Clinical Pharmacokinetics
Introduction
How to use this powerpoint
presentation
• This supplements the other course material
• You can view it on line or download it to your
computer and view it without being connected to
the internet.
• Work through the presentation at the start of the
course and note any issue which are not clear.
• Read up on areas that you are not familiar with
and revisit the presentation from time to time.
• Try the powerpoint based exercises
What is clinical
pharmacokinetics ?
• Study of the time course of a drug’s
movement through the body.
• Understanding of what the body does to (or
with) the drug.
• Application of Therapeutic Drug Monitoring
(TDM) and individualisation of drug therapy.
Outline
• Review of Concepts
– Clearance, K, Half-Life, Volume of Distribution
• Therapeutic drug Monitoring
• Pharmacokinetic Drug Interactions
• Cases
• Discussion/Questions
Pharmacokinetics (PK) &
pharmacodynamics (PD)
• PK - What the body does to the drug?
– Absorption; distribution, metabolism,
excretion (ADME)
• PD - What the drug does to the body?
– Drug concentration at the site of action or
in the plasma is related to a magnitude of
effect
Pharmacokinetics (PK) and
pharmacodynamics (PD)
Plasma
Concentration
Dose
PK
Site
of
Action
Effects
PD
Pharmacokinetics vs
Pharmacodynamics…concept
• Fluoxetine increases plasma
concentrations of amitriptyline. This is a
pharmacokinetic drug interaction.
• Fluoxetine inhibits the metabolism of
amitriptyline and increases the plasma
concentration of amitriptytline.
Pharmacokinetics vs
Pharmacodynamics…concept
• If fluoxetine is given with tramadol serotonin
syndrom can result. This is a
pharmacodynamic drug interaction.
• Fluoxetine and tramadol both increase
availability of serotonin leading to the
possibility of “serotonin overload” This
happens without a change in the
concentration of either drug.
Basic Parameters
• In the next few slides the basic concepts and
paramaters will be described and explained.
• In pharmacokinetics the body is represented
as a single or multiple compartments in to
which the drug is distributed.
• Some of the parameters are therefore a little
abstract as we know the body is much more
complicated !
Volume of Distribution, Clearance and
Elimination Rate Constant
V
Volume 100 L
Clearance
10 L/hr
Volume of Distribution, Clearance and
Elimination Rate Constant
V
V2
Cardiac and
Skeletal Muscle
Volume 100 L (Vi)
Clearance
10 L/hr
V2
Cardiac and
Skeletal Muscle
V
Volume 100 L (Vi)
Clearance
10 L/hr
Volume of Distribution =
Dose_______
Plasma Concentration
V2
Cardiac and
Skeletal Muscle
V
Volume 100 L (Vi)
Clearance
10 L/hr
Clearance =
Volume of blood cleared of drug per unit time
V2
Cardiac and
Skeletal Muscle
V
Volume 100 L (Vi)
Clearance
10 L/hr
Clearance = 10 L/hr
Volume of Distribution = 100 L
What is the Elimination Rate Constant (k) ?
CL = kV
k = 10 Lhr -1 = 0.1 hr -1
100 L
10 % of the “Volume” is cleared (of drug) per hour
k = Fraction of drug in the body removed per hour
CL = kV
If V increases then k must decrease as
CL is constant
Important Concepts
• VD is a theoretical Volume and
determines the loading dose
• Clearance is a constant and determines
the maintenance dose
• CL = kVD
• CL and VD are independent variables
• k is a dependent variable
Volume of Distribution
Apparent volume of distribution is the
theoretical volume that would have to be
available for drug to disperse in if the
concentration everywhere in the body were
the same as that in the plasma or serum,
the place where drug concentration
sampling generally occurs.
Volume of Distribution
• An abstract concept
• Gives information on HOW the drug is
distributed in the body
• Used to calculate a loading dose
Loading Dose
Dose = Cp(Target) x VD
Question
• What Is the is the loading dose required
fro drug A if;
• Target concentration is 10 mg/L
• VD is 0.75 L/kg
• Patients weight is 75 kg
• Answer is on the next slide
Answer: Loading Dose of Drug A
•
•
•
•
•
•
Dose = Target Concentration x VD
VD = 0.75 L/kg x 75 kg = 56.25 L
Target Conc. = 10 mg/L
Dose = 10 mg/L x 56.25 L
= 565 mg
This would probably be rounded to 560 or
even 500 mg.
Clearance
• Ability of organs of elimination (e.g.
kidney, liver to “clear” drug from the
bloodstream
• Volume of fluid which is completely
cleared of drug per unit time
• Units are in L/hr or L/hr/kg
• Pharmacokinetic term used in
determination of maintenance doses
Maintenance Dose
Calculation
• Maintenance Dose = CL x CpSSav
• CpSSav is the target average steady state
drug concentration
• The units of CL are in L/hr or L/hr/kg
• Maintenance dose will be in mg/hr so for total
daily dose will need multiplying by 24
Question
• What maintenance dose is required for
drug A if;
• Target average SS concentration is 10
mg/L
• CL of drug A is 0.015 L/kg/hr
• Patient weighs 75 kg
• Answer on next slide.
Answer
• Maintenance Dose = CL x CpSSav
• CL = 0.015 L/hr/kg x 75 = 1.125 L/hr
• Dose = 1.125 L/hr x 10 mg/L
= 11.25 mg/hr
• So will need 11.25 x 24 mg per day
= 270 mg
Half-Life and k
• Half-life is the time taken for the drug
concentration to fall to half its original
value
• The elimination rate constant (k) is the
fraction of drug in the body which is
removed per unit time.
Drug Concentration
C1
Exponential decay
C2
dC/dt  C
= -k.C
Time
Log Concn.
C0
C0/2
t1/2
t1/2
t1/2
Time
Time to eliminate ~ 4 t1/2
Integrating:
-kt
.e
Cp2 = Cp1
Logarithmic transform:
lnC2= lnC1 - kt
logC2 = logC1 - kt/2.303
Elimination Half-Life:
t1/2 = ln2/k
t1/2 = 0.693/k
Steady-State
• Steady-state occurs after a drug has been given
for approximately five elimination half-lives.
• At steady-state the rate of drug administration
equals the rate of elimination and plasma
concentration - time curves found after each
dose should be approximately superimposable.
Accumulation to Steady State
100 mg given every half-life
175
187.5
194 …
200
150
100
87.5 94
75
50
97
…
100
C
Cpav
t
Four half lives to reach steady state
What is Steady State (SS) ?
Why is it important ?
• Rate in = Rate Out
• Reached in 4 – 5 half-lives (linear
kinetics)
• Important when interpreting drug
concentrations in TDM or assessing
clinical response
Therapeutic Drug Monitoring
Some Principles
Therapeutic Index
• Therapeutic index = toxic dose/effective
dose
• This is a measure of a drug’s safety
– A large number = a wide margin of safety
– A small number = a small margin of safety
Drug Concentrations May Be
Useful When There Is:





An established relationship between
concentration and response or toxicity
A sensitive and specific assay
An assay that is relatively easy to perform
A narrow therapeutic range
A need to enhance response/prevent
toxicity
Why Measure
Drug Concentrations?
•
•
•
•
Lack of therapeutic response
Toxic effects evident
Potential for non-compliance
Variability in relationship of dose and
concentration
• Therapeutic/toxic actions not easily
quantified by clinical endpoints
Potential for Error When
Using TDM
• Assuming patient is at steady-state
• Assuming patient is actually taking the drug
as prescribed
• Assuming patient is receiving drug as prescribed
• Not knowing when the drug concentration was measured in
relation to dose administration
• Assuming the patient is static and that changes in
condition don’t affect clearance
• Not considering drug interactions