Multiple Dosage regimen

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 : The size of the drug dose. 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. 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? The repetitive equal dose are given at a constant frequency (interval). Drug accumulation occurs and plasma drug conc. reach to a plateau level. 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 n th dose will overlay or superimpose the blood level attained after the ( n -1) th dose. At steady state AUC (∫ ∞ C p dt ) = AUC (∫ t2 t 1 C p dt ) Single dose Multiple dose

13. 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.

14. 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.

15. At steady state, the plasma drug levels fluctuate between C max and C min . 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.

16. 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 C max after the first dose and at steady state yields-

17. 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.

18. 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 t 1/2 is directly proportional to the elimination t 1/2.

19. 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:

20. Another parameters following repetitive injection- maximum amount of drug in the body at steady state conc. minimum amounts of drug in the body at steady state D min = D max – D

21. 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.

22. a. Here,

23. 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.

24. 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 V d = 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.

25. 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.