the solution and measured the amount of drug contained in eac
aliquot. The following data were obtained.

a. Is the decomposition of this antibiotic a first-order or a zero-order process?

Zero order because the amount of drug A is decreasing at a constant rate (The line will
be straight on the ordinary paper )

b. What is the rate of decomposition of this antibiotic?

dc/dt = −k0
k0 = - Slope
Slope = (y2−y1)/(x2−x1) = −6.7
k0 = − Slope = − (−6.7) = 6.7
dc/dt = −k0 = - 6.7 µg/ml.hr
c. How many milligrams of antibiotics were in the original solution prepared by the
pharmacist?
A0= ?? (required)
Co ( intercept) = 87µg/ml
87µg ------------ 1ml
Ao ------------- 100 ml
Ao = (87×100)/1 = 8700 µg = 8.7 mg
µg
Or initial amount = initial concentration × Volume = 87( ) × 100(ml)
𝑚𝑙

= 8700 µg = 8.7 mg
d. Give the equation for the line that best fits the experimental data
Zero order equation
c = c0 − k0t or A= Ao – kot
so equation for the line that best fits the experimental data
C= 87 – 6.7t
Another answer :
the unit of k0 in this example is µg/ml.hr. If we change it into (µg/hr )by ((× 100 ml)) =
670 µg/hr or 0.67 mg/hr
Then equation for the line that best fits the experimental data could also be

A=8700−670t or A=8.7 – 0.67 t

Notice differences in units

Problem(3)

Plot the following data on both semi-log graph paper and standard
rectangular coordinates.
a. Does the decrease in the amount of drug A appear to be a zero-
order or a first-order process?
From the graph, Zero order because the amount of drug A is decreasing at
a constant time interval (The line will be straight on the ordinary paper )
b. What is the rate constant k?
k0 = - Slope = - (y2-y1)/(x2-x1) = 0.77 mg/min
c. What is the half-life t 1/2?
t1/2 = A0/ 2Ko = 104/ (2×0.77) = 68.42 min ( A0 is intercept of graph )
d. Does the amount of drug A extrapolate to zero on the x axis?
yes

e. What is the equation for the line produced on the graph?

A= Ao – kot
A= 104 – 0.76t

Problem (4):

How many half-lives (t 1/2) would it take for 99.9% of any initial
concentration of a drug to decompose? Assume first-order kinetics.
Answer: 10 t1/2

Problem (5):

If the half-life for decomposition of a drug is 12 hours,

how long will it take for 125 mg of the drug to decompose
by 30%? Assume first-order kinetics and constant
temperature.
Answer : 6.1 hours

Problem (6):
Two different drugs (A and B) were administrated on different occasions in
different doses to the same subject by I.V bolus injections.
Half-lives (t1/2) of both drugs from different doses were determined:

Dose t 1/2 of t 1/2 of

(mg) drug A drug B
(hr) (hr)
40 10 3.5
60 15 3.5
80 20 3.5

Which of them is eliminated by first order and why ?

Answer: Drug B, because ……?

If a 10 mg dose of the drug eliminated by first order, were administrated

to the same patient, how much time would be required to eliminate 7 mg
of the drug?
Answer: 6.08 hr
Problem (7)
For most drugs, the overall rate of drug elimination is proportional to the amount of
drug remaining in the body. What does this imply about the kinetic order of drug
elimination?

Problem (8)
Plot the following data on both standard rectangular and semi-log graph paper
coordinates

1-Does the decrease in the amount of drug A appear to be a zero-order or a first-order

process?

First-order process
2-What is the rate constant k?
0.03 minute −1

3-What is the half-life t1/2?

22 minutes

4-Does the amount of drug A extrapolate to zero on the x axis?

No, the amount of drug, A, does not extrapolate to zero on the x axis of rectangular
paper as it is first order rate kinetics

5- What is the equation for the line produced on the graph?

𝒌𝒕
log(A) = log(A0) − general first order equation
𝟐.𝟑𝟎𝟑

𝟎.𝟎𝟑𝒕
log(A) = log(78) − or simplify it more
𝟐.𝟑𝟎𝟑

Or

A = 78 e−0.03t
x
x
x