Basic concepts of Clinical Pharmacokinetics

1. CLINICAL
PHARMACOKINETICS
Dr. Ramesh Bhandari
Asst. Professor,
Department of Pharmacy Practice
KLE College of Pharmacy, Belagavi

2. Dr.RameshBhandari
Basics of
Pharmacokinetics
REVISIT

3. Dr.RameshBhandari
Pharmacokinetics
The study of the time course of
 Absorption
 Distribution
 Metabolism
 Excretion

4. Dr.RameshBhandari
Mechanism of Absorption
1. Passive Diffusion
2. Carrier meditated Transport
i. Facilitated Diffusion
ii. Active Transport

5. Dr.RameshBhandari
Diffusion

6. Dr.RameshBhandari
Passive Diffusion
Is it possible to attain this equilibrium?

7. Dr.RameshBhandari
NO
Because of SINK
Condition Diluted in blood
 Distributed in tissues
 Protein bound
 Metabolized &
 Excreted
So, the concentration of the GIT is always greater
than the concentration of the drug in blood.

8. Dr.RameshBhandari
Carrier Mediated Transport
Facilitated diffusion:

9. Dr.RameshBhandari
Carrier Mediated Transport
Active Transport:

10. Dr.RameshBhandari
Distribution
100 mg of Drug absorbed
Fat 25%
Plasma Proteins 13% Target Tissue 2%
Tissue 50%
Plasma 10%

11. Dr.RameshBhandari
Metabolism

12. Dr.RameshBhandari
Excretion
Excretory
Route
Mechanism Drug Excreted
Urine Free, Hydrophilic, Unchanged Drugs or
metabolites of MW < 300
Bile Active Secretion Hydrophilic, Unchanged Drugs or
metabolites of MW > 500
Lung Passive
Diffusion
Gaseous and volatile, Blood and tissue
insoluble drugs
Saliva Passive
Diffusion
Active Transport
Free, unionized, lipophilic drugs, some
polar drugs
Milk Passive
Diffusion
Free, unionized, lipophilic drugs (basic)

13. Dr.RameshBhandari
A drug’s effect its concentration
at the SITE OF ACTION
Is it PRACTICABLE to measure the
drug concentration in the
RECEPTOR SITES / TISSUES??
Depends on

14. Dr.RameshBhandari
Not PRACTICABLE
Because Receptor sites of Drugs are
generally inaccessible to our
observations.
(Digoxin in Myocardium)
or
widely distributed in the body.

15. Dr.RameshBhandari
Then, How to Measure
Drug Concentration??
Answer is:
Kinetic Homogeneity
It describes the predictable relationship
between plasma drug concentration and
concentration at the receptor site.

16. Dr.RameshBhandari
Changes in the plasma drug
concentration reflect
Proportional changes in the
drug concentration in other
tissues.

17. Dr.RameshBhandari
Drug in
Tissue
Drug in
Blood
Sample removed for drug
concentration determination
Most often sampled for drug concentration determination is
Blood.

18. Dr.RameshBhandari
Fig: Relationship of Plasma to tissue drug concentration
Concentration of
drug in Tissues
Plasmadrug
concentration

19. Dr.RameshBhandari
Drug
concentration
Time
High
Low
Kidney
Plasma
Receptor
Fig: Drug Concentration versus Time

20. Dr.RameshBhandari
 Pharmacokinetic homogeneity is the foundation
on which all therapeutic and toxic plasma drug
concentrations are established.
 When studying concentration of drug in plasma,
we assume that these plasma concentrations
directly relate to concentrations in tissues where
the disease is to be modified by the drug. (e.g.
CNS in parkinson’s disease and bone in
osteomyelitis)
 However this may not be true for all drugs.

21. Dr.RameshBhandari
Clinical Correlation
Drugs concentrate in some tissues because
of physical or chemical properties.
Examples: digoxin, which concentrates in
the myocardium,
and
lipid-soluble drugs such as benzodiazepines,
which concentrate in fat.

22. Dr.RameshBhandari
Pharmacodynamics
 It refers to the relationship
between drug concentration at the
site of action and the resulting
effect, including the time course
and intensity of therapeutic and
adverse effects.

23. Dr.RameshBhandari Pharmacodynamics in relation with
Pharmacokinetics
50%
100%
1
0
100
Fig: Plasma Drug Concentration at the receptor site to effect
Plasma Drug Concentration
(mg/ml)
Effect(%)

24. Dr.RameshBhandari
Clinical Pharmacokinetics
 Clinical Pharmacokinetics is the application of the
pharmacokinetic principles, using drug
concentration and pharmacodynamic criteria to
optimize drug therapy in individual patient.
 Application of pharmacokinetic principles to the safe
and effective therapeutic management of the drugs in
patient.
 Applied pharmacokinetics is a broader term.

25. Dr.RameshBhandari Applications of Clinical
Pharmacokinetics
 TDM
 Dosage Adjustment in an individual patient
 Formulation development: BA/BE, ADME
studies
 Drug development process: Deciding Dosage
regimen
 Rational Drug design

26. Dr.RameshBhandari Linear versus Nonlinear
Pharmacokinetics
 When drugs are given in a constant
basis, such as continuous intravenous
infusion or an oral medication given
every 12 hours, serum drug
concentrations increases until the rate
of drug administration equals the rate
of drug elimination.

27. Dr.RameshBhandari
 When the rate of drug administration
equals the rate of drug elimination, the
amount of drug contained in the body
reaches a constant value. This
equilibrium condition is known as
steady state.

28. Dr.RameshBhandari
 If a steady state concentration versus
dose yields a straight line, the drug is
said to follow Linear pharmcokinetics.
 In this situation steady state serum
concentration increases or decreases
proportionally with dose.

29. Dr.RameshBhandari
 When steady state concentration
change in a disproportionate fashion
after the dose is altered, a plot of steady
state concentration versus dose is not a
straight line and the drug is said to
follow non-linear pharmacokinetics.

30. Dr.RameshBhandari
Michaelis-menten
Linear
Saturate Protein
binding or
autoinduction
Dose (mg/d)
Steadystate
concentration(mg/ml)
0
100
200
300
400
200 400 600 800

31. Dr.RameshBhandari
Concept of Distribution
Add Drug Obtain a sample
Assay for concentration
Calculate Volume
Drug concentration = Amount added / volume of beaker

32. Dr.RameshBhandari
Administer
Drug
Obtain Plasma sample
Assay for drug
concentration (Dp)
Calculate Volume
(Vd)
Vd = A/Dp

33. Dr.RameshBhandari
Vd = A/Dp
Rearranging: A = Vd*Dp
Suppose you want desirable Dp
Then, A(target) = Vd*Dp(target)

34. Dr.RameshBhandari  If patient has no drug in the body then can
administer an amount called loading dose to
achieve a given Atarget and Dp(target).
 Since loading dose must provide Atarget
amount of drug in body, since not all
administered dose is absorbed.
 LD*B = Atarget then LD = Atarget / B
 LD = Vd * Dp / B

35. Dr.RameshBhandari
LD = Vd * Dp
B
The amount of drug that must be
given to achieve rapidly a target
concentration of the drug in the
plasma is solely depends on Vd, B
and Dp.

36. Dr.RameshBhandari Vd is easily obtained
 Give bolus of
drug.
 Measure plasma
levels overtime.
 Extrapolate to
find plasma level
at time 0.
Vd = DoseIV / Dp
0
Dp
0
1
2
3
4
5
6
4 8 12 16 20 24
Time (in hours)LogDp(mcg/ml)

37. Dr.RameshBhandari Examples of using Vd to calculate
LD
Pharmacokinetic Parameter
for digoxin
 Dp(target) = 1.5 mcg
 Vd = 580 L
 Oral Bioavailability = 0.7
Calculate LD?

38. Dr.RameshBhandari
Concept of Clearance
By definition,
Cl = Rate of Drug Elimination
Dp
Unit of Cl,
Cl = Amount / time = Volume/time
Amount / volume

39. Dr.RameshBhandari
Concept of Clearance
 Clearance determines the maintenance
dose (MD) that is required to obtain a
given steady-state serum concentration
(Css).
MD = Css.Cl

40. Dr.RameshBhandari How does Clearance influence
Dp
ss
 According to definition,
Steady state is said to exist when:
Rate of Drug Administration = Rate of drug elimination

41. Dr.RameshBhandari
 Rearranging equation of Cl,
Dp = Rate of drug Elimination
Cl
 Applying steady state in above Cl equation,
Dp
ss = Rate of drug Elimination at steady state
Cl

42. Dr.RameshBhandari  Applying steady state in above Cl equation,
Dp
ss = R0 (Rate of drug administration = rate of drug elimination)
Cl
Maintenance dose = amount of drug taken at regular
intervals
Dosing interval = Time between MDs
Bioavailability = fraction of dose absorbed in systemic
circulation

43. Dr.RameshBhandari
Rate of drug administration = Amount of drug delivered to the systemic circulation
Time
R0 = B x MD
DI
Then substituting value of R0 in steady state equation of Cl,
Dp
ss = B x MD
DI x Cl
Hence, Dp
ss wont depend on absolute value of MD and DI
but it will depend on ratio of MD and DI

44. Dr.RameshBhandari