Introduction to clinical pharmacokinetics

Basic information on clinical pharmacokinetics

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

2. Dr.
Ramesh
Bhandari Basics of Pharmacokinetics
REVISIT

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

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

5. Dr.
Ramesh
Bhandari
Diffusion

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

7. Dr.
Ramesh
Bhandari
NO
Because of SINK Condition
Dilutedin 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.
Ramesh
Bhandari
Carrier Mediated Transport
Facilitated diffusion:

9. Dr.
Ramesh
Bhandari
Carrier Mediated Transport
Active Transport:

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

11. Dr.
Ramesh
Bhandari
Metabolism

12. Dr.
Ramesh
Bhandari
Excretion
Excretory
Route
Mechanism Drug Excreted
Urine Free,Hydrophilic, Unchanged Drugs or
metabolites of MW < 300
Bile ActiveSecretionHydrophilic, Unchanged Drugs or metabolites
of MW > 500
Lung Passive DiffusionGaseousand volatile, Blood and tissue
insoluble drugs
Saliva Passive Diffusion
ActiveTransport
Free,unionized, lipophilicdrugs, some polar
drugs
Milk Passive DiffusionFree,unionized, lipophilicdrugs (basic)
Sweat Passive DiffusionFree,unionized, lipophilicdrugs
IntestinePassive DiffusionWater soluble Ionizeddrugs

13. Dr.
Ramesh
Bhandari
Pharmacodynamics
Itreferstotherelationship
betweendrugconcentrationatthe
siteofactionandtheresulting
effect,includingthetimecourse
andintensityoftherapeuticand
adverseeffects.

14. Dr.
Ramesh
Bhandari
Pharmacodynamicsin relation with Pharmacokinetics
50%
100%
10 100
Fig: Plasma Drug Concentration at the receptor site to effect
Plasma Drug Concentration (mg/ml)
Effect(%)

15. Dr.
Ramesh
Bhandari
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

16. Dr.
Ramesh
Bhandari
Not PRACTICABLE
Because Receptor sites of Drugs are
generally inaccessibleto our
observations.
(Digoxinin Myocardium)
or
widely distributed in the body.

17. Dr.
Ramesh
Bhandari
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.

18. Dr.
Ramesh
Bhandari
Changesin the plasma drug
concentration reflect Proportional
changes in the drug concentration
in other tissues.

19. Dr.
Ramesh
Bhandari
Drug in
Tissue
Drug in
Blood
Sample removed for drug
concentration determination
Most often sampled for drug concentration determination is Blood.

20. Dr.
Ramesh
Bhandari
Fig: Relationship of Plasma to tissue drug concentration
Concentrationof
drug in Tissues
Plasma
drug
concentration

21. Dr.
Ramesh
Bhandari
D
rug
concentration
Time
High
Low
Kidney
Plasma
Receptor
Fig: Drug Concentration versus Time

22. Dr.
Ramesh
Bhandari
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’sdisease and bone in
osteomyelitis)
However this may not be true for all drugs.

23. Dr.
Ramesh
Bhandari
Clinical Correlation
Drugs concentratein some tissuesbecause
of physical or chemical properties.
Examples: digoxin,which concentrates in
the myocardium,
and
lipid-soluble drugs such as benzodiazepines,
which concentrate in fat.

24. Dr.
Ramesh
Bhandari
Clinical Pharmacokinetics
ClinicalPharmacokineticsistheapplicationofthe
pharmacokineticprinciples, using drug
concentrationandpharmacodynamiccriteriato
optimizedrugtherapyinindividualpatient.
Applicationofpharmacokineticprinciplestothesafe
andeffectivetherapeuticmanagementofthedrugsin
patient.
Appliedpharmacokineticsisabroaderterm.

25. Dr.
Ramesh
Bhandari
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.
Ramesh
Bhandari
Linear versus Nonlinear Pharmacokinetics
Whendrugsaregiveninaconstant
basis,suchascontinuousintravenous
infusionoranoralmedicationgiven
every12hours,serumdrug
concentrationsincreasesuntiltherate
ofdrugadministrationequalstherate
ofdrugelimination.

27. Dr.
Ramesh
Bhandari
Whentherateofdrugadministration
equalstherateofdrugelimination,the
amountofdrugcontainedinthebody
reachesaconstantvalue.This
equilibriumconditionisknownas
steadystate.

28. Dr.
Ramesh
Bhandari
Ifasteadystateconcentrationversus
doseyieldsastraightline,thedrugis
saidtofollowLinearpharmacokinetics.
Inthissituationsteadystateserum
concentrationincreasesordecreases
proportionallywithdose.

29. Dr.
Ramesh
Bhandari
Whensteadystateconcentration
changeinadisproportionatefashion
afterthedoseisaltered,aplotofsteady
stateconcentrationversusdoseisnota
straightlineandthedrugissaidto
follownon-linearpharmacokinetics.

30. Dr.
Ramesh
Bhandari
Michaelis-menten
Linear
Saturate Protein
binding or
autoinduction
Dose (mg/d)
Steady state concentration (mg/ml)
0
100
200
300
400
200400600800

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

32. Dr.
Ramesh
Bhandari
Administer
Drug
Obtain Plasma sample
Assay for drug
concentration (D
p)
Calculate Volume
(V
d)
V
d= A/D
p

33. Dr.
Ramesh
Bhandari
V
d= A/D
p
Rearranging: A = V
d*D
p
Suppose you want desirable D
p
Then, A
(target)= V
d*D
p(target)

34. Dr.
Ramesh
Bhandari
If patient has no drug in the body then can
administer an amount called loading dose to
achieve a given A
targetand D
p(target).
Since loading dose must provide A
target
amount of drug in body, since not all
administered dose is absorbed.
LD*B = A
targetthen LD = A
target/ B
LD = V
d* D
p/ B

35. Dr.
Ramesh
Bhandari
LD = V
d* D
p
B
Theamountofdrugthatmustbe
giventoachieverapidlyatarget
concentrationofthedruginthe
plasmaissolelydependsonV
d,B
andD
p.

36. Dr.
Ramesh
Bhandari
V
dis easily obtained
Give bolus of
drug.
Measure plasma
levels overtime.
Extrapolate to
find plasma level
at time 0.
V
d= Dose
IV/ D
p
0
D
p
0
1
2
3
4
5
6
4 812162024
Time (in hours)
Log
Dp
(mcg/ml)

37. Dr.
Ramesh
Bhandari
Examples of using V
dto calculate LD
Pharmacokinetic Parameter
for digoxin
D
p(target) = 1.5 mcg
V
d= 580 L
Oral Bioavailability = 0.7
Calculate LD?

38. Dr.
Ramesh
Bhandari
Concept of Clearance
By definition,
Cl= Rate of Drug Elimination
D
p
Unitof Cl,
Cl= Amount / time = Volume/time
Amount / volume

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

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

41. Dr.
Ramesh
Bhandari
Rearrangingequation of Cl,
D
p= Rate of drug Elimination
Cl
Applyingsteady state in above Clequation,
D
p
ss
= Rate of drug Elimination at steady state
Cl

42. Dr.
Ramesh
Bhandari
Applyingsteady state in above Clequation,
D
p
ss
= R
0
(Rate of drug administration = rate of drug elimination)
Cl
Maintenancedose = amount of drug taken at regular
intervals
Dosing interval =Time between MDs
Bioavailability= fraction of dose absorbed in systemic
circulation

43. Dr.
Ramesh
Bhandari
Rateof drug administration= Amount of drug delivered to the systemic circulation
Time
R
0 = B x MD
DI
Then substituting value of R
0in steady state equation of Cl,
D
p
ss
= B x MD
DI x Cl
Hence, D
p
ss
wont depend on absolute value of MD and DI
but it will depend on ratio of MD and DI

44. Dr.
Ramesh
Bhandari