LEARNING OBJECTIVES

• This chapter elaborate the importance of multiple dosing ,

• Why we need MD
• How they effect and
• What factors affected on it
• Difference with the change of route of administration.
 Dosage regimen
It is defined as the manner in which a drug is taken.
For certain analgesics, hypnotics, anti-emetics etc. a
single dose may provide an effective treatment. But the
duration of most illness is longer than the therapeutic
effect produced by a single dose. In such cases drugs
are required to be taken on a repetitive basis over a
period of time.
3
3
Objective of dosageregimen
The overall objective of dosage regimen design is to achieve
a target drug concentration at the receptor site

4
 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 5
SINGLE DOSING
A single dose of a drug is usually administered in
order to attain therapeutic concentration of drug in
the plasma for a very brief period of time. For
instance, a single dose of an analgesic (e.g., aspirin,
ibuprofen, or acetaminopben) is usually sufficient to
treat an acute condition such as an occasional
headache. It is also not uncommon for a therapeutic
agent to be administered in more than just one dose,
but for a relatively short period of time, e.g., if the
condition being treated persists for 2 or 3 days.
MULTIPLE DOSING

In most clinical situations it is necessary that the drug

be administered for relatively longer periods of time
(i.e., on a chronic basis) in order to maintain
therapeutic plasma concentrations for prolonged
periods. Examples include treatments that last a few
weeks (e.g., antibiotics and sulfonamides), or a few
months, (e.g., hormones), or for periods extending
into years (e.g.., anti-diabetics and anti- coagulants).
Singledosage regimen
When the duration of treatment of disease is smaller than
the therapeutic activity of drug, single dose are given e.g.
Aspirin

8
When the duration of treatment of disease is larger than
the therapeutic effect of drug, Multiple dosage regimen
are given e.g. antibiotics

9
INTRAVENOUS ADMINISTRATION

When administered intravenously, the entire drug

dose appears in plasma immediately after the dose is
administered and drug elimination begins according
to first-order kinetics. If the dosing interval between
each dose is such that the previous dose is virtually
eliminated before the next dose is administered (e.g.,
if biological half-life of the drug is 3 hours and the
drug is administered every 24 hours (at least 8 times
of biological half-life), the concentration of drug in
plasma just before administration of the next dose
will be virtually zero (i.e., there will be no
accumulation of drug from each dose administered).
In such cases, administration of the second dose will yield a
plasma profile virtually identical to the plasma profile obtained
after the administration of the first dose, because, during
multiple dosing the amount of drug remaining in the body
from the previous administered dose is virtually zero.
Therefore, the concentration of drug in plasma versus time plot
will exhibit a series of single-dose profiles as shown in Fig.
13-1
 DRUG ACCUMULATION :
To appreciate the extent of drug accumulation in the body following each dose, consider the case of a
drug which is administered as a 400 mg dose (D = 400 mg) at its biological half-life intervals (dosing
interval is equal to biological half-life of the drug, i.¢., + = tz). If the biological half-life of this drug is
6 hours, then the dosing interval z is also 6 hours. Since #2 = 6 hours, therefore the rate constant of
elimination, K is:

The mathematics of drug accumulation as each constant dose (400 mg) is administered at the fixed
dosing interval of 6 hours is as follows. When the first dose is administered, the amount of drug in the
body is equal to the dose, i.c., 400 mg. After 6 hours, just before the second dose is given, 50% of the
first dose is eliminated and the amount of drug in the body is reduced to (0.5)(400 mg) = 200 mg, i.e.,
amount of drug in the body ranged between 400 mg (maximum amount) and 200 mg (minimum
amount) during the first dose period. When the second dose is administered, the amount of drug in
the body is increased to 200 mg + 400 mg = 600 mg and 6 hours after administration of the second
dose, 50% of the amount of drug in the body is eliminated, i.e., amount of drug in the body is reduced
to (0.5)(600) mg = 300 mg. This means that amount of drug in the body ranges between 600 mg
(maximum amount during the second dose period) and 300 mg (minimum amount during the second
dose period). For the first three doses the following happens: :
12
13
14
Summary
the knowledge about the multiple dosing,
Drug accumulation and its observations
• We have studied factors of multiple dosing of a drug.
• We have studied solved example of persistence factor, loss
factor and accumulation factor.
• the importance of Persistence factor, loss factor and accumulation
factor
• As well as effect of repetitive IV injection, and infusion effect on
drug concentration in plasma and body

15
REFERENCE BOOKS
• Biopharamaceutics and Clinical pharmacokinetics by Milo Gibaldi
• Applied biopharmaceutics and pharmacokinetics Textbook by Leon Shargel
• Pharmacokinetic-pharmacodynamic modeling and simulation Book by Peter L.
Bonate
• Essentials of Biopharmaceutics and Pharmacokinetics Book by Ashutosh Kar
• Pharmacokinetics: Principles and Applications by Mehdi Boroujerdi
• Basic Pharmacokinetics by Mohsen A. Hedaya
• Clinical Pharmacokinetics: Concepts and Applications by Malcolm
Rowland, Thomas N. Tozer
• Biopharmaceutics and Pharmacokinetics Book by A. P. Pawar and J. S. Kulkarni
LEARNING OBJECTIVES
• This chapter elaborate the importance of multiple dosing ,
• Why we need MD
• How they effect and
• What factors affected on it
• Difference with the change of route of administration.
 Dosage regimen
It is defined as the manner in which a drug is taken.
For certain analgesics, hypnotics, anti-emetics etc. a
single dose may provide an effective treatment. But the
duration of most illness is longer than the therapeutic
effect produced by a single dose. In such cases drugs
are required to be taken on a repetitive basis over a
period of time.
3
3
Objective of dosageregimen
The overall objective of dosage regimen design is to achieve
a target drug concentration at the receptor site

4
 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 5
 PERSISTENCE FACTOR
As defined above, persistence factor represents the fraction of each dose that persists in the body
during multiple dosing. This is the fraction that was not eliminated. Therefore, the fraction of dose
persisting in the body can be determined from the equation describing the first-order rate process
because elimination is a first-order process. The first-order equation describing concentration of
drug in the body after administration of a dose is:

C is the concentration of drug at time t,

Co is the concentration of drug at time 0,
K is the first-order rate constant of elimination and
t is the time.
During multiple dosing, the first-order rate constant K is first-order rate constant of elimination,
and time t is dosing interval . Substituting τ for t into equation we have:

Since concentration = amount of drug /volume of distribution

where, D is the amount of drug in the body, De (= dose) is the amount of drug in the body at time 0,
and V is the apparent volume of distribution.
6
Dividing both sides of equation (13-3) by Do yields the following equation.

ratio D/Do represents the fraction of dose in the body at the end of the dosing
interval, i.e., this ratio is the fraction of dose persisting in the body during the dosing
interval, r. therefore equivalent to:
Persistence Factor = P =e-kτ

7
LOSS FACTOR
Loss of drug from the body refers to drug elimination. The fraction
of each dose not persisting in the body represents the fraction of
each dose that is lost (Le., eliminated from the body). Since the
amount of drug lost from the body (eliminated) plus the amount of
drug still in'the body (persistence) is equal to the amount of dose
administered, the fraction of dose lost plus the fraction of dose
persisting should be equal to one. In other words,

Loss Factor = E =1- Persistence Factor

Loss Factor = E =1-P = 1- e-kt

EXAMPLE 1
If the biological half-life of a drug is 6 hours, calculate the Loss
Factor if identical doses are administered
(a)every 6 hours,
(b)every 12 hours.
SOLUTION
Since t1/2 = 6 hours, therefore, K 0.693/t1/2 = 0.693/6 hr =
0.1155/hr
(a)When τ = 6 hours, the loss factor according to equation (13-
6) is

Thus, 50% of each dose will be eliminated before the next dose
is administered.
(b) Similarly, in Example 1 it was found that when the drug is
administered every 12 hours, persistence factor = 0.25. Using
equation to calculate the loss factor,
E = 1 - P = 1 - 0.25 = 0.75
Thus, 75 % of each dose will be eliminated before the next dose
is administered.
ACCUMULATION FACTOR
Accumulation of drug during multiple dosing is due to
accumulation of each successive dose of drug that persists in the
body. The accumulation factor, S, after administration of n doses
is determined using the following ratio

(13.7)

After a large number of doses are administered, i.e., when n

becomes sufficiently large. value of the exponential term nKt
increases, the term e-nKr approaches 0. The accumulation factor
becomes

(13.8)
EXAMPLE 13-3 :
If the biological half-life of a drug is 6 hours and identical
doses are administered every 6 hours calculate the
accumulation factor after
(a)3 doses and
(b)after 20 doses. . ,
SOLUTION
Since t1/2 6 hours, therefore K = O.693/6hr = O.1155/hr,
(a) Accumulation factor after 3 doses: From equation (13-7),

The accumulation of drug after 3 doses is (1.75)(Dose) or

175% of the dose.
(b) Accumulation factor after 20 doses: Equation (13-8)
may be used to calculate accumulation factor after 20
doses,

After administration of 20 doses, each dose administered

at 6-hour intervals, the accumulation of the drug will be
(2)(Dose) or 200% of the dose
PRACTICE PROBLEM
The half-life of a drug is 6 hours. Calculate persistence
factor if the dose is administered
(a)every 6 hours and
(b)every 12 hours.

SOLUTION
Since t1/2 = 6 hours, therefore K = 0.693/t1/2 =0.693/6 hr
=0.1155/hr
(a) When τ = 6 hours, P = e-kt

That is 50% of each dose will persist in the body before the
next dose is administered at 6 hours intervals.
(b) When τ = 12 hours, P = e-kt

This means that when the dosing interval is 12

hours, 25% of each dose will persist in the body
before the next dose is administered.
Example 2
• If drug is given with initial dose of 300 mg and after certain time amount
eliminated is 200 mg what will be persistence factor?
P=D/Do
P=300/200
P=0.66
P=0.66*100= 66%
Summary
the knowledge about the multiple dosing,
Drug accumulation and its observations
• We have studied factors of multiple dosing of a drug.
• We have studied solved example of persistence factor, loss
factor and accumulation factor.
• the importance of Persistence factor, loss factor and accumulation
factor
• As well as effect of repetitive IV injection, and infusion effect on
drug concentration in plasma and body

22
REFERENCE BOOKS
• Biopharamaceutics and Clinical pharmacokinetics by Milo Gibaldi
• Applied biopharmaceutics and pharmacokinetics Textbook by Leon Shargel
• Pharmacokinetic-pharmacodynamic modeling and simulation Book by Peter L.
Bonate
• Essentials of Biopharmaceutics and Pharmacokinetics Book by Ashutosh Kar
• Pharmacokinetics: Principles and Applications by Mehdi Boroujerdi
• Basic Pharmacokinetics by Mohsen A. Hedaya
• Clinical Pharmacokinetics: Concepts and Applications by Malcolm
Rowland, Thomas N. Tozer
• Biopharmaceutics and Pharmacokinetics Book by A. P. Pawar and J. S. Kulkarni