cl in brief

8/7/2019 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

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