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PHARMACOKINETICS
[Clinical PK]
V
Dr. Rathnakar U.P.
MD.DIH.PGDHM
Associate Professor
Departments of Pharmacology
Kasturba Medical College
Mangalore
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Target Dose
Treatment No effect or adverse effect
Why? Plasma concn. Less or More
How much to increase or decrease? Is loadingdose required? Clinical pharmacokinetics
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PK Parameters for Target
concn.strategy
Bioavailability- F
Clearance- CL
Volume of dist. aVD
Elimination half life- t
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10 Equations
[1]- t=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 xTarget
Cpss/Measured Cpss
[7] CL=Rate of elimination/Plasma concn. [8] V=Amount of drug in the body/Plasma
concn.
[9] F= AUC oral/AUC i.v
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2 Equations!
=Rate of elimination
Plasma concn.
=Amount of drug in the body
Plasma concn.
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Bioavailability
Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
To
systemic
circulation
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
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Bio-availability [F
oral
]
Fraction i.v. = 100% Propranolol95% absorbed Plasma concn-25%-45%
[0.25-0.45] F [Fractional availability]= AUC oral
AUC i.v.
AUC oral
Concn Toxic concn.
Th.Concn.
AUC i.v.
Time30
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V.D
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Drug in beakerDrug + Charcoal in beaker
Concn=20mg/LaVD=10/20mg/L
=0.5L
=Vol.of
beaker
Concn=2mg/L
aVD=10/2mg/L
=5L
=Much more
thanVol.of Beaker
and charcoal
Apparent Volume of Distribution
Vol 0.5L Vol 0.5L
Drug 10mgDrug 10mg
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Distribution. Where do drugs go?
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Volume of distribution
Plasma: 4 liters.
Interstitial volume:
10 liters.
Intracelullar
volume: 28 liters
Relative size of variousdistribution volumes
within
a 70-kg individual
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Blood & Plasma compartment
Vd: around 5 L.
Very high molecular weight
drugs, or drugs that bind to plasma
proteins excesively
Example: Heparin 4L (3-5)
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Extracellular fluid
Vd: between 4 and 14 L.
Drugs that have a low
molecular weight but are
hydrophilic. Example:
Atracuronium 11 L (8-15)
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Vd equal or higher than total body
water
Small water-soluble molecules
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
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Plasma half life [t][Elimination half life]
It is the time required for the plasma conc.of the drug to be reduced to half of itsoriginal [previous] value
Single dose 4-5 t 22
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100
50
150
75
175
87.5
187.5
93.5
193.5
96.5
196.5
98
198
99
199
100
Takes 4-5 half lives to reach steady state concn.
Steady state[Plataeu principle]
Multiple doses
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Target[plasma concn.]level
strategy
Target has to be maintained
1. Effect not quantifiable[antiepileptics]
2. Safety margin is narrow[Digoxin]3. Organ damage
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Drugs with short t1/2
Dose if given [as usually done] at intervals longer than t1/2-
target levels are achieved intermittently
Hours
1 2 34
5 6 7 8 9
Target
80
40
Dose
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Dr gs ith long t1/2 if the dose req ired to prod ce target
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200 mg
198.5197194
97
199
100
99.2598.5
100100100
Concn
Time
Steady state plasma concn.
Dose is large-toxicity
Small dose-delayed effect
200 mg
100 mg
194 mg
[Loading dose][maintenance doses]
Drugs with long t1/2 if the dose required to produce target
concn is repeated will accumulate and produce toxicity
Hence Loading and maintenance dose strategy
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Drugs with long t1/2 if the dose required to produce target
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200 mg
198.5197194
97
199
100
99.2598.5
100100100
Concn
Time
Drugs with long t1/2 if the dose required to produce target
concn is repeated will accumulate and produce toxicity
Hence Loading and maintenance dose strategy
Steady state plasma concn.
200
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Kinetics of Elimination
Clearance
THE CLEARANCE OF A DRUG IS THETHEORETICAL VOLUME OF PLASMAFROM WHICH THE DRUG IS
COMPLETELY REMOVED IN UNIT TIME.
CL=
Rate of elimination
Plasma conc.( C)
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First order[Constant Fraction]
10% of 200mg=20mg
10% of 180mg=18mg
10% of 160mg=16mg
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Pharmacokinetics
10mg
10mg
10mg
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Q. A
Pt. is suffering from acute asthma. What is the 1rate of i.v.infusionand 2loading dose of Theophylline to achieve aTARGET CONCN. OF 10MG./L in a patient Weighing 70kg.?Also calculate the 3maintenance dose by oral route for 48th
hourly,5
12hourly and6
once a dayadministration.What is the 7plasma half life?
Data: 1. CL=2.8L/h/70kg.
2. Foral = 0.96.3. aVD= 35L
4. Target concn=10mg/L
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Half-life
Half life= 0.693xVD/CL
=0.693x35L/70kg2.8L/h/70kg=8.6h
For steady state????= =Data: 1. CL=2.8L/h/70kg.
2. Foral = 0.96.
3. aVD= 35L
4-5 t1/2 36hs
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Calculation Loading dose:
VD= Total amount of drug in the body
Plasma 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. Targetconcn.=10mg/L
[Loading dose]
[target concn]
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Calculation: Dosing rate
Maintenance dose
CL = Rate of elimination
Plasma concn.
= Rate of administration! [Dosing rate] =CLxTarget concn
=Dosing rate = 2.8 L/h/70kg 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= 35L4. Target concn=10mg/L
[Rate of administration!][Target concn.!]
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Calculation
Divided oral doses:
Dosing rate = 28mg/h = 720mg[Appx]/24h
But F= 0.96
So Oral Dosing rate = i.v dosing rate/ 0.96= 750mg.
= Once a day dose = 750mg,= 8thhourly = 750/3 = 250mg tid
= 12thhourly = 750mg/2 = 350 mg bid.
I.V
8th hourlyOnce a day
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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 large doses leadaccumulation and toxicity
If small dose are tried takes very long for
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TDM
Monitoring of therapy by measuring plasmaconcn.
Utilizes the principle that the clinical
response of a drug is directly related toits concentration in blood
Monitoring is carried out to support themanagement of patients receivingcertain drugs
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TDM
Monitoring of therapy by measuring plasma concn
Useful
Narrow therapeutic range,
A direct relationship existsbetween the drug levels in plasmaand the pharmacological or toxiceffects,
The therapeutic effect can not bereadily assessed by the clinicalobservation,
Large individual variability in
steady state plasma concentrationexits at any given dose
Appropriate analytic techniquesare available to determine the drugand metabolite levels.
Not useful
Response easily
measurable
Activated in body Hit and run drugs
Irreversible action
Drugs with widetherapeutic range such
as beta blockers and
calcium channel
blockers. 6
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TDM-Indications
1. Low therapeutic index2. Poorly defined clinical end point
3. Non compliance
4. Therapeutic failure5. Drugs with saturable metabolism
6. Wide variation in the metabolism of
drugs7. Major organ failure
8. Prevention of adverse drug effects
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Revised dosing rate
[After TDM]
Expected concn=10mg/l
Measured by TDM=15mg/L
Revised dosing = Previous D.R x Target Cpss
Rate Measured Cpss
750mg/day x 10mg/L = 500mg/day
15mg/L
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Consider liver
and
renal functions