1. Clinical Pharmacokinetics
Introduction

2. 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

3. 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.

4. Outline Review of Concepts Therapeutic drug Monitoring
Clearance, K, Half-Life, Volume of Distribution
Therapeutic drug Monitoring
Pharmacokinetic Drug Interactions
Cases
Discussion/Questions

5. 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

6. Pharmacokinetics (PK) and pharmacodynamics (PD)
Plasma Site
Concen of
tration Action
Dose
Effects PK PD

7. 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.

8. 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.

9. 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 !

10. Volume of Distribution, Clearance and Elimination Rate Constant
Volume 100 L
Clearance
10 L/hr

11. Volume of Distribution, Clearance and Elimination Rate Constant
Volume 100 L (Vi) V2
Cardiac and
Skeletal Muscle
Clearance
10 L/hr

12. Volume of Distribution =
Cardiac and
Skeletal Muscle
Volume 100 L (Vi) V
Clearance
10 L/hr
Volume of Distribution =
Dose_______
Plasma Concentration

13. Volume of blood cleared of drug per unit time
Cardiac and
Skeletal Muscle
Volume 100 L (Vi) V
Clearance
10 L/hr
Clearance =
Volume of blood cleared of drug per unit time

14. Volume 100 L (Vi) Clearance = 10 L/hr Volume of Distribution = 100 L
Cardiac and
Skeletal Muscle
Volume 100 L (Vi) V
Clearance
10 L/hr
Clearance = 10 L/hr
Volume of Distribution = 100 L
What is the Elimination Rate Constant (k) ?

15. 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

16. CL = kV
If V increases then k must decrease as CL is constant

17. 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

18. 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.

19. Volume of Distribution
An abstract concept
Gives information on HOW the drug is distributed in the body
Used to calculate a loading dose

20. Loading Dose
Dose = Cp(Target) x VD

21. 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

22. Answer: Loading Dose of Drug A
Dose = Target Concentration x VD
VD = 0.75 L/kg x 75 kg = L
Target Conc. = 10 mg/L
Dose = 10 mg/L x L
= 565 mg
This would probably be rounded to 560 or even 500 mg.

23. 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

24. 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

25. Question What maintenance dose is required for drug A if;
Target average SS concentration is 10 mg/L
CL of drug A is L/kg/hr
Patient weighs 75 kg
Answer on next slide.

26. Answer Maintenance Dose = CL x CpSSav
CL = L/hr/kg x 75 = L/hr
Dose = L/hr x 10 mg/L = mg/hr
So will need x 24 mg per day = 270 mg

27. 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.

28. Intravenous Bolus Injection dC/dt œ C = -k.C = -(CL/V).C
Drug Concentration
Time C1
Exponential decay
dC/dt  C
= -k.C C2
Intravenous Bolus Injection
Exponential Decay:
dC/dt œ C = -k.C = -(CL/V).C
Integrating:
C(t) = C(0).e-kt

29. Intravenous Bolus Injection log C(t) = log C(0) - (kt/2.303)
Log Concn.
Time C0
C0/2
t1/2
t1/2
t1/2
Intravenous Bolus Injection
Logarithmic Transform:
log C(t) = log C(0) - (kt/2.303)
Elimination Half-Life:
t1/2 = ln 2/k = V/CL
Time to eliminate ~ 4 t1/2

30. Logarithmic transform: Elimination Half-Life:
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

31. 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.

32. Accumulation to Steady State 100 mg given every half-life…
200
194
187.5
175
150
100 … 97
100 94
87.5 75 50

34. 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

35. Therapeutic Drug Monitoring
Some Principles

36. 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

37. 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

38. 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

39. 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