dosages rgimen and repititive dosing

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SEMINAR ON DOSAGE REGIMEN AND REPETITIVE DOSING PRESENTED BY- Chandan Kumar Singh M.Pharm (Pharmaceutics)

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23 September 2010 BBDNITM , Lucknow 2 CONTENTS

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23 September 2010 BBDNITM , Lucknow 3 INTRODUCTION

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23 September 2010 BBDNITM , Lucknow 4 Objective of dosage regimen The overall objective of dosage regimen design is to achieve a target drug concentration at the receptor site

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23 September 2010 BBDNITM , Lucknow 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 Modify objective Continue Regimen Stop Therapy Steps in the initiation and management of the drug therapy

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23 September 2010 BBDNITM , Lucknow 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.

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23 September 2010 BBDNITM , Lucknow 7 Function of Therapeutic Drug Monitoring

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23 September 2010 BBDNITM , Lucknow 8 Drug selection- Done by Physician on the basis of - Therapeutic consideration and therapeutic equivalence Pharmacokinetic and Pharmacodynamic data of drug are periodically reviewed and updated by Institutional Pharmacy and Therapeutic committees. Factor Producing variability in Drug response A. Age Weight Pathophysiology Nutritional status Genetic variability Gender

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23 September 2010 BBDNITM , Lucknow 9 Design of Dosage Regimen Generally , the initial dosage of the drug is estimated using average population pharmacokinetic parameter obtained from the literature. After evaluation of the patient , adjustment of the dosage regimen using the patient’s individual pharmacokinetic may be indicated , with further therapeutic drug monitoring. Many software are available for dose calculation., Datakinetic(ASHSP) Abbottbase Pharmacokinetic system

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23 September 2010 BBDNITM , Lucknow 10 1 ) INDIVIDUALIZED DOSAGE REGIMEN- Most accurate approach Based on patient’s age, weight, lean body weight and creatinine clearance Not feasible for calculation of initial dose 2 ) DOSAGE REGIMEN BASED ON POPULATION AVERAGES This method used avg. Pharmacokinetic parameter obtained from clinical studies published in drug literature. based on Fixed model Adaptive model

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23 September 2010 BBDNITM , Lucknow 11 Fixed model assume that Pharmacokinetic parameter such as Ka, F, Vd and KE are remain constant. Drug follow the Pharmacokinetic of a One-compartment model. In case multi-dosage regimen , multi dose eq. are used to calculate Dose.

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23 September 2010 BBDNITM , Lucknow 12 Adaptive model based on patient variable such as weight, age, sex, body surface area and patient Pathophysiology such as renal disease It assume that pharmacokinetic parameter such as drug clearance do not change from one dose to the next.

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23 September 2010 BBDNITM , Lucknow 13 3) Dosage regimen based on partial Pharmacokinetic parameters For many drugs, the entire pharmacokinetic profile for the drug is not available, so some assumption are made to calculate the dosage regimen( e.g. use of avg. Patient population characteristics). 4) Empirical Dosage Regimen Dosage regimen are calculated on the basis of - Empirical clinical data Personal experience Clinical observation

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23 September 2010 BBDNITM , Lucknow 14 Drug Dosage Form Selection of dosage form depends upon Route of administration Desired onset and duration of clinical response Because it directly affect the Rate of absorption Drug bioavailability

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23 September 2010 BBDNITM , Lucknow 15 Evaluation of Patient response After selection of drug product, patient receives the initial dosage regimen Dosage regimen are reviewed for Adequacy Accuracy Patient compliance Measurement of serum Drug concentration It relate the therapeutic or toxic effect of the drug. Blood sample are taken at 3 or 4 elimination half life approximately give steady state drug conc.

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23 September 2010 BBDNITM , Lucknow 16 Assay of Drug - Techniques used for drug measurement are - High pressure liquid chromatography Gas chromatography Spectrophotometery Fluorometery Immuonoassay Radio isotopic method e.g. Abbott TDx system ( fluoresscence polarization immunoassay ) – for antiarrhythmics & aminoglycoside.

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23 September 2010 BBDNITM , Lucknow 17 Method used for assay of drug should be validated for- Specificity Sensitivity Linearity and dynamic range Precision Accuracy Ruggedness Pharmacokinetic evaluation of serum drug conc. After the assay of drug conc. in serum ,data are evaluated for the total drug ( free plus bound drug ) conc. in serum.

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23 September 2010 BBDNITM , Lucknow 18 Serum conc. lower than anticipated Patient compliance Error in dosage regimen Wrong drug product Poor bioavailability Rapid elimination Reduced plasma protein binding Enlarged volume of distribution Timing of blood sample Changing hepatic blood flow Steady state not reached

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23 September 2010 BBDNITM , Lucknow 19 Serum conc. Higher than anticipated Rapid bioavailability Smaller than anticipated apparent volume of distribution Slow elimination Increased plasma protein binding Drug interaction due to inhibition of elimination Serum conc. correct but patient does not respond to therapy Altered receptor sensitivity Drug interaction at receptor site Changing hepatic blood flow

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23 September 2010 BBDNITM , Lucknow 20 Dosage adjustment- Dosage adjustment are done on the basis of Pharmacokinetic parameter derived from the Patient’s serum drug concentration. Special Recommendation- If the patient may not response to drug therapy due to other factor, special recommendation are given e.g. Patient noncompliance

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23 September 2010 BBDNITM , Lucknow 21 Major parameter in development of dosage regimen Dose size- The quantity of drug administered each time 2 ) Dosing frequency – The interval between doses. DOSE SIZE - The magnitude of both therapeutic and toxic responses depends upon the dose size. Greater the dose size, greater the fluctuation between Css,max and Css,min during each dosing interval and greater the chance of toxicity.

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23 September 2010 BBDNITM , Lucknow 22 Time( in hr) Plasma conc. MSC MEC DOSES τ τ τ τ τ PLOT SHOWING EFFECT OF DOSE SIZE

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23 September 2010 BBDNITM , Lucknow 23 DOSE FREQUENCY - Calculated on the basis of half life of the drug. If the interval is increased and the dose is unchanged , Cmax , Cmin and Cav decrease but the ratio Cmax/Cmin increase and vice versa also , leads to greater drug accumulation in the body and toxicity. A proper balance between both dose size and dosing frequency is often desired to attain steady state conc. with min. fluctuation and to ensure therapeutic efficacy and safety

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23 September 2010 BBDNITM , Lucknow 24 When the half life of the drug is long e.g. Amiodarone ( 25 days ) At first ,800 to 1600 mg/day taken in divided dose. Then 600 mg to 800 mg per day for 1 month followed by 400 mg per day. When the half of the drug is short, e.g. diclofenac, morphine, metoprolol Diclofenac – conventional, enteric , extended release tablet Metoprolol – conventional and sustained release tablet

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23 September 2010 BBDNITM , Lucknow 25 PLOT SHOWING EFFECT OF DOSING FREQUENCY Time ( hr) Plasma conc. MSC MEC High dosing frequency (τ< t₁ ∕₂),lesser fluctuation Optimum dosing frequency(τ=t₁ ∕ ₂) Less dosing frequency (τ> t₁ ∕ ₂)

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23 September 2010 BBDNITM , Lucknow 26 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

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23 September 2010 BBDNITM , Lucknow 27 When the duration of treatment of disease is larger than the therapeutic effect of drug, Multiple dosage regimen are given e.g. antibiotics

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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- KE τ τ= Dosing interval KE = Elimination half life BBDNITM , Lucknow 29 05 June 2009

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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 0τ 5τ 1X0 2X0 Dosing interval in hr ( τ = t½) Amount of drug in the body X0 X0 X0 X0 X0 Steady state Upper Asymptote, Xss,max Lower asymptote, Xss,min ½Xo Xo +½X0

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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. 05 June 2009 30 BBDNITM , Lucknow

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05 june 2009 BBDNITM , Lucknow 31 REPETITIVE INTRAVENOUS INJECTION After single rapid IV injection, DB = D0e -k t If the τ is the dosing interval, then amount of drug remaining in the body after several hr, DB= D0e -k τ The fraction of the Dose remaining in the body f = DB/D0 = e -k τ

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05 June 2009 BBDNITM , Lucknow 32 Problem of missed Dose - Plasma drug conc. at t hr after the nth dose- Cp = D0 e ( 1 – e )/ VD ( 1 – e ) ……1 -k t -nk τ Conc. contributed by missing dose is Cp’ = D0 e / VD……………………………2 -k tmiss So missing dose, (eq 1 – eq 2)is Cp = D0(1 – e )(e - e )/VD( 1 – e ) -nk τ -k t -k tmiss -k τ -kt

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05 June 2009 BBDNITM , Lucknow 33 e.g. of missing dose

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05 June 2009 BBDNITM , Lucknow 34 INTERMITTENT INTRAVENOUS INFUSION The drug may not reach steady state Conc. after one or more short IV infusion Cp = D ( 1 – e ) / tinf VD k -k t

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05 June 2009 BBDNITM , Lucknow 35 Where , D / tinf = Rate of infusion .i.e. R D = Size of infusion dose tinf = infusion period VD = volume of distribution k = elimination rate constant Drug conc. post IV infusion is Cp = Cstop e -kt Where, Cstop = Conc. when infusion stop t = time elapsed since infusion stopped

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05 june 2009 BBDNITM , Lucknow 36 MULTIPLE – ORAL- DOSE REGIMEN The plasma conc. at any time during oral multiple dose regimen, Cp = F.kaDo VD(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

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05 June 2009 BBDNITM , Lucknow 37 Cav = F D0 / ClT τ FOR MULTIPLE ORAL DOSE ∞ Cmax = F Do e / VD ( 1 – e ) ∞ -k tp - kτ Cmin = ka F D0 e / VD ( ka – k )(1 – e ) - kτ -kτ ∞

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05 June 2009 BBDNITM , Lucknow 38 Max. Conc. & min. Conc. during multiple dosing Css,max = C0 / 1 – e Css,min = Css,max . e -kτ -kτ Ratio of Cmax / Cmin is known as fluctuation, Greater the ratio, greater the fluctuation. Css,av = F X0 / ClT .τ.

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05 June 2009 BBDNITM , Lucknow 39 LOADING AND MAINTENANCE DOSE An initial or first dose intended to be therapeutic is called as priming or loading dose D0,L = Css, av VD / F For 1 compartment model, LD = For 2 compartment model, LD = VD ×D(P)target F VD(ß) ×D(P)target F

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05 June 2009 BBDNITM , Lucknow 40 ∞ OBJECTIVE- to achieve desired plasma conc., Cav , as quickly as possible. DImax =1.44 t½ × log TW Route of Drug administration ( MD /DI)= D(P)target × Cl F While, TW= MSC MEC

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05 June 2009 BBDNITM , Lucknow 41 A maintenance dose is given to maintain Cav 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 = t½ , dose ratio should be equal to 2 τ > t½ , dose ratio should be smaller than 2 τ < t½ dose ratio should be greater than 2

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05 June 2009 BBDNITM , Lucknow 42 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)

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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

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05 June 2009 BBDNITM , Lucknow 44 PREVIOUS YEAR QUESTION Describe the principle underlying the design of multiple dosage regimen.

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REFERENCES Shargel Leon, Andrew Yu B.C., “Applied biopharmaceutics and pharmacokinetics” , 5th edition, published by Mc Graw Hill ,page no. 185 .207,613-625. Gibaldi M., “Biopharmaceutics And Clinical Pharmacokinetics” 4th edition, Pulished by Pharma Med Press,Page no.345. Brahmankar D.M., Jaiswal S.B., “ Biopharmaceutics and Pharmacokinetics” 1st edition, Published by Vallabh Prakashan , Page no.307-315. Notari Robert E., “Biopharmaceutics & clinical pharmacokinetics.”, Fourth Edition, published by Marcell Dekker, page no.351-397.

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BBDNITM , Lucknow THANKING YOU. . .