Determination of dose and dosing interval

Information on determining dose and dosing interval

1. Determination of Dose
and Dosing Interval
Dr. RameshBhandari
Asst. Professor
Department of Pharmacy Practice
KLE College of Pharmacy, Belagavi

2. Dr.
Ramesh
Bhandari
Asst. Professor
Calculationofthestartingdoseofadrug
anddosingintervalisbasedontheobjective
ofdeliveringadesirable(target)
therapeuticlevelofthedruginthebody.
Formanydrugs,thedesirabletherapeutic
druglevelsandpharmacokinetic
parametersareavailableintheliterature.

3. Dr.
Ramesh
Bhandari
Asst. Professor
However,Insomecases,literaturemay
nothavecompletedruginformationthen,
pharmacokineticistmustmakecertain
necessaryassumptionsinaccordancewith
thebestpharmacokineticinformation
available.

4. Dr.
Ramesh
Bhandari
Asst. Professor
Foradrugthatisgiveninmultipledoses
foranextendedperiodoftime,thedosage
regimenisusuallycalculatedtomaintain
theaveragesteady-statebloodlevelwithin
thetherapeuticrangeandgivenby
followingequation:
C
∞
av= 1.44D
0t
1/2F
Vdτ

5. Dr.
Ramesh
Bhandari
Asst. Professor
Examples:
1.Pharmacokinetic data for clindamycinwere
reported by DeHaanet al (1972) as follows:
K=0.247h
-1
, t
1/2=2.81h, V
d=43.9L/1.73M
2
What is the steady-state concentration of the
drug after 150 mg of the drug is given orally
every 6 hours for a week? (Assume the drug
is 100% absorbed.)

6. Dr.
Ramesh
Bhandari
Asst. Professor
Solution:
C
∞
av= 1.44D
0t
1/2F
Vdτ
C
∞
av= 1.44x1,50,000x2.81x1
43900x6
C
∞
av=2.3mcg/ml

7. Dr.
Ramesh
Bhandari
Asst. Professor
Example: 2
2.AccordingtoRegameyetal(1973),the
eliminationhalf-lifeoftobramycinwas
reportedtobe2.15hoursandthevolumeof
distributionwasreportedtobe33.5%of
bodyweight.
Whatisthedoseforan80-kgindividualifa
steady-statelevelof2.5μg/mLisdesired?
Assumethatthedrugisgivenbyintravenous
bolusinjectionevery8hours

8. Dr.
Ramesh
Bhandari
Asst. Professor
Determination of Both Dose and
Dosage Interval
Both the doseand the dosing interval
should be considered in the dosage
regimen calculations.
For Intravenous multiple-dosage
regimens, the ratio of C
∞
max/ C
∞
minmay
be expressed by:

9. Dr.
Ramesh
Bhandari
Asst. Professor
C
∞
max= C
0
p/(1 -e
-kτ
)
C
∞
minC
0
pe
-kτ
(1 -e
-kτ
)
C
∞
max= 1
C
∞
min e
-kτ
Fromaboveequation,amaximumdosageinterval(τ),maybe
calculatedthatwillmaintaintheserumconcentrationbetweendesired
C
∞
minandC
∞
max.Afterthedosageintervaliscalculated,thenadose
maybecalculated.

10. Dr.
Ramesh
Bhandari
Asst. Professor
Example:1
Theeliminationhalf-lifeofanantibioticis3
hourswithanapparentvolumeofdistribution
equivalentto20%ofbodyweight.Theusual
therapeuticrangeforthisantibioticisbetween
5and15μg/mL.Adversetoxicityforthisdrug
isoftenobservedatserumconcentrations
greaterthan20μg/mL.Calculateadosage
regimen(multipleIVdoses)thatwilljust
maintaintheserumdrugconcentration
between5and15μg/mL.

11. Dr.
Ramesh
Bhandari
Asst. Professor
Solution:
Determine the maximum possible dosage
interval (τ).
Determine the dose required to produce
from C
∞
max
C
∞
max=D
0/ V
d
1 –e
-Kτ

12. Dr.
Ramesh
Bhandari
Asst. Professor
Effect of changing dose and dosing
interval on C
∞
min, C
∞
maxand C
∞
av.
Duringintravenousinfusion,C
ssmaybe
usedtomonitorthesteady-stateserum
concentrations.
WhenconsideringTDM ofserum
concentrationsaftertheinitiationofa
multiple-dosageregimen,thetroughserum
drugconcentrationsorC
∞
minmaybeused
tovalidatethedosageregimen.

13. Dr.
Ramesh
Bhandari
Asst. Professor
Thebloodsamplewithdrawnjustpriorto
theadministrationofthenextdose
representsC
∞
min.
ToobtainC
∞
max,thebloodsamplemustbe
withdrawnexactlyatthetimeforpeak
absorption.

14. Dr.
Ramesh
Bhandari
Asst. Professor
Inpractice,anapproximatetimefor
maximumdrugabsorptionisestimated
andabloodsampleiswithdrawn.
Becauseofdifferenceinabsorptionrate,
C
∞
maxobtainedisonlyapproximation
ratherthantruevalue.
SotheC
∞
avisusedmostoftenlyfor
dosagecalculation.

15. Dr.
Ramesh
Bhandari
Asst. Professor
TheadvantageofusingC
∞
avasan
indicatorfordecidingtherapeuticblood
levelisthatC
∞
avisdeterminedonasetof
pointsandgenerallyfluctuateslessthan
eitherC
∞
maxorC
∞
min.
Moreover,whenthedosingintervalis
changed,thedosemaybeincreased
proportionally,tokeepC
∞
avconstant.

16. Dr.
Ramesh
Bhandari
Asst. Professor
Ingeneral,ifadrughasarelativelywide
therapeuticindexandarelativelylong
eliminationhalf-life,thenflexibilityexists
inchangingthedoseordosinginterval
(τ),usingC
∞
avasanindicator.
Whenthedrughasanarrowtherapeutic
index,C
∞
maxandC
∞
minmustbemonitored
toensuresafetyandefficacy.

17. Dr.
Ramesh
Bhandari
Asst. Professor
Asthedoseordosageintervalschange
proportionately,theC
∞
avmaybethesamebut
thesteadystatepeak,C
∞
max,andtrough,C
∞
min,
druglevelswillchange.
C
∞
maxisinfluencedbythedoseandthedosage
interval.
Anincreaseinthedosegivenatalonger
dosageintervalwillcauseanincreaseinC
∞
max
andadecreaseinC
∞
min.

18. Dr.
Ramesh
Bhandari
Asst. Professor