Pharmacokinetics of multiple dosing

1. 23 September 2014 1 UNDER THE GUIDENCE OF Dr.SATYABRATA BHANJA M . Pharm, Ph.D. Department of Pharmaceutics Mallareddy College Of Pharmacy PRESENTED BY : K.V.SIVA PRASAD M.Pharm (Pharmaceutics). 256213886018 Mallareddy College of pharmacy PHARMACOKINETICS OF MULTIPLE DOSING

2. CONTENTS Dosage regimen Objectives of dose regimen Therapeutic drug monitoring Multiple dosage regimen Multiple dosing with respect to I.V. Multiple dosing with respect to Oral route. Concept of loading dose, maintenance dose. Drug accumulation References 2

3. 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. 3

4. Objective of dosage regimen The overall objective of dosage regimen design is to achieve a target drug concentration at the receptor site 23 September 2014 4

5. 23 September 2014 5 Examine patient, collect data, and make diagnosis Define therapeutic objective Choose Drug and Dosage Regimen Evaluate how well objective has been achieved Modify Regimen Or Change Drug Modif y objective Stop Therapy Continue Regimen Steps in the initiation and management of the drug therapy

6. Therapeutic Drug Monitoring The success of Drug therapy is highly dependent on Choice of Drug and Drug Product Design of the Dosage Regimen While the choice of Drug and Drug product is based on Patient's characteristics Pharmacokinetic of Drug Every patient have different Drug absorption , distribution , and elimination as well as different pathophysiological condition , so for the improvement in the clinical effectiveness of the drug THERAPEUTIC DRUG MONITORING are done. 23 September 2014 6

7. 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. 7

8. Indications for TDM 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. 8

9. 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. 9

10. Examples of drugs analyzed by therapeutic drug monitoring : 10

11. BBDNITM , Lucknow 11 Function of Therapeutic Drug Monitoring

12. Multiple dosage regimen When the duration of treatment of disease is smaller than the therapeutic activity of drug, single dose are given e.g. Aspirin 23 September 2014 12

13. When the duration of treatment of disease is larger than the therapeutic effect of drug, Multiple dosage regimen are given e.g. antibiotics 23 September 2014 13

14. 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 2 nd dose will be administered before all of the absorbed drug from 1 st dose is eliminated. Consequently plasma conc. resulting from 2 nd dose will be higher than from 1 st 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 14

15. Plasma drug C onc v/s time 15 15 Plasma drug conc. time C max C min

16. 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 16

17. Plasma drug concentration v/s time 17 17 C ss max C ss min Steady state time Plsama drug conc.

18. Drug Accumulation - When the drug is administered at a fixed dose and a fixed dosing interval, “ accumulation occur because drug from previous dose has not been remove.” Accumulation of drug depend upon the dosing interval and elimination half life and is independent of the dose size. Accumulation index = 1 1 – e - K E τ τ = Dosing interval K E = Elimination half life 29

19. In drug accumulation, Time for 90 % steady state plasma conc. – 3.3 times of elimination half life. Time for 99 % steady state plasma conc. – 6.6 times of elimination half life τ 5 τ 1 X0 2 X0 Dosing interval in hr ( τ = t ½ ) Amount of drug in the body X0 X0 X0 X0 X0 Steady state Upper Asymptote, Xss,max Lower asymptote, Xss,min ½Xo Xo +½X0

20. e . g. of Drug Accumulation For a avg. adult , rate of metabolism of ethanol is 10 gm/ hr 45 ml of whiskey contain 14 gm of ethanol. If drink 45 ml of whiskey every hr , will accumulate 4 gm ethanol per hr and develop coma in 48 hr. However, can drink 30ml whiskey ( 9 gm ethanol) every hr. 23 September 2014 20

21. 21 REPETITIVE INTRAVENOUS INJECTION After single rapid IV injection, D B = D e -k t If the τ is the dosing interval , then amount of drug remaining in the body after several hr, D B = D e -k τ The fraction of the Dose remaining in the body f = D B /D = e -k τ

22. 22 Problem of missed Dose - Plasma drug conc. at t hr after the nth dose- C p = D e ( 1 – e )/ V D ( 1 – e ) ……1 -k t -nk τ Conc. contributed by missing dos e is C p ’ = D0 e / V D…………………………… 2 -k t miss So missing dose, (eq 1 – eq 2)is C p = D (1 – e )(e - e )/V D ( 1 – e ) -nk τ -k t -k t miss -k τ -kt

23. 23 INTERMITTENT INTRAVENOUS INFUSION The drug may not reach steady state Conc. after one or more short IV infusion C p = D ( 1 – e ) / t inf V D k -k t

24. 24 Where , D / t inf = Rate of infusion .i.e. R D = Size of infusion dose t inf = infusion period V D = volume of distribution k = elimination rate constant Drug conc. post IV infusion is Cp = C stop e -kt Where, C stop = Conc. when infusion stop t = time elapsed since infusion stopped

25. 25 MULTIPLE – ORAL- DOSE REGIMEN The plasma conc. at any time during oral multiple dose regimen, Cp = F.kaDo V D (k – ka) 1 - e 1 - e -nka τ -ka τ e - kat 1 – e 1 - e -nk τ -k τ e -k t Where, n= no. of doses τ = dosing interval F = fraction of dose absorbed

26. 26 C av = F D / Cl T τ FOR MULTIPLE ORAL DOSE ∞ C max = F D o e / V D ( 1 – e ) ∞ -k t p - k τ C min = ka F D e / V D ( ka – k )(1 – e ) - k τ -k τ ∞

27. 27 Max. Conc. & min. Conc. during multiple dosing Css,max = C0 / 1 – e Css,min = Css,max . e -k τ -k τ Ratio of Cmax / Cmin is known as fluctuation, Greater the ratio, greater the fluctuation. Css,av = F X0 / Cl T . τ .

28. 28 LOADING AND MAINTENANCE DOSE An initial or first dose intended to be therapeutic is called as priming or loading dose D0, L = Css, av V D / F For 1 compartment model, LD = For 2 compartment model, LD = V D ×D ( P)target F V D(ß) ×D (P)target F

29. 29 ∞ OBJECTIVE - to achieve desired plasma conc., C av , as quickly as possible . DI max =1.44 t ½ × log TW Route of Drug administration ( MD /DI )= D (P) target × Cl F While, TW= MSC MEC

30. A maintenance dose is given to maintain C av ∞ and steady state so that the therapeutic effect is also maintained The ratio of loading dose to maintenance dose X0, L / X0 , is called as Dose ratio When, τ = t ½ , dose ratio should be equal to 2 τ > t ½ , dose ratio should be smaller than 2 τ < t ½ dose ratio should be greater than 2 23 September 2014 30

31. 31 Dosing interval in hr Plasma Drug Conc. MEC MSC Dose ratio > 2 Dose ratio = 2 Dose ratio < 2, Loading dose X0 X0 Xo Xo X0 Maintenance Doses X0 ( τ > t ½) ( τ < t ½) ( τ = t ½)

32. Time( in hr) Plasma conc.(µg/ml) MEC MSC Therapeutic range Plot showing the effect of loading dose and maintenance dose. Loading dose Maintenance dose Conventional dose Prolonged release Sustained release

33. REFERENCES Shargel Leon, Andrew Yu B.C., “ Applied biopharmaceutics and pharmacokinetics ” , 5 th edition, published by Mc Graw Hill ,page no. 185 .207,613-625. Gibaldi M., “ Biopharmaceutics And Clinical Pharmacokinetics ” 4 th edition, Pulished by Pharma Med Press,Page no.345. Notari Robert E., “ Biopharmaceutics & clinical pharmacokinetics.”, Fourth Edition, published by Marcell Dekker, page no.351-397. 23 September 2014 BBDNITM , Lucknow 33

34. THANKING YOU. . .