Clinical Pharmacokinetics

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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 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

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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 (or with)
  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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Pharmacokinetics (PK) and pharmacodynamics (PD)
Plasma Site
Concen- of
tration Action
Dose
Effects
PK
PD
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Pharmacokinetics vs Pharmacodynamicsconcept

• 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.

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Pharmacokinetics vs Pharmacodynamicsconcept

• 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.

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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 !

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Volume of Distribution, Clearance and Elimination
Rate Constant
V
Volume 100 L
Clearance 10 L/hr
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Volume of Distribution, Clearance and Elimination
Rate Constant
V
Volume 100 L (Vi)
V2 Cardiac and Skeletal Muscle
Clearance 10 L/hr
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Volume 100 L (Vi)
V2 Cardiac and Skeletal Muscle
V
Clearance 10 L/hr
Volume of Distribution
Dose_______ Plasma Concentration
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Volume 100 L (Vi)
V2 Cardiac and Skeletal Muscle
V
Clearance 10 L/hr
Clearance Volume of blood cleared of drug per
unit time
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Volume 100 L (Vi)
V2 Cardiac and Skeletal Muscle
V
Clearance 10 L/hr
Clearance 10 L/hr Volume of Distribution 100
L What is the Elimination Rate Constant (k) ?
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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
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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 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.

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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 in determination of
  maintenance doses

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Maintenance DoseCalculation

• 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

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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.

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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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Exponential decay
dC/dt ? C
-k.C
C2
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C0
C0/2
t1/2
t1/2
t1/2
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Integrating
Logarithmic transform
lnC2 lnC1 - kt
logC2 logC1 - kt/2.303
Elimination Half-Life
t1/2 ln2/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 administration
  equals the rate of elimination and plasma
  concentration - time curves found after each dose
  should be approximately superimposable.

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Accumulation to Steady State 100 mg given every
half-life
200

194
187.5
175
150
100

97
100
94
87.5
75
50
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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

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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 BeUseful 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/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
  andconcentration
• Therapeutic/toxic actions not easilyquantified
  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 drug as
  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
  in condition dont affect clearance
• Not considering drug interactions