Dr. Rathnakar U.P.

MD.DIH.PGDHM

Associate Professor
Departments of Pharmacology
Kasturba Medical College,
Mangalore

36
Determination of drug dose
[Clinical PK]

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
35
Target 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

34
PK Parameters for Target
concn.strategy

33
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 x Target
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
32
2 Equations!
=Rate of elimination
Plasma concn.
=Amount of drug in the body
Plasma concn.
31
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
31
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.
Time
30

V.D
29
Drug in beaker
Drug + Charcoal in beaker
Concn=20mg/L
aVD=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 10mg
Drug 10mg
28
Distribution. Where do drugs go?
27
Volume of distribution
Plasma: 4 liters.


Interstitial volume:
10 liters.

Intracelullar
volume: 28 liters
Relative size of various
distribution volumes
within
a 70-kg individual
26
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)
25
Extracellular fluid
Vd: between 4 and 14 L.
Drugs that have a low
molecular weight but are
hydrophilic.
Example:
Atracuronium 11 L (8-15)

24
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
23
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 its
original [previous] value
Single dose 4-5 t
22
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
21
Target[plasma concn.]level
strategy
Target has to be maintained
1. Effect not quantifiable[antiepileptics]
2. Safety margin is narrow[Digoxin]
3. Organ damage
20
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 3
4
5
6
7 8 9
Target
80
40
Dose
19
200 mg
198.5
197 194
97
199
100
99.25
98.5
100 100
100
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
18
200 mg
198.5
197 194
97
199
100
99.25
98.5
100 100
100
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
17
Kinetics of Elimination
Clearance
THE CLEARANCE OF A DRUG IS THE
THEORETICAL VOLUME OF PLASMA
FROM WHICH THE DRUG IS
COMPLETELY REMOVED IN UNIT TIME.

CL=
Rate of elimination
Plasma conc.( C)

16
First order[Constant Fraction]
10% of 200mg=20mg
10% of 180mg=18mg
10% of 160mg=16mg
15
Pharmacokinetics
10mg
10mg
10mg
14
Q. A


Pt. is suffering from acute asthma. What is the
1
rate of i.v.
infusion and
2
loading dose of Theophylline to achieve a
TARGET CONCN. OF 10MG./L in a patient Weighing 70kg.?
Also calculate the
3
maintenance dose by oral route for
4
8
th

hourly,
5
12 hourly and
6
once a day administration.
What is the
7
plasma half life?

Data: 1. CL=2.8L/h/70kg.
2. F
oral
= 0.96.
3. aVD= 35L
4. Target concn=10mg/L
13
Half-life

Half life= 0.693xVD/CL

=0.693x35L/70kg
2.8L/h/70kg
=8.6h
For steady state????= =

Data: 1. CL=2.8L/h/70kg.
2. F
oral
= 0.96.
3. aVD= 35L

4-5 t1/2 36hs
12
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. F
oral
= 0.96.
3. aVD= 35L
4. Target
concn.=10mg/L
[Loading dose]
[target concn]
11
Calculation: Dosing rate
Maintenance dose

CL = Rate of elimination
Plasma concn.
= Rate of administration! [Dosing rate] =CLx Target 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. F
oral
= 0.96.
3. aVD= 35L
4. Target concn=10mg/L
[Rate of administration!]
[Target concn.!]
10
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,
= 8
th
hourly = 750/3 = 250mg tid
= 12
th
hourly = 750mg/2 = 350 mg bid.


I.V
8th hourly
Once a day
9
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 lead
accumulation and toxicity
If small dose are tried takes very long for
the effect

8
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
7
TDM
Monitoring of therapy by measuring plasma concn

Useful
Narrow therapeutic range,
A direct relationship exists
between the drug levels in plasma
and the pharmacological or toxic
effects,
The therapeutic effect can not be
readily assessed by the clinical
observation,
Large individual variability in
steady state plasma concentration
exits at any given dose
Appropriate analytic techniques
are available to determine the drug
and metabolite levels.
Not useful
Response easily
measurable
Activated in body
Hit and run drugs
Irreversible action
Drugs with wide
therapeutic range such
as beta blockers and
calcium channel
blockers.
6
TDM-Indications

1. Low therapeutic index
2. Poorly defined clinical end point
3. Non compliance
4. Therapeutic failure
5. Drugs with saturable metabolism
6. Wide variation in the metabolism of
drugs
7. Major organ failure
8. Prevention of adverse drug effects
5
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

4
Consider liver
and
renal functions
3