CONCEPT OF DOSING and KINETICS OF ELIMINATION.pptx

Dosing and ellimination

1. CONCEPT OF LOADING AND MAINTENANCE DOSE 10/28/2024 1

2. CONTENT INTRODUCTION DEFINITION CONCEPT FACTORS REFERENCE 10/28/2024 2

3. INTRODUCTION Most drugs for chronic condition are prescribed in a dosage regimen is based on the administration of a fixed constant dose(D) at fixed regular dosing intervals(T) for long period of time. The D & T recommended by the manufacturer is based on the effective therapeutic concentration of drug in the plasma needed to treat the chronic condition. 10/28/2024 3

4. The T is based on elimination rate constant of the drug. The steady-state concentration of drug in plasma during multiple dosing is given by following equation: 10/28/2024 4

5. The concentration of drug in plasma at steady-state depends on the following 3 factors: C , concentration of drug in plasma. K e , elimination rate constant. T, the dosing interval. 10/28/2024 5

6. DEFINITION & CONCEPT Loading dose: A dose of medication, often larger than subsequent doses, administered for the purpose of establishing a therapeutic level of the medication. Primary purpose of using loading dose in therapeutic treatment is to attain steady-state concentration of the drug as quickly as possible, usually right from the start of the dosage regimen for the treatment. 10/28/2024 6

7. This approach may also reduce the time of onset of drug action, i.e ; the time its takes to achieve the minimum effective concentration. The purpose of administering the loading dose is to reduce the time needed for the drug to accumulate to the steady-state level in the plasma. The size of loading dose will depend on the T of the maintenance dose. 10/28/2024 7

8. INTRAVENOUS ADMINISTRATION A drug when administered intravenously as a single rapid bolus dose, confers the characteristics of one-compartment model on the body. The main purpose of loading dose(D*) is to provide a steady-state concentration in plasma during multiple dosing. 10/28/2024 8

9. Loading dose based on C max ss The max concentration of drug in the plasma at steady-state, C max ss is given by equation C is plasma concentration immediately after administration of a single dose. e -p is persistence factor where P=( K e ) (T) 10/28/2024 9

10. If the drug follows linear pharmacokinetics then C obtained after the administration of single i.v rapid bolus dose is directly proportional to size of dose D(maintenance dose). The max concentration at steady-state is 10/28/2024 10

11. Concentration of drug in plasma immediately after administration of the first dose is given by Vd = apparent volume of distribution therefore 10/28/2024 11

12. The max conc after the first dose is Since C max 1 = C maxss , the conc *C of drug in plasma immediately after (D*) is given by *C 0 = C maxss Substuting *C and C maxss gives 10/28/2024 12

13. The size of loading dose depends on the following factors- Maintenance dose ,D Elimination rate constant , K e Dosing interval ,T. 10/28/2024 13

14. Loading dose based on C min ss The minimum concentration of drug in plasma at steady-state is given by equation If drug follows linear p’kinetics then C is directly proportional to size of D The min concentration of drug in plasma at steady-state is 10/28/2024 14

15. When a single bolus dose of the drug is administered intravenously Therefore 10/28/2024 15

16. The min conc of drug in plasma after administration of first dose For D* C min 1 = (*C ) (e -p ),which should be equal to C min ss Combining eq 10/28/2024 16

17. Common terms canceled 10/28/2024 17

18. Factors affecting size of dose If all doses and all T are kept constant, then the size of D depends on size of D*, T & K e Effect of dosing interval: If the size of D is kept constant & biological halflife of the drug dose not change during the course of therapy, the size of D* depends entirely upon the T of a given drug. 10/28/2024 18

19. EXTRAVASCULAR ADMINISTRATION For the determination of D* during e.v , administration, the simplest case is a drug which, when administered, confers upon the body the characteristics of one-compartment model, & does not exhibit lag-time. The size of D* needed to attain steady-sate conc of drug in plasma depends on: 10/28/2024 19

20. Maximum concentration of drug in plasma at steady state. OR Minimum concentration of drug in plasma at steady state. LOADING DOSE BASED ON C maxss The maximum concn of drug in plasma at steady-state is given by 10/28/2024 20

21. Where B is the back extrapolated y-intercept of the elimination phase after administration of a single dose. R=( K e ) ( t max ) 10/28/2024 21

22. Loading dose based on C min ss The minimum conc of drug in plasma following e.v adminstration of n dose If the drug follows linear pharmacokinetics then B F=fraction of dose absorbed G= (Ka)( T) 10/28/2024 22

23. By setting n=1 in above eq in C min1 Canceling common terms When n becomes large, the two exponential terms e - np e - nG approach 0 10/28/2024 23

24. Since the y-intercept,Cmin1 is directly proportional to D If D is administered at the first dose 10/28/2024 24

25. When Cmin1= Cminss Substituting the values Bringing RHS of eq to common denominator Upon simplification 10/28/2024 25

26. Dividing both side by (e -p – e -G ) Cancelling common term 10/28/2024 26

27. Maintenance Dose After the loading dose is given the another dose is given to maintain the steady- state drug conc. / plateau. Such dose is known as maintenance dose. i.e. maintain the response of drug by replacing drug lost during dosing interval 10/28/2024 27

28. Maintenance dose = loading dose . ( 1- e k ז ) Loading dose = The ratio of loading dose to maintenance dose (X l/X ) is called as dose ratio When ז = t 1/2 the dose ratio =2.0 When ז > t 1/2 the dose ratio < 2.0 when ז < t 1/2 the dose ratio >2.0 10/28/2024 28

29. 10/28/2024 29

30. Maintenance of drug within the therapeutic range The ease or difficulty in maintaining drug concentration within the therapeutic window depends on- The Therapeutic index of drug The Half- life of drug Convenience of dosing 10/28/2024 30

31. REFERENCE Madan PL;Biopharmaceutics and pharmacokinetics. Jaypee.2010(1);365-80. Brahmankar DM, Sunil Jaiswal B; Biopharmaceutics and Pharmacokinetics- A Treatise. Vallabh publication. 2014(3); 374-76. C V S Subrahmanyam . Textbook of Biopharmaceutics & pharmacokinetics.1 st edition 2010;456-61. 10/28/2024 31

32. 10/28/2024 32 THANK YOU