This presentation is about the process by which prolonged therapeutic activity of drug is achieved and it's importance. By this presentation you will learn about dosage regimen, steady state concentration, principle of superposition, drug accumulation, repetitive intravenous injections etc. By this you will also learn how to adjust the dose to the patient.

1. MULTIPLE DOSAGE REGIMEN
Presented by:
MD. MOHABBOT HOSSEN
B.Pharm (Hon’s)
Dhaka International University

2. INTRODUCTION
After single-dose drug administration, the plasma drug level
rises above and then falls below the minimum effective
concentration (MEC), resulting in a decline in therapeutic
effect.
To maintain prolonged therapeutic activity, many drugs
are given in a multiple-dosage regimen.
In calculating a multiple-dose regimen, 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.

3. • There are two main parameters that can be adjusted in
developing a dosage regimen:
1. The size of the drug dose.
2. The frequency of drug administration, ʈ (i.e, the time interval
between doses).

4. Dosage regimen
• Dosage regimen:
The frequency of administration of a drug in a particular dose is called as
Dosage regimen.
• For some drugs like analgesics single dose is efficient for optimal
therapeutic effect however the duration of most illnesses are longer
than the therapeutic effect produced by a single dose, In such cases
drugs are required to be taken on a repetitive bases over a period of time
depending upon the nature of illness.
Multiple Dosage Administrations:
Multiple dose administration refers to the administration of successive
dosage of drug in which a drug is administrated frequently with constant
dose interval. Both dose and dose interval on chosen for that-
The plasma drug concentration maintains with the therapeutic range.
 And to get the maximum therapeutic (clinical) effect.

5. Basic considerations for multiple dosage regimen (MDR)
Some basic consideration should be adjusted in developing a dosage
regimen.
1) Size of dose of the drug.
2) Frequency of drug administration (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. Contd..
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.
Example,
common drug give in MDR.
-Antibiotic (Ampicillin)
-Anticonvulsant (Phenobarbital, phenytoin
-Antiepileptic (phenytoin)
-Anticancers
-Antidiabetics (Insulin)
-Antiasthmatics
/Bronchodilator
(Theophylline)
-Cardiotonics digoxin)
-Contraceptives (Progestin)
(Hormone)

7. Purpose of multiple dose 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. To maintain the desired MTC (Antibiotic).
6. For achieving prolonged therapeutic activity.
7. Single dose is usually unsuitable to maintain the steady-state plasma drug conc. So
MDR is established.
8. For quickly metabolized drug (1st pass effect), MDR is necessary.
9. For prophylactic treatment of many disease.
10. To destroy the infected organism.
11. Narrow therapeutic index drugs may cause toxicity (phenytoin), in such cases
multiple dose is required.

8. MULTIPLE DOSING WITH RESPECT TO ORAL ROUTE
• When an oral multiple dosing regimen is followed, plasma conc. will
increase, reach a maximum and begin to decline. A 2nd dose will be
administered before all of the absorbed drug from 1st dose is
eliminated.
• Consequently plasma conc. resulting from 2nd dose will be higher
than from 1st dose. This increase in conc. with dose will continue to
occur until a steady state is reach at which rate of drug entry into the
body = rate of exit.

9. steady-state drug concentration
steady-state drug concentration:
steady-state drug concentration may be defined as the concentration in
which, the rate of drug entering the body (infusion rate) is equal to the
rate of drug leaving the body. So rate of change plasma drug conc. will
be "0" .
So, in steady-state,
rate of drug in = rate of drug out.

10. How it can be obtained?
1. The repetitive equal dose are given at a constant frequency
(interval).
2. Drug accumulation occurs and plasma drug conc. reach to a plateau
level.
3. Steady state concentration is obtained and drug conc. Fluctuate
within (Cmax and Cmin) and these remain unchanged from dose to
dose.

11. STEADY STATE CONCENTRATION

12. Principle of Superposition
• For calculation of multiple-dose 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.
• At steady state
AUC (∫∞
0C pdt) = AUC(∫t2
t 1 C pdt)
Single dose Multiple dose

14. • The plasma drug concentrations after multiple doses may be
predicted from the plasma drug concentrations obtained after a single
dose.
• The predicted plasma drug concentration in the patient is the total
drug concentration obtained by adding the residual drug
concentration obtained after each previous dose.

16. Drug Accumulation
• If the drug is administered at a fixed dose and a fixed dosage interval,
as is the case with multiple-dose regimens, the amount of drug in the
body will increase and then plateau to a mean plasma level higher
than the peak C p obtained from the initial dose.
• When the second dose is given after a time interval shorter than the
time required to "completely" eliminate the previous dose, drug
accumulation will occur in the body.
• However, if the second dose is given after a time interval longer than
the time required to eliminate the previous dose, drug will not
accumulate.

18. • 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.
• The C ∞
max is also a good indication of drug accumulation.

19. Accumulation Index (R)
Accumulation is affected by the elimination half-life of the drug and the
dosing interval. The index for measuring drug accumulation R is-
Substituting for Cmax after the first dose and at steady state yields-

20. • The above equation shows that drug accumulation measured with
the R index depends on the elimination constant and the dosing
interval and is independent of the dose.
• For a drug given in repetitive oral doses, the time required to reach
steady state is dependent on the elimination half-life of the drug and
is independent of the size of the dose, the length of the dosing
interval, and the number of doses.

21. Accumulation Half-life
An equation for the estimation of the time to reach one-half of the steady-
state plasma levels or the accumulation half-life has been described by van
Rossum and Tomey (1968).
For IV administration, k a is very rapid (approaches ∞); k is very small in
comparison to k a and can be omitted in the denominator of the above
equation. Thus, the above equation reduces to-
Since ka/ka = 1 and log 1 = 0, so the accumulation t1/2 is directly
proportional to the elimination t1/2.

22. Repetitive Intravenous Injections
• The maximum amount of drug in the body following a single rapid IV
injection is equal to the dose of the drug.
• If Ƭ is equal to the dosage interval then the amount of drug remaining in the
body after several hours can be determined with –
• The fraction ( f ) of the dose remaining in the body is related to the
elimination constant (k) and the dosage interval (Ƭ) as follows:

23. Another parameters following repetitive injection-
1. maximum amount of drug in the body at steady state conc.
2. minimum amounts of drug in the body at steady state
Dmin = Dmax – D0

24. EXAMPLES
A patient receives 1000 mg every 6 hours by repetitive IV injection of
an antibiotic with an elimination half-life of 3 hours. Assume the drug is
distributed according to a one-compartment model and the volume of
distribution is 20 L.
a. Find the maximum and minimum amounts of drug in the body.

25. a. Here,

26. LOADING DOSE
• Since extravascular doses require time for absorption into the plasma
to occur, therapeutic effects are delayed until sufficient plasma
concentrations are achieved.
• To reduce the onset time of the drug that is, the time it takes to
achieve the minimum effective concentration a loading (priming) or
initial dose of drug is given.
• The main objective of the loading dose is to achieve desired plasma
concentrations as quickly as possible.

27. LOADING DOSE
So, The "loading dose" is one or a series of doses that may be given at the
onset of therapy with the aim of achieving the target concentration rapidly.
Loading dose = Vd x TC/F
Vd = Volume of distribution
TC = Target concentration
F = Fraction of dose
• For most drug loading dose can be given as single dose by the chosen route
of administration.
• Loading doses tend to be large, and they are often given parenterally and
rapidly.

28. Bioequivalence
Bioequivalence is defined as the absence of a significant difference in
the rate and extent to which the active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical alternatives becomes
available at the site of drug action when administered at the same
molar dose under similar conditions in an appropriately designed study.