U1L1 DESIGN OF DOSAGE REGIMEN, U1L1 DESIGN OF DOSAGE REGIMEN

U1L1 DESIGN OF DOSAGE REGIMEN.pdf

U1L1 DESIGN OF DOSAGE REGIMEN

1. Design
of
Dosage Regimen
Mohammad Javed Ansari, PhD.
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2. OBJECTIVES OF THE LECTURE
•At the end of this lecture, you will be able to explain:
•What is dosage regimen?
•What is design of dosage form / regimen?
•How to design a dosage regimen?
•What are varoius methods for dosage regimen?
•What are varoius factors that affects design of
dosage regimen?
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3. DOSAGE REGIMEN DESIGN -INTRODUCTION
•Dosageregimendesignistheselectionof-
•Drugdose,
•Dosageform,
•Routeofadministration,
•Frequency/intervaland
•Durationofadministration,inaninformedmannerto
achievetherapeuticobjectives.
•Dosageregimendesignisnecessarybecausethe
administrationofdrugsusuallyinvolvesriskofuntoward
effects.
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4. DOSAGE REGIMEN DESIGN -INTRODUCTION
•Dosageform:thewayinwhichatherapeuticagentis
takenoradministered(tablet,capsule,spray).
•Dosageregimen:thescheduleofdosesperunitoftime(no.of
dosesandinterval).
•Dosageformdesign:Developmentoftheoptimumdrug
deliverysystemformaximumbenefitsandminimumharmtothe
patient.
•Dosageregimendesign:DevelopmentoftheoptimumDose,
DosingintervalandDosingDurationofadosageform
formaximumbenefitsandminimumharmtothepatient.
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5. METHODS USED TO DESIGN A DOSAGE REGIMEN
1)DosageRegimensbasedonPopulationaverages
2)DosageRegimensbasedonPartialPharmacokinetic parameters
3)EmpiricalDosageRegimen
4)IndividualizedDosageRegimen
5)NomogramandTabulationinDosageRegimen
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6. METHODS USED TO DESIGN A DOSAGE REGIMEN
1-DosageRegimensbasedonPopulationaverages
The method most often used to calculate a dosage regimen is based
on average pharmacokinetic parameters obtained from clinical
studies published in the drug literature.
•Thereare2 approachesfollowed:
a. Fixedmodel
b. Adaptivemodel
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7. METHODS USED TO DESIGN A DOSAGE REGIMEN
1-DosageRegimensbasedonPopulationaverages
a.Fixedmodel
Thismodelassumes that populationaverage
pharmacokineticparametersmaybeuseddirectlytocalculatea
dosageregimenforthepatient,withoutanyalteration.
Thepractitionermayusetheusualdosagesuggestedbythe
literatureandthenmakeasmalladjustmentofthedosagebased
onthepatient’sweightand/orage
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8. METHODS USED TO DESIGN A DOSAGE REGIMEN
1-DosageRegimensbasedonPopulationaverages
a.Fixedmodel
ThePharmacokineticparameterssuchasKa,F,Vd,kareassumed
asconstantandmostoftendrugisassumedtofollowone
compartmentopenmodel.
Whenamultipledoseregimenisdesigned,multipledosage
equationsbasedontheprincipleofsuperpositionareusedto
evaluatethedose.
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9. METHODS USED TO DESIGN A DOSAGE REGIMEN
1-DosageRegimensbasedonPopulationaverages
b. Adaptivemodel
This model attemptsto adapt ormodifydosageregimen
according to the need of the patient.
It uses patient variable such as weight, age, sex, body surface area,
and known patient’s pathophysiology such as, renal disease, as
well as known population average pharmacokinetic parameters of
the drug.
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10. METHODS USED TO DESIGN A DOSAGE REGIMEN
2-DosageRegimensbasedonpartialPKParameter
Thismodelisusedwhentheentirepharmacokineticprofileforthe
drugisunknownorunavailable.
TheClinicianneedstomakesomeassumptionsinordertocalculate
thedosageregimen,dependingonthesafety,efficacy,and
therapeuticrangeofthedrug.
Theuseofpopulationpharmacokineticsusesaveragepatient
populationcharacteristicsandonlyafewserum/plasma
concentrationfromthepatient
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11. METHODS USED TO DESIGN A DOSAGE REGIMEN
3-DosageRegimensbasedonEmpiricaldata
Inmanycases,physicianselectsadosageregimenofthepatient
withoutusinganypharmacokineticvariables.
Thephysicianmakesthedecisionbasedon-
Empiricalclinicaldata,
Personalexperienceand
Clinicalobservations.
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12. METHODS USED TO DESIGN A DOSAGE REGIMEN
4-IndividualizedDosageRegimens
Dosageregimenisbasedonthepharmacokineticsofthedruginthe
individualpatientderivedfrommeasurementofserum/plasma
druglevels.
Mostdosingprogramrecordthepatient’sageandweightand
calculatetheindividualdosebasedoncreatinineclearanceandlean
bodyweight.
Itisoneofthemostaccurateapproaches.
Itisnotfeasibleforcalculationoftheinitialdose,however,once
thepatienthasbeenmedicated,readjustmentofthedosemaybe
done.
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13. METHODS USED TO DESIGN A DOSAGE REGIMEN
5-NomogramsandTabulationinDesigningDosageRegimen
Manycliniciansrelyonnomogramstocalculatethequickand
properdosageregimenfortheirpatients.
Theuseofnomogrammaygiveaquickdosageregimenadjustment
forpatientswithcharacteristicsrequiringadjustmentssuchasage,
bodyweight,andphysiologicstate.
Ingeneral,nomogramofadrugisbasedonpopulation
pharmacokineticdatacollectedandanalyzedusingaspecific
pharmacokineticmodel.
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14. METHODS USED TO DESIGN A DOSAGE REGIMEN
5-NomogramsandTabulationinDesigningDosageRegimen
Nomogramsorequations,whichdescribetherelationshipsbetween
patientcharacteristicssuchas-
-Age,weight,gender,diseasestates,interactingdrugs,smoking&
foodand
-Pharmacokineticparametersinapopulation,
areoftenusedtoestimatetheinitialpharmacokineticparametersfor
drugdosinginindividualpatientsforwhompatient-specific
parametersarenotknown.
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15. METHODS USED TO DESIGN A DOSAGE REGIMEN
5-NomogramsandTabulationinDesigningDosageRegimen
Anomogramtypicallyhasthreescales:twoscalesrepresentknown
valuesandonescaleisthescalewheretheresultisreadoff.
Theknownscalesareplacedontheoutside;i.e.theresultscaleisin
thecentre.
Eachknownvalueofthecalculationismarkedontheouterscales
andalineisdrawnbetweeneachmarkwherethelineandtheinside
scaleintersectsistheresult.
Examplesinclude:height–BMI–weight,
Totalclearance–maintenancedose–leanbodyweight,etc.
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16. METHODS USED TO DESIGN A DOSAGE REGIMEN
5-NomogramsandTabulationinDesigningDosageRegimen
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17. METHODS USED TO DESIGN A DOSAGE REGIMEN
5-NomogramsandTabulationinDesigningDosageRegimen
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18. METHODS USED TO DESIGN A DOSAGE REGIMEN
5-NomogramsandTabulationinDesigningDosageRegimen
Therecommendedadultdoseofadrugis70mg/m2.
Usingthenomogramcalculatethedoseforachildweighing25kg
andmeasuring70cm.
Approach:
Firststep:EstimatetheBSAusingthenomogramforchildren.
Secondstep:PutBSAintoequationtocalculatethechilddose.
NarmogramprovidedBSAof0.64m2
Thechilddosewillbe70mg/m2×0.64m2=44.8mg
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19. METHODS USED TO DESIGN A DOSAGE REGIMEN
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Thisnomogramis
basedonobservations
from81childrenaged
6–12years and
requiresthepatient’s
heightandserum
creatinine
concentration.
Nomogramof
TraubandJohnson

20. FACTORS AFFECTING DESIGN OF DOSAGE REGIMEN
a)Drugrelatedfactors
b)DosageformsandRouteofadministrations
c)Patientrelatedfactors
d)Otherfactors
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21. FACTORS AFFECTING DESIGN OF DOSAGE REGIMEN
a)Drugrelatedfactors
1.Drugabsorptioncharacteristics
2.Accumulationofdrugatabsorptionsite,e.g.
intramusculardepots
3.Presenceofpresystemicelimination
4.Half-life:infusionmaybenecessaryfordrugs
withshortt
1/2 releaseformulation.
5.Half-life:dosageintervalcangenerallybe
extendedinrelationtohalf-life.
6.Druginteractions
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22. FACTORS AFFECTING DESIGN OF DOSAGE REGIMEN
a)Drugrelatedfactors
1.Existenceofatherapeuticortoxicconcentration.
2.Therapeuticindex:ifhigh,high loadingdose.
3.Therapeuticindex:thehighertheTI,thelonger
anintervalcanbespaced withhigherdoses.
4.Availabilityoftreatmentforoverdose.
5.Sideeffectswhichmayrequirespecial
administrationtimes,e.g.bedtimeto avoid
sedation.
6.Documentednonlinearityofpharmacokinetics.
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23. FACTORS AFFECTING DESIGN OF DOSAGE REGIMEN
b)DosageformsandRouteofadministrations
1.Needforimmediateonsetofaction
2.Easeofadministration
3.Patientacceptanceofrouteanddosageform
4.Costofmedication
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24. FACTORS AFFECTING DESIGN OF DOSAGE REGIMEN
c)Patient/diseaserelatedfactors
1.Changing pathophysiology
2.Autoorexogenousenzymeinduction
3.Developmentofpharmacodynamic tolerance
4.Co morbidity
5.Disease/ food / Druginteractions
6.Easeofadministration
7.Patientacceptanceofrouteanddosageform
8.Costofmedication
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25. FACTORS AFFECTING DESIGN OF DOSAGE REGIMEN
d)Otherchallenges
1.Activemetabolites
2.Analyticalmethodologyandreliabilityinmonitoring
C
p
3.Needforbaselinecon.datawithrecenthistoryof
druguse.
4.Sideeffectsnotdoseorconcentrationrelated
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26. Questions..
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