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Dosage Regimen
Presented By
Shah Vrushank N.
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Introduction
Multiple Dosing
Designing of Dosage regimen
Concept of Loading Dose.
Maintenance Dose.
Accumulation Index.
References
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Introduction
Definition :- Dosage regimen is defined as the Manner in
which a drug is taken.
For successful therapy, design of an optimal multiple dosage
regimen is necessary.
Multiple dosage regimen:- is defined as the manner in which
the drug is administered in suitable doses by suitable route,
with sufficient frequency that insures maintenance of plasma
conc. within therapeutic window for entire period of therapy.
In designing a dosage regimen:-
All pkinetic parameters of the drug remain constant during the
course of therapy once the Dosage regimen is established.
The calculations are based on one- compartment model which
can also applied for two- compartment models. K
E

V
d,ss
Vd



Definisi: - Dosis regimen didefinisikan sebagai Manner di mana obat
diambil.
Untuk terapi sukses, desain dari beberapa regimen dosis optimal
diperlukan.
Beberapa dosis rejimen: - didefinisikan sebagai cara di mana obat
diberikan dalam dosis yang sesuai dengan rute yang sesuai, dengan
frekuensi yang cukup yang menjamin pemeliharaan conc plasma.
dalam jendela terapi untuk seluruh masa terapi.
Dalam merancang regimen dosis: -
Semua parameter p'kinetic obat tetap konstan selama terapi setelah
rejimen Dosis didirikan.
Perhitungan didasarkan pada model satu kompartemen yang juga dapat
diterapkan untuk model dua-kompartemen. KE
Vd, ss Vd
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In Designing dosage
regimen the two major
parameters that can be
adjusted in developing a
dosage regimen are
1) The Dose size The qty.
of Drug administered.
Greater dose size
greater fluctuation btw
C
ssmax,
& C
ssmin
and
greater chance of
toxicity
2) The Dosing frequency
The time interval
between Doses.


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Design of dosage regimen from plasma
concentration :
If the Vd and clearance or half life of the drug is known,
then dosage regimen can be design to maintain the drug
conc. in the therapeutic range.
Maximum dosing interval which ideally depends upon the
therapeutic index and elimination half life of the drug can
be expressed as :


max
= 2.303 log ( C
upper
/ C
lower
)
K
E

Where K
E
= 0.693/t
1/2

Desain regimen dosis dari konsentrasi plasma

Jika Vd dan pembersihan atau paruh obat diketahui, maka
regimen dosis dapat desain untuk menjaga conc obat.
dalam kisaran terapeutik.
Interval pemberian dosis maksimum yang idealnya
tergantung pada indeks terapeutik dan eliminasi paruh obat
dapat dinyatakan sebagai:
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max
= 3.32 t
1/2
log ( C
upper
/ C
lower
)
Mostly dosing interval selected is always smaller than
max
the maximum maintenance dose X
0max
can be expressed as

X
0max
= V
d
( C
upper
- C
lower
)
F
After the convenient dosing interval , smaller than
max
has
been selected, maintenance dose is given as :

X
0
= C
ss,av
=
X
o max

max


( C
upper
/ C
lower
)
2.303 log ( C
upper
/ C
lower
)
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Multiple dosing
For chronic diseases, there is necessity of multiple dosing
i.e. administration of drugs in number of frequencies.
On continuous steady administration of a drug, plasma
concentration will rise fast at first then more slowly and
reach a plateau, where:
Rate of administration = Rate of elimination
( steady state is achieved )
Therefore, at steady state:
Dose (Rate of Administration) = Clearance x Plasma conc.
Or
If you aim at a target plasma level and you know the
clearance, you can calculate the dose required.`

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Effect of multiple doses
If the plasma concentration prior to next dose is >0
concentration and elimination is of first order, then plasma
concentration will increase Increase in elimination rate and
eventually steady state.

For first order elimination kinetic the time to obtain
steady state is dependent only of the half time of the drug
The steady state concentration is determinated by dose
(D) and dose frequency


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Effects of dose and dose frequency

Increase in dose
Increase in C
mean

Larger difference between C
max
and C
min
Increased risk for side effects for drugs with small
therapeutic windows
Increase in frequency
Increase in C
mean

Larger inconvenience for patient

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Loading Dose
Concept of loading dose

For drugs with long half-lives, the time to reach steady
state might be long. It takes about 5 half- lives to reach
steady state.
In a such cases the plateau can be achieved by
administering a dose that gives the desired steady- state.
Such an initial/ first dose is called as Loading dose.





X
o,
L =
C
ss,av
V
d
F
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When Vd is not known then loading dose may be
calculated as



The above eq. is applied when Ka >> Ke & drug is
distributed rapidly.
But in case of I.V. route the absorption is very fast
therefore , absorption phase is neglected then above eq.


X
o
L
X
0 (1 e

Ka

)
(1 e
Ke

)
1
=
X
o,
L
X
0
=
1 e
-Ke


1
= R
ac
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Maintenance Dose
After the loading dose is given the another dose (I.V) is
given to maintain the steady- state drug conc. Or plateau.
Such dose is known as maintenance dose.
i.e. maintain the response of drug by replacing drug lost
during dosing interval.
Maintenance dose = loading dose x ( 1- e
-k
)

Loading dose =

maintenance dose
1 e
-K

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The ratio of loading dose
to maintenance dose
(X
0
L/X
0
) is called as dose
ratio
When = t
1/2
the dose ratio
=2.0
When > t
1/2
the dose ratio
< 2.0
when < t
1/2
the dose
ratio >2.0
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Accumulation Index
In case of multiple dosage regimen (drugs are frequently
administered) in such a cases the 1
st
drug conc. remaining
in a body after certain time, is added to the next dose, this
condition is known as Accumulation
The accumulation occurs because previous doses has not
been removed completely from body.
After some time the rate of absorption is equal to rate of
elimination i.e. conc. of drug in plasma approaches to a
constant value this condition is called as steady- state,
plateau/ infusion equilibrium.

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Consider the Amount of drug in the body-time profile as
shown in the Graph.
After admin of first dose X
0
= 1X
0

At next dosing interval when X = X
0
, amt of drug
remaining in the body
Admin of next i.v. dose raises the body content to
X = X
0
+
1
/
2
X
0
As the amount of drug in the body rises gradually due to
Accumulation, the rate of elimination also rises
proportionally until a steady-state or Plateau is reached.

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The maximum & minimum values of X i.e. X
ss,max
&
X
ss,min
approach respective asymptotes at plateau.
Plateau X
ss,min
= 1X
0
(

amt of drug in body after first dose )
X
ss,max
= 2X
0
( equals twice the first dose)
Also (X
ss,max
- X
ss,min
) = X
0
X
ss,max
/

X
ss,min
= 2


All this applied only when = t
1/2

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When < t
1/2
, the degree of Accumulation is greater &
vice-versa.
Thus, the extent to which a drug accumulates in the body
during multiple dosing, is a function of dosing interval &
elimination half life & is independent of dose size.
The extent to which a drug will accumulate with any dosing
interval in the patient can be derived from information
obtained with a single dose and is given by accumulation
index Rac as:
=


R
ac
1
1-e
-KE

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References
Applied Biopharmaceutics & Pharmacokinetics
by Leon Shargel & Andrew B. C. Yu, 4
th
Edition

Biopharmaceutics & Pharmacokinetics
A Treatise, D. M. Brahmankar & Sunil B. Jaiswal

Clinical Pharmacokinetics, Concepts &
Application, 3
rd
Edition,
by Malcom Rowland & Thomas N. Tozer, Lea & Febiger
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