5/20/2024

MULTIPLE-DOSAGE
REGIMENS

Muhammad Faheem
Lecturer,
Department of Pharmacy,
University of Swabi

• Many drugs are given in a multiple-dosage

regimen for prolonged therapeutic activity.

• Among these drugs are antibacterials,

cardiotonics, anticonvulsants, hormones and many
other therapeutic agents.
• The plasma levels is maintained within narrow
limits to achieve maximal clinical effectiveness.

1
 5/20/2024

• Ideally, a dosage regimen should be

established for each drug to provide the
correct plasma level without excessive
fluctuation and drug accumulation.

• When the duration of treatment of disease is larger than the

therapeutic effect of drug, multiple dosage regimen are given e.g.

antibiotics.
• The plasma levels of drugs given in multiple doses must be
maintained within the narrow limits of the therapeutic window
(CP above the MEC and below the MTC) to achieve optimal
clinical effectiveness.
• Dosage regimen is established for drug to provide the correct
plasma level without excessive fluctuation and drug
accumulation outside the therapeutic window.

2
 5/20/2024

Thus an “optimal multiple dosage regimen” is the

one in which the drug is
“administered in appropriate doses, by suitable
route, with sufficient frequency that ensures
maintenance of plasma concentration within the
therapeutic window without excessive fluctuation
and drug accumulation for the entire duration of
therapy”.

3
 5/20/2024

The desired or target plasma drug

concentration must be related to a
therapeutic response, and the multiple-
dose regimen must be designed to
produce plasma concentrations within
the therapeutic window.

Objective of dosage regimen

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

4
 5/20/2024

Purpose of Multiple Dosage Regimen

1. To maintain the plasma level within the therapeutic range.
2. To maintain the plasma level without excessive fluctuation and
drug accumulation.
3. To maintain the maximum effective concentration (MEC).
4. To maintain the steady-state plasma and tissue drug conc. for
the long term management of disease.

5. For achieving prolonged therapeutic activity.

6. Single dose is usually unsuitable to maintain the steady-state plasma

drug conc. So MDR is established.

7. For quickly metabolized drug (1st pass effect), MDR is necessary.

8. For prophylactic treatment of many disease.
9. To destroy the infected organism.
10. Narrow therapeutic index drugs may cause toxicity (phenytoin), in
such cases multiple dose is required.

5
 5/20/2024

Criteria for optimum dosage regimen

I. The plasma levels of drug given must be maintained

within the therapeutic window.
 Ex. The therapeutic range of theophylline is 10-20µg/L.
So, the best is to maintain the CP around 15µg/L.
II. Should be convenient to the patient.
 It is difficult to take I.V. injection every ½ hour or one
tablet every 2 hour, this lead to poor compliance.

Factors Affecting the Design of

Multiple Dosage Regimen
(1) The size of the drug dose.
(2) The frequency of drug administration (τ) (i.e., the
time interval between doses).
(3) Successive doses of the drug.
(4) Dose interval should be such that the drug does not
leave the body completely before the next dose.
(5) Steady state concentration must be maintained
between the MEC and MTC level.

6
 5/20/2024

.
6) Excessive fluctuation in drug level should not be allowed.
7) Drug should not be accumulated.
8) Desired plasma drug conc. must be related to therapeutic response.
9) Pharmacokinetic parameter should be obtained after single dose.
10) In MDR, it is necessary to decide whether successive does have any
effect on previous dose.
Common drug give in MDR.
-Antibiotic (Ampicillin) -Anticonvulsant (Phenobarbital,
phenytoin)
-Antiepileptic (phenytoin) -Anticancers
-Antidiabetics (Insulin) -Antiasthmatics/Bronchodilator
(Theophylline)
-Cardiotonics (digoxin) -Contraceptives (Progestin)
(Hormone)

The two main parameters that can be adjusted in

developing a dosage regimen are:

1 • the size of the drug dose is adjusted

• the frequency of drug administration

2 i.e., the time interval between doses is
fabricated.

7
5/20/2024

8
 5/20/2024

PRINCIPLE OF SUPERPOSITION
To calculate multiple-dosage regimens, it is necessary to
decide whether successive doses of drug will have any
effect on the previous dose.
The principle of superposition assumes that early doses of
drug do not affect the pharmacokinetics of subsequent
doses.
Therefore, the blood levels after the second, third, or nth
dose will overlay or superimpose the blood level attained
after the (n ―1)th dose.

9
 5/20/2024

In addition, the AUC single dose

during a dosing interval at steady state must be similar

The principle of superposition allows one to project the

plasma drug concentration-time curve of a drug after
several consecutive doses based on the plasma drug
concentration-time curve obtained after a single dose.

The basic assumptions are that the drug is eliminated

by first-order kinetics and that the pharmacokinetics of
the drug after a single dose (first dose) is not altered
after taking multiple doses.

10
 5/20/2024

If plasma drug concentration obtained after a single

dose, the plasma drug concentrations after multiple
doses may be predicted (Table I).

PLASMA DRUG CONCENTRATION (µg/mL)

DOSE TIME DOSE DOSE DOSE DOSE DOSE DOSE

NUMBER (HR) 1 2 3 4 5 6 TOTAL
1 1. 0 0
1. 21.0 21
1. 22.3
1. 19.8
2 1. 16.9 0
1. 14.3 21.0 35.3
1. 12.0 22.3
1. 10.1 19.8
3 1. 8.50 16.9 0
1. 7.15 14.3 21.0 42.45
1. 6.01 12.0 22.3
1. 5.06 10.1 19.8
4 1. 4.25 8.50 16.9 0
1. 3.58 7.15 14.3 21.0 45.13
1. 3.01 6.01 12.0 22.3
1. 2.53 5.06 10.1 19.8
5 1. 2.13 4.25 8.50 16.9 0
1. 1.79 3.58 7.15 14.3 21.0 46.12
1. 1.51 3.01 6.01 12.0 22.3
1. 1.27 2.53 5.06 10.1 19.8
6 1. 1.07 2.13 4.25 8.50 16.9
1. 0.90 1.79 3.58 7.15 14.3 21 48.7
1. 0.75 1.51 3.01 6.01 12.0
1. 0.63 1.27 2.53 5.06 10.1
1. 0.53 1.07 2.13 4.25 8.50

11
 5/20/2024

First of all the plasmas drug concentrations from 0 to 24

hours are measured after a single dose. A constant dose of
drug is given every 4 hours and plasma drug concentrations
after each dose are generated from the data after the first
dose.
Thus, the predicted plasma drug concentration in the patient
would be the total drug concentration obtained by adding
the residual drug concentration obtained after each previous
dose.

The superposition principle may be used to predict drug

concentrations after multiple doses of many drugs. Because the
superposition principle is an overlay method, it may be used to
predict drug concentrations after multiple doses given at equal and
unequal dosage intervals.

For example, a drug dose may be given every 8 hours or three

times a day before meals at 8 AM, 12 noon, and 6 PM. There are
situations, however, for which the superposition principle does not
apply.

12
 5/20/2024

The pharmacokinetics of the drug dosage interval change after

multiple dosing due to various factors, that includes:
I. Changing pathophysiology in the patient
II. Saturation of a drug carrier system
III. Enzyme induction and enzyme inhibition

Drugs that follow nonlinear pharmacokinetics generally do not

have predictable plasma drug concentrations after multiple doses
using the superposition principle.

Drug Accumulation
• When a drug is administered at regular intervals over a prolonged
period, the rise and fall of drug concentration in blood will be
determined by the relationship between the half-life of
elimination and the time interval between doses.
• If the drug amount administered in each dose has been eliminated
before the next dose is applied, repeated intake at constant
intervals will result in similar plasma levels.
• If intake occurs before the preceding dose has been eliminated
completely, the next dose will add on to the residual amount still
present in the body, i.e., the drug accumulates.

13
 5/20/2024

.
• The shorter the dosing interval relative to the elimination half-
life, the larger will be the residual amount of drug to which the
next dose is added and the more extensively will the drug
accumulate in the body.

• At a given dosing frequency, the drug does not accumulate

infinitely and a steady state (Css) or accumulation equilibrium is
eventually reached.

• This is so because the activity of elimination processes is

concentration dependent.

• The higher the drug concentration rises, the greater is the amount
eliminated per unit of time.

14
 5/20/2024

Accumulation is affected by the elimination half-life of

the drug and the dosing interval that can be measured as
follow:

Substituting for Cmax after the first dose and at steady

state yields the following equation:

OR

Equation 2 shows that drug accumulation measured with

the R index depends on the elimination constant and the
dosing interval and is independent of the dose.

15
 5/20/2024

• If dose (D) and (τ) interval are properly selected, blood levels will rise
and fall between peak (Cmax) and (Cmin) within the therapeutic range
(TR).
• At steady state, the plasma drug levels fluctuate between Cmax and
Cmin.
• Once steady state is obtained, C ∞ max and C ∞ min are constant and
remain unchanged from dose to dose.
• The C ∞max is important in determining drug safety.
• The C ∞max should always remain below the minimum toxic
concentration.

• From a clinical viewpoint, the time needed to reach 90%

steady state plasma concentration is 3.3 times the elimination
half-life.

• Whereas the time required to reach 99% of the steady state

plasma concentration is 6.6 times the elimination half-lifes.

16
 5/20/2024

Furthermore, if
the drug is given
at the same
dosing rate (e.g.
25 mg/hr), but
with different
doses and dose
interval
fluctuations
between Cmax and
Cmin will vary.

17
 5/20/2024

Time to reach one-half of the steady-steady-state plasma levels or

the accumulation half-life can been described by van Rossum and
Tomey (1968).

For IV administration, ka is very rapid; and k is very small in

comparison with ka and can be omitted in the denominator of
Equation 3 Thus, reduces to

18