od surgeons and physicians’ Clinical trial

Clinical PK
And
Clinical trials

Dr.U.P.Rathnakar
MD.DIH.PGDHM
www.pharmacologyfordummies.blogspot.c
 Why physicians and surgeons
should waste time on
pharmacology?
• Dose predictions
• Dose? ←Narrow TI[Digoxin, Li]
• Range →OK for Wide TI
• Mfrs → Dose range
• Doses →Mfrs. [Population PK]
• PK →Dose
• PD →Effect of drugs & ADE
• Pharmacology →Therapeutics
• Clinical knowledge → Diagnosis
 Dose
• Treatment
• ↓
• No effect or adverse effect
• ↓
• Why?
• ↓
• Plasma concn. Less or More
• ↓
• How much to increase or decrease? Is
loading dose required?
• ↓
• Clinical pharmacokinetics
 Target concentration[Dose]

80% chance of beneficial eff

Quinidine 8 mg/L

20% chance of adverse effe

o attention was paid PK

arget concn.-based on PD-good & ba

IDEA!

Drug concn. Therapeutic

decisions
 Target concentration[Dose]
[Therapeutic triangle]
Appropriate dose Rational Desired Th.effect
Therapeutics

PD
PK

VD Target Concentration Emax

CL intervention EC50

Dose [Plasma] Concentration Effect

 PK Parameters for Target
concn.strategy
• Bioavailability-
F
• Elimination half life-
t½
• Clearance-
CL
• Volume of dist.
 10 Equations!
• [1]- t½=0.7xV/CL
• [2]- Cpss=Dose rate/CL
• [3] Dosing rate=Target CpssxCL
• [4] Dosing rate=Target
CpssxCL/F
• [5] Loading dose=targetCpxV/F
• [6] Revised dose rate=Previous D.R x
Target Cpss/Measured
Cpss
• [7] CL=Rate of elimination/Plasma
concn.
• [8] V=Amount of drug in the
2 Equations!

=Amount of drug in
the body
Plasma
concn.

=Rate of
elimination
Plasma concn.
 Bio-availability [Foral]
• Fraction
• i.v. = 100%
• Propranolol→95% absorbed →Plasma concn-25%-45%
[0.25-0.45]
• F [Fractional availability]= AUC oral
AUC i.v.

Concn Toxic concn.

AUC i.v.
Th.Concn.
AUC oral

Time
 V.D
• Factors affecting
• Lipidsolubility & Ionization-Lignocaine
and Heparin
• Plasma protein binding
• Tissue binding-Digoxin bound to
heart,liver
• Disease-CHF, Uremia
• Fat:Lean body mass
 Apparent Volume of Distribution
Drug + Charcoal in
Drug in beaker
beaker Drug=10mg
Drug=10mg Concn=2mg/L
Concn=20mg/ aVD=10/2mg/
L L
aVD=10/20m =5L
g/L =Much
=0.5L
0.5L =Vol.of
0.5L more
thanVol.of
Beaker

beaker
5L and charcoal
 Apparent volume of distribution
• aVD: “The volume that would accommodate all the
drug in the body, if the concn.throughout was the
same as in plasma”

• Lipid insoluble: Small aVD-Eg.Gentamicin-.25L/kg

• Highly protein bound-Eg.Diclofenac-0.15L/kg.

• Highly tissue bound-Eg.Morphine-3.5L/kg

 High vol. of distribution-poisoning-difficult to remove

by dialysis
Distribution. Where do drugs go?
 Volume of distribution
Relative size of various
distribution volumes
within
• Plasma: 4
a 70-kg individual liters.
• Interstitial
volume: 10
liters.
• Intracelullar
volume: 28
liters
Plasma compartment

• Vd: around 5 L.
• Very high molecular
weight drugs, or drugs
that bind to plasma
proteins excesively
• Example: Heparin 4L (3-
5)
Extracellular fluid
Vd: between 4 and 14
L.
Drugs that have a low
molecular weight but
are hydrophilic.
Example:
Atracuronium 11 L (8-
15)
Vd equal or higher than total body
water

• Diffusion to intracelullar
fluid . Vd equal to total
body water.
– Ethanol 38 L (34-41)
– Alfentanyl 56 L (35-77)
• Drug that binds strongly to
tissues. Vd higher than
total body water.
– Fentanyl: 280 L
– Propofol: 560 L
– Digoxin:385 L
 Plasma half life [t½]
[Elimination half life]

It is the time required for the plasma conc. of

the drug to be reduced to half of its original
value

Single dose 4-5 t½

Takes 4-5 halflives to reach steady state
concn. 193.5
196.5 198 199
Steady state
187.5 [Plataeu principle

175
98 99
96.5
150 93.5

87.5
100
75 Multiple
100 doses

50
 194

Loading Dose
•Drugs with long t1/2
•In emergency

Concn

199
194 197
198.5
Steady state plasma concn

98.5 99.25
97

194 mg 100 100

100 100
Time
Models
of drug
distribution
and
elimination
 Kinetics of Elimination
1. Clearance
THE CLEARANCE OF A DRUG IS THE
THEORETICAL VOLUME OF PLASMA
FROM WHICH THE DRUG IS
COMPLETELY REMOVED IN UNIT TIME.
Rate of elimination
CL= …………………………
Plasma conc.( C)
First order[Constant
Fraction]

10% of 200mg=20mg

10% of 180mg=18mg

10% of 160mg=16mg
Pharmacokinetics

10mg

10mg

10mg
Q. A Pt. is suffering from acute asthma.
What is the rate of i.v. infusion and loading
dose of Theophylline to achieve a TARGET
CONCN. OF 10MG./L in a patient
Weighing 70kg.?
Also calculate the maintenance dose by
oral route for 8th hourly,12 hourly and once
a day administration.

Data:
1. CL=2.8L/h/70kg.
2. Foral = 0.96.
3. aVD= 35L
 Calculation
Loading dose:
Loading dose:
VD= Total amount of drug[Loading dose]
in the body
Plasma concn.
[target concn]
= Loading dose = VD x Target concn.
= 35L x 10mg/L
=Loading dose= 350mg. Given as bolus
i.v

Data:
1. CL=2.8L/h/70kg.
2. Foral = 0.96.
3. aVD= 35L
4. Target
concn.=10mg/L
 Calculation: Dosing rate:
Dosing rate:
[Rate of administration!]
CL = Rate of elimination
[Target concn.!]
Plasma concn.
= Rate of administration! [Dosing rate] =CLx
Target concn

=Dosing rate = 2.8 L/h x 10mg/L =

= Dosing rate[i.v.infusion]= 28mg/h/70kg
man.
Data:
1. CL=2.8L/h/70kg.
2. Foral = 0.96.
3. aVD= 35L
4. Target
 Calculation
d oral doses:
ng rate = 28mg/h = 720mg[Appx]/24h
F= 0.96
ral Dosing rate = i.v dosing rate/ 0.96= 7
ce a day dose = 750mg,
hourly = 750/3 = 250mg tid
hourly = 750mg/2 = 350 mg bid.
Once a day

8 th hourly

I.V
 Dosage regimens
• Target level strategy: Why?
 Effect not quantifiable[anti-epileptic, anti-
deppressants]
 Narrow safety margin[Theophylline, Digoxin]
• Loading and maintenance dose: Why?
• Drugs with long t1/2-
 If the initial dose is large to achieve target
level- subsequent doses leads accumulation
and toxicity
 If small dose are tried takes very long for
the effect
 Loading Dose
•Drugs with long t1/2
•In emergency

Dose is large

Concn

199
194 197
198.5
Steady state plasma concn

Small dose

98.5 99.25
97

194 mg 100 100

100 100
Time
 TDM
• Monitoring of therapy by measuring
plasma concn.
•Utilizes the principle that the
clinical response of a drug is
directly related to its concentration
in blood

•Monitoring is carried out to

support the management of patients
receiving certain drugs
 TDM
Monitoring of therapy by measuring plasma
concn
Useful Not useful
• Low safety margin- • Response easy to
eg.digoxin, measure-BP, blood
Theophylline sugar, GA
• Individual variations • Activated in body-
large-Li levodopa
• Renal failure-AG • Hit & run drugs-
Reserpine
• Failure to respond-
AMA • Irreversible action-
OP
• Check Pt.
compliance
 Revised dosing rate
• Cpss- Depends on V, CL, F
• Each of these show individual variation
• Cpss May vary between 1/3 to 3 times.

• Revised dosing = Previous D.R x

Target Cpss
Rate Measured Cpss

• 750mg/day x 10mg/L = 500mg/day

15mg/L
Consider liver
and
renal functions
Thank You