SEMINAR ON

DOSAGE REGIMEN AND REPETITIVE DOSING

PRESENTED BY-
Chandan Kumar Singh
M.Pharm
(Pharmaceutics)
 INTRODUCTION
OBJECTIVE OF DOSAGE REGIMEN
THARAPEUTIC DRUG MONITORING
DOSE SIZE AND DOSE FREQUENCY
MULTIPLE DOSING REGIMEN
REPETITIVE AND INTERMITENT IV INJECTION
MULTIPLLE-ORAL-DOSE REGIMEN
LOADING AND MAINTENANCE DOSE

REFERENCES

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Dosage Regimen is defined as the manner in which
a drug is taken .

Multiple Dosage Regimen is one which the drug is

administered in a suitable dose ( by a suitable route) , with
sufficient frequency that ensure maintenance of plasma conc.
with in therapeutic window for entire duration of therapy.

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The overall objective of dosage regimen design is to
achieve a target drug concentration at the receptor
site

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 Examine patient, collect data, and make diagnosis

Define therapeutic objective

Choose Drug and Dosage Regimen

Evaluate how Modify Regimen

Modify Or
objective well objective
has been Change Drug
achieved
Continue Stop
Regimen Therapy

Steps in the initiation and management of the drug therapy

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The success of Drug therapy is highly dependent on
Choice of Drug and Drug Product
Design of the Dosage Regimen
While the choice of Drug and Drug product is based on
Patient's characteristics
Pharmacokinetic of Drug

Every patient have different Drug absorption,

distribution, and elimination as well as different
pathophysiological condition, so for the improvement in
the clinical effectiveness of the drug THERAPEUTIC
DRUG MONITORING are done.
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Function of Therapeutic Drug Monitoring
Selection of Drug

Dosage Regimen Design

Evaluation of Patient Response

To Determine need for measuring serum drug conc.

Monitoring serum drug concentration

Assay of drug concentration in biological fluid

Pharmacokinetic evaluation of drug concentration

Recommend special requirement. 7

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 Drug selection-
Done by Physician on the basis of -
Therapeutic consideration and therapeutic equivalence
Pharmacokinetic and Pharmacodynamic data of
drug are periodically reviewed and updated by
Institutional Pharmacy and Therapeutic committees.
Factor Producing variability in Drug response
A. Age
A. Weight
B. Pathophysiology
C. Nutritional status
D. Genetic variability
E. Gender
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Generally , the initial dosage of the drug is estimated
using average population pharmacokinetic parameter
obtained from the literature.

After evaluation of the patient , adjustment of the dosage

regimen using the patients individual pharmacokinetic
may be indicated , with further therapeutic drug
monitoring.

Many software are available for dose calculation.,

Datakinetic(ASHSP)
Abbottbase Pharmacokinetic system
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1 ) INDIVIDUALIZED DOSAGE REGIMEN-
Most accurate approach
Based on patients age, weight, lean body weight and
creatinine clearance
Not feasible for calculation of initial dose

2 ) DOSAGE REGIMEN BASED ON POPULATION

AVERAGES
This method used avg. Pharmacokinetic parameter
obtained from clinical studies published in drug
literature.
based on
Fixed model
Adaptive model
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Fixed model assume that
Pharmacokinetic parameter such as Ka, F, Vd and
KE are remain constant.
Drug follow the Pharmacokinetic of a One-
compartment model.
In case multi-dosage regimen , multi dose eq. are
used to calculate Dose.

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Adaptive model based on

patient variable such as weight, age, sex,

body surface area and patient
Pathophysiology such as renal disease

It assume that pharmacokinetic parameter

such as drug clearance do not change from
one dose to the next.

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3) Dosage regimen based on partial
Pharmacokinetic parameters
For many drugs, the entire pharmacokinetic profile
for the drug is not available, so some assumption are
made to calculate the dosage regimen( e.g. use of avg.
Patient population characteristics).
4) Empirical Dosage Regimen
Dosage regimen are calculated on the basis of -
Empirical clinical data
Personal experience
Clinical observation

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 Drug Dosage Form
Selection of dosage form depends upon
Route of administration
Desired onset and duration of clinical response
Because it directly affect the
Rate of absorption
Drug bioavailability

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Evaluation of Patient response
After selection of drug product, patient receives the
initial dosage regimen
Dosage regimen are reviewed for
Adequacy
Accuracy
Patient compliance
Measurement of serum Drug concentration
It relate the therapeutic or toxic effect of the drug.
Blood sample are taken at 3 or 4 elimination half
life approximately give steady state drug conc.

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Assay of Drug -
Techniques used for drug measurement are -
High pressure liquid chromatography
Gas chromatography
Spectrophotometery
Fluorometery
Immuonoassay
Radio isotopic method

e.g. Abbott TDx system ( fluoresscence

polarization immunoassay ) for antiarrhythmics
& aminoglycoside.

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Method used for assay of drug should be validated for-

Specificity
Sensitivity
Linearity and dynamic range
Precision
Accuracy
Ruggedness
Pharmacokinetic evaluation of serum drug conc.
After the assay of drug conc. in serum ,data are
evaluated for the total drug ( free plus bound drug )
conc. in serum.
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Serum conc. lower than anticipated

Patient compliance
Error in dosage regimen
Wrong drug product
Poor bioavailability
Rapid elimination
Reduced plasma protein binding
Enlarged volume of distribution
Timing of blood sample
Changing hepatic blood flow
Steady state not reached

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 Serum conc. Higher than anticipated
Rapid bioavailability
Smaller than anticipated apparent volume of
distribution
Slow elimination
Increased plasma protein binding
Drug interaction due to inhibition of elimination
Serum conc. correct but patient does not respond
to therapy
Altered receptor sensitivity
Drug interaction at receptor site
Changing hepatic blood flow

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Dosage adjustment-
Dosage adjustment are done on the basis of
Pharmacokinetic parameter derived from the
Patients serum drug concentration.

Special Recommendation-
If the patient may not response to drug therapy
due to other factor, special recommendation are
given
e.g. Patient noncompliance

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Major parameter in development of dosage regimen

1) Dose size- The quantity of drug administered each time

2 ) Dosing frequency The interval between doses.

DOSE SIZE -
The magnitude of both therapeutic and toxic responses
depends upon the dose size.

Greater the dose size, greater the fluctuation between

Css,max and Css,min during each dosing interval and
greater the chance of toxicity.
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 PLOT SHOWING EFFECT OF DOSE SIZE
DOSES

Plasma conc.

MSC

MEC

Time( in hr)
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 DOSE FREQUENCY -
Calculated on the basis of half life of the drug.

If the interval is increased and the dose is unchanged ,

Cmax , Cmin and Cav decrease but the ratio
Cmax/Cmin increase and vice versa also , leads to
greater drug accumulation in the body and toxicity.

A proper balance between both dose size and dosing

frequency is often desired to attain steady state conc.
with min. fluctuation and to ensure therapeutic
efficacy and safety

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When the half life of the drug is long e.g. Amiodarone
( 25 days )
At first ,800 to 1600 mg/day taken in divided dose. Then
600 mg to 800 mg per day for 1 month followed by 400 mg
per day.

When the half of the drug is short, e.g. diclofenac,

morphine, metoprolol

1) Diclofenac conventional, enteric , extended release tablet

2) Metoprolol conventional and sustained release tablet

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 PLOT SHOWING EFFECT OF DOSING FREQUENCY

High dosing
frequency (<
t ),lesser
Plasma conc.

fluctuation
MSC
Optimum
dosing
frequency(=
t )
MEC
Less
dosing
frequency
(> t )
Time ( hr)
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 When the duration of treatment of disease is smaller
than the therapeutic activity of drug, single dose are
given e.g. Aspirin

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 When the duration of treatment of disease is larger
than the therapeutic effect of drug, Multiple dosage
regimen are given e.g. antibiotics

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 Drug Accumulation -
When the drug is administered at a fixed dose and a
fixed dosing interval, accumulation occur because
drug from previous dose has not been remove.
Accumulation of drug depend upon the dosing
interval and elimination half life and is independent
of the dose size.

Accumulation index = 1
1 e- K E
= Dosing interval
KE = Elimination half life
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 In drug accumulation,
Time for 90% steady state plasma conc. 3.3 times
of elimination half life.
Time for 99% steady state plasma conc. 6.6 times
of elimination half life
X0 X0 X0 X0 X0
Amount of drug in the body

Upper
Asymptote,
2X0 Xss,max
Xo +X0
Steady state

1X0 Lower
asymptote,
Xo Xss,min

0 Dosing interval in hr ( = t) 5
 e. g. of Drug Accumulation

For a avg. adult , rate of metabolism of ethanol

is 10 gm/hr

45 ml of whiskey contain 14 gm of ethanol.

If drink 45 ml of whiskey every hr, will

accumulate 4 gm ethanol per hr and develop
coma in 48 hr.

However, can drink 30ml whiskey ( 9 gm

ethanol) every hr.
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After single rapid IV injection,
DB = D0e-k t
If the is the dosing interval, then amount of drug
remaining in the body after several hr,
DB= D0e-k
The fraction of the Dose remaining in the body
f = DB/D0 = e -k

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 Problem of missed Dose -
Plasma drug conc. at t hr after the nth dose-
-k t -nk
Cp = D0 e (1e )/ VD ( 1 e -k ) 1

Conc. contributed by missing dose is

Cp = D0 e-k tmiss/ VD2

So missing dose, (eq 1 eq 2)is

-nk -k t
Cp = D0(1 e )(e - e -k tmiss )/VD( 1 e -kt)

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 If the missing dose is recent, it
1 will affect present drug level more

If the missing dose is several half

2 life later (> 5 t) , the missing
dose may be omitted

e.g. of missing dose

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 The drug may not reach steady state

Another short IV
Short IV infusion Elimination period
infusion

Conc. after one or more short IV infusion

Cp = D ( 1 e -k t ) / tinf VD k

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 Where , D / tinf = Rate of infusion .i.e. R
D = Size of infusion dose
tinf = infusion period
VD = volume of distribution
k = elimination rate constant

Drug conc. post IV infusion is

Cp = Cstop e-kt

Where, Cstop = Conc. when infusion stop

t = time elapsed since infusion stopped

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The plasma conc. at any time during oral multiple
dose regimen,

-nka -nk
F.kaDo 1-e -kat 1e -k t
Cp = e e
VD(k ka) 1-e -ka
1 - e -k

Where, n= no. of doses

= dosing interval
F = fraction of dose absorbed
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 FOR MULTIPLE ORAL DOSE

C = F D0 / ClT
av

-k tp - k
Cmax = F Do e / VD ( 1 e )

Cmin = ka F D0 e- k/ VD ( ka k )(1 e-k)

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 Max. Conc. & min. Conc. during multiple dosing

Css,max = C0 / 1 e-k

Css,min = Css,max . e -k

Ratio of Cmax / Cmin is known as fluctuation,

Greater the ratio, greater the fluctuation.

Css,av = F X0 / ClT ..

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 An initial or first dose intended to be therapeutic is
called as priming or loading dose

D0,L = Css, av VD / F

For 1 compartment model, For 2 compartment model,

VD() D(P)target
VD D(P)target LD =
LD = F
F

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OBJECTIVE- to achieve desired plasma conc., C av , as
quickly as possible.

DImax =1.44 t log TW

MSC
While, TW=
MEC

D(P)target Cl
Route of Drug administration ( MD /DI)=
F

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A maintenance dose is given to maintain Cav and
steady state so that the therapeutic effect is also
maintained

The ratio of loading dose to maintenance dose

X0, L / X0 , is called as Dose ratio

When, = t , dose ratio should be equal to 2

> t , dose ratio should be smaller than 2
< t dose ratio should be greater than 2

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 Loading dose Maintenance Doses X0
X0 X0 Xo Xo X0

Dose ratio > 2

Plasma Drug Conc.

( < t )
Dose ratio = 2
( = t )
MSC

MEC

Dose ratio < 2,

( > t )

Dosing interval in hr

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 Maintenance
Sustained Loading dose dose
release

MSC

Therapeutic
Plasma conc.(g/ml)
Prolonged

range
release

MEC
Convention
al dose

Time( in hr)

Plot showing the effect of loading dose and maintenance dose.

 Describe the principle underlying the design of
multiple dosage regimen.

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 Shargel Leon, Andrew Yu B.C., Applied biopharmaceutics
and pharmacokinetics , 5th edition, published by Mc Graw Hill
,page no. 185 .207,613-625.

Gibaldi M., Biopharmaceutics And Clinical

Pharmacokinetics 4th edition, Pulished by Pharma Med
Press,Page no.345.

Brahmankar D.M., Jaiswal S.B., Biopharmaceutics and

Pharmacokinetics 1st edition, Published by Vallabh Prakashan ,
Page no.307-315.
Notari Robert E., Biopharmaceutics & clinical
pharmacokinetics., Fourth Edition, published by Marcell
Dekker, page no.351-397.
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