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

Plasma Site Concen- of tration Action

Effects

PK PD

Pharmacokinetics (PK) and pharmacodynamics (PD)

Dose

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 !

V

Volume 100 L

Clearance10 L/hr

Volume of Distribution, Clearance and Elimination Rate Constant

V

Volume 100 L (Vi)

Clearance10 L/hr

Volume of Distribution, Clearance and Elimination Rate Constant

V2

Cardiac and Skeletal Muscle

VVolume 100 L (Vi)

Clearance10 L/hr

V2

Cardiac and Skeletal Muscle

Volume of Distribution =

Dose_______Plasma Concentration

VVolume 100 L (Vi)

Clearance10 L/hr

V2

Cardiac and Skeletal Muscle

Clearance =Volume of blood cleared of drug per unit time

VVolume 100 L (Vi)

Clearance10 L/hr

V2

Cardiac and Skeletal Muscle

Clearance = 10 L/hrVolume of Distribution = 100 LWhat is the Elimination Rate Constant (k) ?

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

CL = kVIf 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 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

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

Time

C1

Exponential decay

dC/dt C= -k.C

C2

Log Concn.

Time

C0

C0/2 t1/2

t1/2

t1/2

Time to eliminate ~ 4 t1/2

Integrating:

Cp2 = Cp1.e-kt

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.

100100

187.5187.5194194

175175

150150

757587.587.5 9494 9797

5050

200200

100100……

……

Accumulation to Steady State

100 mg given every half-life

C

t

Cpav

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 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/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 inrelation to dose administration

• Assuming the patient is static and that changes in condition don’t affect clearance

• Not considering drug interactions