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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]
IDEA!
PD
PK
=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.
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”
• 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]
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
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
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