DOSAGE REGIMEN

1. DOSAGE REGIMEN Prof. Dr. Basavaraj K. NanjwadeM.Pharm., Ph. D Department of Pharmaceutics KLE University’s College of Pharmacy BELGAUM – 590010, Karnataka, India Cell No: 0091 9742431000 E-mail: bknanjwade@yahoo.co.in KLECOP, Nipani

2. Multiple dosing with respect to I.V. and Oral KLECOP, Nipani

3. CONTENTS • Dosage regimen • General concepts • Multiple dosing with respect to I.V. • Multiple dosing with respect to Oral route. • Concept of loading dose, maintenance dose, • Accumulation, Adjustment of dosage in renal • and hepatic impairment • Individualization of therapy • References. KLECOP, Nipani

4. 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. KLECOP, Nipani

5. Continue… Thus an “optimal multiple dosage regimen” is the one in which the drug is administered in suitable 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. KLECOP, Nipani

6. Two major parameters that can be adjusted in developing a dosage regimen are: • The dose size :- It is the quantity of the drug administered each time. The magnitude of therapeutic & toxic responses depend upon dose size. Amount of drug absorbed after administration of each dose is considered while calculating the dose size. Greater the dose size greater the fluctuation between Css,max & Css,min (max. and min. steady state concentration) during each dosing interval & greater chances of toxicity. KLECOP, Nipani

7. 2. Dose frequency :- It is the time interval between doses. Dose interval is inverse of dosing frequency. Dose interval is calculated on the basis of half life of the drug. When dose interval is increased with no change in the dose size ,Cmin, Cmax & Cav decrease, but when dose interval is reduced, it results in greater drug accumulation in the body and toxicity. KLECOP, Nipani

8. Certain concepts • Drug accumulation during multiple dosing: following the 1st dose, if the 2nd dose is given early enough so that not the entire 1st dose is eliminated then the drug will start accumulating and we will get higher concentration with the 2nd and 3rd dose. Upon repeating the dose, it is seen that the drug accumulation continue until a limit is reached. The reason being that as the plasma conc. increases the rate of elimination will also increase following 1st order elimination KLECOP, Nipani

9. B) Time to reach steady state during multiple dosing: The time required to reach steady state depends primarily upon the half life of the drug. Provided Ka>>Ke, plateau is reached in approximately 5 half lives. The time taken to reach steady state is independent of dose size, dose interval & no. of doses. It is determined only by Ke KLECOP, Nipani

10. Multiple dosing with respect to I.V. On repeated drug administration, the plasma conc. will be added upon for each dose interval giving a plateau or steady state with the plasma conc. fluctuating between a minimum and maximum KLECOP, Nipani

11. Css max Steady state Css min Plsama drug conc. time KLECOP, Nipani

12. 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 KLECOP, Nipani

13. C max Plasma drug conc. C min time KLECOP, Nipani

14. Concept Of Accumulation Index, Loading Dose And Maintenance Dose KLECOP, Nipani

15. Loading Dose • A drug dose does not show therapeutic activity unless it reaches the desired steady state. • It takes about 4-5 half lives to attain it and therefore time taken will be too long if the drug has a long half-life. • Plateau can be reached immediately by administering a dose that gives the desired steady state instantaneously before the commencement of maintenance dose X0. • Such an initial or first dose intended to be therapeutic is called as priming dose or loading dose X0,L. KLECOP, Nipani

16. Size And Administration • After e.v. administration, Cmax is always smaller than that achieved after i.v. and hence loading dose is proportionally smaller. • For the drugs having a low therapeutic indices, the loading dose may be divided into smaller doses to be given at a various intervals before the first maintenance dose. KLECOP, Nipani

17. Calculation Of Loading Dose • A simple equation for calculating loading dose is : X0,L = • When Vd is not known, loading dose may be calculated by the following equation : Css,av Vd F X0,L X0 1 (1 – e-KEt) (1 – e-Kat) = KLECOP, Nipani

18. Calculation Of Loading Dose • Given equation applies when Ka >> Ke and drug is distributed rapidly. When drug is given i.v. or when absorption is extremely rapid, the absorption phase is neglected and the above equation reduces to : X0,L X0 • Theratio of loading dose and maintenance dose X0,L/X0 is called as dose ratio. • As a rule when T (dosing interval) = t1/2 dose ratio should be 2 1 (1 – e-KEt) = Rac = KLECOP, Nipani

19. Calculation Of Loading Dose • When T > t1/2 dose ratio is smaller than 2.0 • When T< t1/2 dose ratio is greater than 2.0 • If the loading dose is not optimum either too low or too high, the steady state is attained within a 4-5 half lives in a manner similar to when no loading dose is given. KLECOP, Nipani

20. loading dose X0,L X0 X0 X0 X0 T T T T T MSC MEC dosing interval in hrs Dose ratio >2 maintenance dose X0 Dose ratio 2 Cp KLECOP, Nipani

21. Maintenance Of Drug Within The Therapeutic Range • The ease or difficulty in Maintaining drug concentration within the therapeutic window depends upon – - Therapeutic index of the drug - Half life of the drug - Convenience of dosing. • For a drug with low half-life and TI it is extremely difficult. Example – heparin • However the drug with low half-life (0.9 hrs) and high TI can be given less frequently every 4-6 hrs) provided maintenance dose is large. KLECOP, Nipani

22. Drugs with half-lives greater than 8 hrs are more convenient to dose. Given once every half life. • For drugs with very long half-lives 24 hrs e.g. amlodipine, once daily dose is very convenient KLECOP, Nipani

23. Accumulation Index(multiple dose regimen of i.v bolus) • drug accumulation during multiple dosing X0+1/2X0 (½+1/4) X0 1/2X0 KLECOP, Nipani

24. After administration of first dose X0 at t=0 the amount of drug in the body X=1X0. • At the next dosing interval X=1/2X0, the amount of drug remain in the body, administration of next i.v dose raises the body content to X=X0 + ½ X0 i.e. drug accumulation occurs in the body. • Accumulation occurs because drug from previous doses has not been removed completely. • As the amt. of drug gradually rises in the body rate of elimination also rises proportionally until plateau is reached. KLECOP, Nipani

25. Thus the extent to which a drug accumulates in the body is a function of its dosing interval and elimination of half-life and is independent of dose size. • The extent to which any drug accumulate with any dosing interval in a patient can be derived from information obtained with a single dose and is given by accumulation index Rac as : 1 (1 – e-KEt) Rac = KLECOP, Nipani

26. Therapeutic drug monitoring KLECOP, Nipani

27. Therapeutic drug monitoring • It specializes in the measurement of medication levels in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed. • Therapeutic drug monitoring is important as Insufficient levels of drug in the plasma will lead to under treatment or resistance, and excessive levels can lead to toxicity and tissue damage. KLECOP, Nipani

28. Indications for Therapeutic Drug monitoring include: • There is narrow therapeutic window. • There are potential patient compliance problems. • The drug dose cannot be optimized by clinical observation alone. • Knowledge of the drug level influences management. KLECOP, Nipani

29. Sampling and drug analysis • Usually, plasma or serum is used for drug assays. • Drug assay methods should have adequate sensitivity, be specific for the drug (or metabolite) to be measured and have appropriate accuracy and precision. • Automated immunoassay methods, High performance liquid chromatography (HPLC) and Gas liquid chromatography (GLC) (e.g. amiodarone, perhexiline) can be used. KLECOP, Nipani

30. Examples of drugs analysed by therapeutic drug monitoring : KLECOP, Nipani

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34. Reference • Biopharmaceutics And Pharmacokinetics A Treatise, Brahmankar DMVallabh prakashan page no. 309-314. • “Text Book Of Biopharmaceutics & Pharmacokinetics”,Dr. Shobha Rani R. Hiremath.. KLECOP, Nipani

35. THANKYOU Cell No: 0091 9742431000 E-mail: bknanjwade@yahoo.co.in KLECOP, Nipani