Pharmacokinetics

calculations
Pharmacokinetic
8
models
 Pharmacokinetic models are
hypothetical structures that are
used to describe the fate of a drug
in a biological system following its
administration.
 Compartmental models use linear
equations to predict the time course of
drug concentrations in the body. These
compartments have no physiological
or anatomical meaning
One-compartment model

 Following drug administration, the body is

depicted as a kinetically homogeneous unit
 This assumes that the drug achieves
instantaneous distribution throughout the body
and that the drug equilibrates instantaneously
between tissues.
 drug concentration–time profile shows a
monophasic response (i.e. it is
monoexponential)
Figure
1
 Two-compartment model
• The two-compartment model is the simplest multi compartment
model which resolves the body into:
a central compartment and a peripheral compartment.

• Central compartment (CC) comprises tissues that are highly perfused

such as heart, lungs, kidneys, liver and brain.

• The peripheral compartment (PC) comprises less well-perfused

tissues such as muscle, fat and skin.

• Assumptions of two compartment: following drug administration into

the central compartment, the drug distributes between central
compartment and the peripheral compartment.
5
Order of reaction
Important in considering ADME processes:
Zero-order reaction
Consider the rate of elimination of drug A from the
body. If the amount of the drug, A, is decreasing at a
constant rate, then the rate of elimination of A can

 𝑑𝑥 =
𝑑𝑦
be described as:

𝑘 ∗
where k* is the zero-order rate constant.
The reaction proceeds at a constant rate and is
independent of the concentration of A present in the
body. An example is the elimination of alcohol. Drugs
that show this type of elimination will show
accumulation of plasma levels of the drug and hence
nonlinear pharmacokinetics
First-order reaction
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Amount of drug A decrease at a rate that is
proportional to amount of drug remaining in the
body, 𝑑𝑦
𝑑
= −𝑘𝐴
rate of elimination of drug A
𝑥
k=first order rate constant
Reaction proceeds at a rate that is
dependent on the
concentration of A present in the body.

It is assumed that the processes of ADME follow

first-order
reactions and most drugs are eliminated in this
manner.
 First Order
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For drugs with first-order elimination process;

As the amount of drug administered increases, the body is able

to eliminate the drug accordingly and accumulation will not
occur.

If dose is doubled, plasma concentration doubles

With continuous increase in amount of drug administered drug

process may change from a first-order process to a zero-order
process, for example in an overdose situation.
2
Pharmacokinetics
2 parameters
 Elimination rate constant - Ke

 Half life – T1/2

 Volume of distribution - Vd

 Clearance - CL
 Elimination rate
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constant
The elimination rate constant (ke) is the fraction of drug in
the body which is removed per unit time.
(eg 0.02min-1 implies 2% of drug is eliminated in one

 𝒅 = −𝒌𝑿
minute.)
𝒅𝑿

𝑿
𝒕
�𝒐𝒆
� −𝒌
integrating…
=

𝑳𝒏 𝑿 𝒕= 𝑳𝒏𝑿 𝟎
− 𝑲𝒕
𝑳𝒐𝒈𝑿 = � 𝟐.𝟑𝟎
𝑲
𝒕
𝒍𝒐𝒈𝑿 X = amount
(Ln X = 2.303
� of𝟑drug X,Log
−
where X0 = X)
dose
and k = first-order elimination rate
Cp-time curve on linear gragh
 using natural logarithms ie 𝐿𝑛𝐶𝑝𝑡 =
2
The curve can be converted to a linear form
by
𝐿𝑛𝐶0 − 𝑘𝑡
5 �
�
 Half Life
62 The time required
𝐿𝑛 𝑝 = 𝐿𝑛𝐶 �
0 − 𝑘𝑡

𝐶 𝑡 then �
toreduce the plasma
ln 𝑝𝐶 = � −
0
concentration to one
02 1/
𝑙𝑛𝐶 � 𝑘𝑡 2
half its initial value is

𝑘𝑡 1/2 = 𝑙𝑛𝐶

defined as the half-
0
- 𝑝𝐶
life (t1/2).
02
𝑝 ln
C = Coe - kt
C/Co = 0.50 𝑡 1/ = 𝐿𝑛2 =
2 0.693
𝑘
0.50 = e – k t
ln 0.50 = -k t ½
-0.693 = -k t ½ 𝑘

t 1/2 = 0.693 / k
 Usefulness and clinical significance
of half life
27
 Gives an indication of time required for the dosing
regimen to attain steady state concentration (Css) of the
drug in the body
 useful in dosage adjustments and choosing a dosing
interval that dose not produce excessively high peaks (toxic
levels) and low troughs (ineffective levels) in drug
concentrations.
 estimate for how long a drug should be stopped if a
patient has toxic drug levels, assuming the drug shows
linear one-compartment pharmacokinetics
 It takes about 5-7 half-lives to completely
eliminate a drug from the body- relevant in
poison management
Half life vs Steady state
 Usefulness and clinical significance of half
life…

• It takes about 5-7 half-lives to completely eliminate a drug

from the body. This is needed in poison management and
culture & sensitivity tests to evaluate antibiotic therapy.
• Protein binding serves as a depot and prolongs drug action.
Drugs that are highly protein bound require a loading dose eg
chloroquine.
• Drugs that are highly bound to tissue protein such as
butazolidine are not suitable for intramuscular administration
but oral.
• t1/2 = 0.693/ K, t1/2 = 0.693 Vd/ Cl, recall Cl = kel Vd .

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Use of t ½ and kel data
• If drug has short duration of action, design drug
with larger t ½ and smaller kel

• If drug too toxic, design drug with smaller t ½

and larger kel
Volume of distribution

Volume of distribution

The volume of distribution (V) is a hypothetical volume that is the proportionality constant which relates the concentration of drug in the blood or serum (C) and the amount of drug in the body (A = C · V
Volume of distribution
• The volume of distribution (Vd) has no direct physical
measurement
• it is not a ‘real’ volume and is usually referred to as the
apparent volume of distribution.
• It is defined as that volume of plasma in which the total
amount of drug in the body would be required to be dissolved
in order to reflect the drug concentration attained in plasma.
• It is a dilution space
• The body is not a homogeneous unit
• even though a one-compartment model can be used to
describe the plasma concentration–time profile of a number of
drugs, concentration of drug in plasma is not necessarily
same in other organs.

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 applications of Vd

• Provides insight into the extent of vascular distribution

• Value around 4 Litres indicate the drug is mainly in the
intravascular space - lipid insoluble, such as neuromuscular
blockers
• Values around 15 Liters indicate the drug is distributed in
extracellular space
• Values above 15 Liters indicate distribution into intracellular
space
• Drugs that are highly lipid soluble or accumulate in tissues such
as digoxin, have a very high volume of distribution (500 litres).
• Vd is useful in estimating Loading Dose
Clearance
• Drug clearance (CL) is defined as the volume of
plasma in the vascular compartment cleared of drug
per unit time by the processes of metabolism and
excretion.
• Clearance for a drug is constant if the drug is
eliminated by first-order kinetics.
• Drug can be cleared by renal excretion or by
metabolism or both. With respect to the kidney and
liver, etc., clearances are additive, that is:
• CLtotal = CLrenal + CLnonrenal

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 Clearance …
• Mathematically, clearance is the product of the first-order
elimination rate constant (k) and the apparent volume of
distribution (Vd).
• Thus
• Hence the clearance is the elimination rate constant – i.e.
the fractional rate of drug loss the volume of distribution.
• Clearance is related to half-life by

• If a drug has a CL of 2 L/h, this tells you that 2 litres of the

Vd is cleared of drug per hour. If the Cp is 10 mg/L, then 20
mg of drug is cleared per hour
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Pharmacokinetic applications
• Single IV administration
QI A patient D has a potentially toxic digoxin level of
4.5µg/L. Given that the half-life of digoxin in this
patient is 60 h, and assuming that renal function is
stable and absorption is complete, for how long should
the drug be stopped to allow the level to fall to 1.5µg/L

A =94.7h ie 4 days

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 Area under the plasma concentration
time curve (AUC)
• Knowlegde of important for determining systemic, renal
and metabolic clearance of the drug
• also essential for determining the administered dose of
a drug, extent of absorption and to obtain the
maximum tolerated exposure (AUC Dosing).
• Useful to assess bioavailability
• independent of the route of administration and process of
drug elimination provided the elimination process does
not change (Non compartmental approach …)
• When a graph of Cp vs time drug is plotted, the area
under the curve is AUC
• = +
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AUC determination via trapezoidal method

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 Using the trapezoidal method

• Determination of
•
• = average Cp ×dt etc
• = sum of individual trapezoid values
• is the time of last sample
• Unit of AUC is µg mL-I h

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 Using trapezoidal method

Therefore the total AUC can be calculated as :-

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Determination of AUC from intravenous bolus dose
• , we also now know that
• =
• Hence
• = (integrating IV bolus eq)
•
• When t = , = 0 and when t = 0, =1
• =
• == =
• = systemic clearance of a drug
• Note: AUC from extravascular route
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 Q2 After an I.V. bolus dose of 500 mg of drug X, the data in the table below was obtained. Plot the data on semi-
log graph paper. Calculate ke and V, Cl, T1/2, AUC (0 to infinity) (equation and graph)

Time (hr) 1 2 3 4 6 8 10

Cp 72 51 33 20 14 9 4
(µg/ml)

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 Q3: AUC sample table: work it out
Concentration (µg/ml) delta AUC AUC (µ[Link]/ml)
Time (hr)
0 100
1 71 85.5 85.5
2 50 60.5 146.0
3 35 42.5 188.5
4 25 30.0 218.5
6 12 37.0 255.5
8 6.2 18.2 273.7
10 3.1 9.3 283.0
Total 8.9 291.9

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