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Transcript of cl in brief
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Clinical Pharmacokinetics
Introduction
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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 tothe internet.
Work through the presentation at the start of thecourse and note any issue which are not clear.
Read up on areas that you are not familiar withand revisit the presentation from time to time.
Try the powerpoint based exercises
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What is clinical
pharmacokinetics ? Study of the time course of a drugs
movement through the body.
Understanding of what the body does to (orwith) the drug.
Application of Therapeutic Drug Monitoring(TDM) and individualisation of drug therapy.
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Outline
Review of Concepts Clearance, K, Half-Life, Volume of Distribution
Therapeutic drug Monitoring
Pharmacokinetic Drug Interactions
Cases
Discussion/Questions
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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
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Plasma Site
Concen- of
tration ActionEffects
PK PD
Pharmacokinetics (PK) and
pharmacodynamics (PD)
Dose
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Pharmacokinetics vs
Pharmacodynamicsconcept Fluoxetine increases plasma
concentrations of amitriptyline. This is a
pharmacokineticdrug interaction.
Fluoxetine inhibits the metabolism of
amitriptyline and increases the plasmaconcentration of amitriptytline.
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Basic Parameters
In the next few slides the basic concepts andparamaters will be described and explained.
In pharmacokinetics the body is representedas a single or multiple compartments in towhich the drug is distributed.
Some of the parameters are therefore a littleabstract as we know the body is much morecomplicated !
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V
Volume 100 L
Clearance
10 L/hr
Volume of Distribution, Clearance and
Elimination Rate Constant
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V
Volume 100 L (Vi)
Clearance
10 L/hr
Volume of Distribution, Clearance and
Elimination Rate Constant
V2
Cardiac and
Skeletal Muscle
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V
Volume 100 L (Vi)
Clearance10 L/hr
V2
Cardiac and
Skeletal Muscle
Volume of Distribution =
Dose_______
Plasma Concentration
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V
Volume 100 L (Vi)
Clearance10 L/hr
V2
Cardiac and
Skeletal Muscle
Clearance =Volume of blood cleared of drug per unit time
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V
Volume 100 L (Vi)
Clearance10 L/hr
V2
Cardiac and
Skeletal Muscle
Clearance = 10 L/hrVolume of Distribution = 100 L
What is the Elimination Rate Constant (k) ?
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CL = kVk = 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
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CL = kV
If V increases then k must decrease as
CL is constant
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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
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Volume of Distribution
Apparent volume of distribution is thetheoretical volume that would have to be
available for drug to disperse in if theconcentration everywhere in the body werethe same as that in the plasma or serum,the place where drug concentration
sampling generally occurs.
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Volume of Distribution An abstract concept
Gives information on HOW the drug is
distributed in the body
Used to calculate a loading dose
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Loading Dose
Dose = Cp(Target) x VD
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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
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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.
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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 indetermination of maintenance doses
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Maintenance Dose
Calculation
Maintenance Dose = CL x CpSSav
CpSSav is the target average steady statedrug concentration
The units of CL are in L/hr or L/hr/kg
Maintenance dose will be in mg/hr so for totaldaily dose will need multiplying by 24
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Question What maintenance dose is required for
drug A if;
Target average SS concentration is 10mg/L
CL of drug A is 0.015 L/kg/hr
Patient weighs 75 kg
Answer on next slide.
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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
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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.
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Drug Concentration
Time
C1
Exponential decay
dC/dtw C
= -k.CC2
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Log Concn.
Time
C0
C0/2t1/2
t1/2
t1/2
Time to eliminate ~ 4 t1/2
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Integrating:
Cp2=Cp1.e-ktLogarithmic transform:
lnC2= lnC
1- kt
logC2= logC1 - kt/2.303
Elimination Half-Life:
t1/2= ln2/k
t1/2 = 0.693/k
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Steady-State
Steady-state occurs after a drug has been given
for approximately five elimination half-lives.
At steady-state the rate of drug administrationequals the rate of elimination and plasma
concentration - time curves found after each
dose should be approximately superimposable.
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100100
187.5187.5194194
175175
150150
7575
87.587.5 94949797
5050
200200
100100
Accumulation to Steady State
100 mg given every half-life
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C
t
Cpav
Four half lives to reach steady state
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What is Steady State (SS) ?
Why is it important ? Rate in = Rate Out
Reached in 4 5 half-lives (linearkinetics)
Important when interpreting drugconcentrations in TDM or assessingclinical response
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Therapeutic Drug Monitoring
Some Principles
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Therapeutic Index Therapeutic index = toxic dose/effective
dose
This is a measure of a drugs safety
A large number = a wide margin of safety
A small number = a small margin of safety
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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 perfor A narrow therapeutic range
A need to enhance response/preventtoxicity
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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
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Potential for Error When
Using TDM Assuming patient is at steady-state
Assuming patient is actually taking the drugas prescribed
Assuming patient is receiving drug as prescribed
Not knowing when the drug concentration was measured inrelation to dose administration
Assuming the patient is static and that changes incondition dont affect clearance
Not considering drug interactions