multiple-dosage-regimen.pdf

multiple-dosage-regimen

1. MULTIPLE-DOSAGE REGIMENS

2. Demonstrate multiple-dose regimens
calculation, necessary to decide whether
successive doses of drug will have any effects
on the previous dose
compare successive dosage in repetitive dose
between IV Infusion and oral
Analysebioavailability and bioequivalence in
a multiple oral dose regimen

3. 3
•To maintain prolonged therapeutic activity, many drugs are given in
a multiple-dosage regimen.
•The plasma levels of drugs given in multiple doses must be
maintained within the narrow limits of the therapeutic window (eg,
plasma drug concentrations above the MEC but below the minimum
toxic concentrationor MTC) to achieve optimal clinical effectiveness.

4. To calculate a multiple-dose regimen for a
patient or patients, pharmacokinetic
parameters are first obtained from the
plasma level–time curve generated by single-
dose drug studies.
To calculate multiple-dose regimens, it is
necessary to decide whether successive doses
of drug will have any effect on the previous
dose.

5. Theprincipleofsuperpositionallowsonetoprojectthe
plasmadrugconcentration–timecurveofadrugafter
multipleconsecutivedosesbasedontheplasmadrug
concentration–timecurveobtainedafterasingledose.
Thebasicassumptionsarethatthedrugiseliminatedby
first-orderkineticsandthatthepharmacokineticsofthedrug
afterasingledose(firstdose)arenotalteredaftertaking
multipledoses.
Simulated data showing blood levels after administration of multiple
doses and accumulation of blood levels when equal doses are given at
equal time intervals

6. The dose given at similar time interval and same
dosage
In Table: dose given is 350µg/ml at every 4hrs

7. There are situations, however, in which the
superposition principle does not apply.
In these cases, the pharmacokinetics of the drug
change after multiple dosing due to various
factors:
◦changing pathophysiologyin the patient,
◦saturation of a drug carrier system,
◦enzyme induction, and
◦enzyme inhibition
◦Drugs that follow nonlinear pharmacokinetics generally do
not have predictable plasma drug concentrations after
multiple doses using the superposition principle.
When the second dose is given after a time interval
shorter than the time required to "completely"
eliminate the previous dose, drug accumulation
will occur in the body.

8. As repetitive equal doses are given at a constant frequency,
the plasma level–time curve plateaus and a steady state is
obtained.
At steady state, the plasma drug levels fluctuate between C
∞
maxand C
∞
min. Once steady state is obtained, C
∞
max
and C
∞
minare constant and remain unchanged from dose to
dose.
The C
∞
maxis important in determining drug safety. The C
∞
maxshould always remain below the minimum toxic
concentration. The C
∞
maxis also a good indication of drug
accumulation.
If a drug produces the same C
∞
maxat steady state, compared
with the (C
n=1)
maxafter the first dose, then there is no drug
accumulation. If C
∞
maxis much larger than (C
n=1)
max, then
there is significant accumulationduring the multiple-dose
regimen.
Accumulation is affected by the elimination half-life of the
drug and the dosing interval.

9. The index for measuring drug accumulation
Ris
Substituting for C
maxafter the first dose and at steady state
yields
Equation 11.2
Equation 11.1

10. Equation 11.2 shows that drug accumulation measured
with the Rindex depends on the elimination constant
and the dosing interval and is independent of the
dose.
For a drug given in repetitive oral doses, the time
required to reach steady state is dependent on the
elimination half-life of the drug and is independent of
the size of the dose, the length of the dosing interval,
and the number of doses.
Furthermore, if the drug is given at the same dosing
rate but as an infusion (eg, 25 mg/hr), the average
plasma drug concentrations (C
∞
av) will be the same
but the fluctuations between C
∞
maxand C
∞
minwill
vary.

11. An equation for the estimation of the time to reach one-half of the
steady-state plasma levels or the accumulation half-life has been
described by :
For IV administration, k
ais very rapid (approaches ∞); kis very small in
comparison to k
aand can be omitted in the denominator of Equation
8.3. Thus, Equation 11.3 reduces to
Because k
a/k
a= 1 and log 1 = 0, the accumulation t
1/2of a drug
administered intravenously is the elimination t
1/2 of the drug. From this
relationship, the time to reach 50% steady-state drug concentrations is
dependent on the elimination t
1/2 and not on the dose or dosage
interval.
As shown in Equation 11.4, the accumulation t
1/2 is directly proportional
to the elimination t
1/2. gives the accumulation t
1/2 of drugs with various
elimination half-lives
Equation 11.3
Equation 11.4

12. The maximum amount of drug in the body following a single rapid IV
injection is equal to the dose of the drug. For a one-compartment open
model, the drug will be eliminated according to first-order kinetics.
If זis equal to the dosage interval (ie, the time between the first dose
and the next dose), then the amount of drug remaining in the body after
several hours can be determined with
The fraction (f) of the dose remaining in the body is related to the
elimination constant (k) and the dosage interval (ז) as follows:
With any given dose, fdepends on kand ז. If is large, fwill be smaller
because D
B(the amount of drug remaining in the body) is smaller.
Equation 11.5
Equation 11.6
Equation 11.7

13. A patient receives 1000 mg every 6 hours by
repetitive IV injection of an antibiotic with an
elimination half-life of 3 hours. Assume the drug is
distributed according to a one-compartment model
and the volume of distribution is 20 L.
a.Find the maximum and minimum amount of
drug in the body.
b.The average amount of drug in the body at
steady state, D
∞
av
c.Determine the maximum and minimum plasma
concentration of the drug.

14. a.
b.

15. c. To determine the concentration of drug in the body after multiple doses,
divide the amount of drug in the body by the volume in which it is dissolved.
For a one-compartment model, the maximum, minimum, and steady -state
concentrations of drug in the plasma are found by the following equations:

16. Thepatientinthepreviousexamplereceived1000
mgofanantibioticevery6hoursbyrepetitiveIV
injection.Thedrughasanapparentvolumeof
distributionof20Landeliminationhalf-lifeof3
hours.Calculate
(a)theplasmadrugconcentrationC
pat3hours
aftertheseconddose,
(b)thesteady-stateplasmadrugconcentrationC
∞
pat3hoursafterthelastdose,
(c)C
∞
max,
(d)C
∞
min,and
(e)C
SS.

17. a &b

18. Generally,ifthemissingdoseisrecent,itwillaffectthe
presentdruglevelmore.Ifthemissingdoseisseveralhalf-
liveslater(>5t
1/2),themissingdosemaybeomittedbecause
itwillbeverysmall.
Concentrationcontributedbythemissingdoseis
t
miss= time elapsed since the
scheduled dose was missed
the missing dose as shown in Equation below:
If steady state is reached (ie, either n= large or after many doses), the equation
simplifies to

19. A cephalosporin (k= 0.2 hr
–1
, V
D= 10 L)
was administered by IV multiple dosing; 100
mg was injected every 6 hours for 6 doses.
What was the plasma drug concentration 4
hours after the 6th dose (ie, 40 hours later) if
(a)the 5th dose was omitted,
(b)the 6th dose was omitted,
(c)the 4th dose was omitted?

21. When one of the drug doses is taken earlier or later than
scheduled, the resulting plasma drug concentration can still
be calculated based on the principle of superposition. The
dose can be treated as missing, with the late or early dose
added back to take into account the actual time of dosing
in which t
miss= time elapsed since the dose (late or early) is
scheduled, and t
actual= time elapsed since the dose (late or
early) is actually taken.

22. Assume the same drug as above (ie, k= 0.2
hr
–1
, V
D= 10 L) was given by multiple IV
bolus injections and that at a dose of 100 mg
every 6 hours for 6 doses. What is the plasma
drug concentration 4 hours after the 6th
dose, if the 5th dose were given an hour late?

24. Theplasmaconcentrationatanytimeduringanoralor
extravascularmultiple-doseregimen,assumingaone-compartment
modelandconstantdosesanddoseinterval,canbedeterminedas
follows:
where n= number of doses,ז= dosage interval, F= fraction of dose
absorbed, and t= time after administration of ndoses.

25. The mean plasma level at steady state, C
∞
av, is determined by a similar
method to that employed for repeat IV injections
Because proper evaluation of Fand V
Drequires IV data, the AUC of a
dosing interval at steady state may be substituted to obtain C
∞
av
The magnitude of C
∞
avis directly proportional to the size of the dose
and the extent of drug absorbed. Furthermore, if the dosage interval (ז)
is shortened, then the value for C
∞
avwill increase. The C
∞
avwill be
predictably higher for drugs distributed in a small V
D(eg, plasma water)
or that have long elimination half-lives than for drugs distributed in a
large V
D(eg, total body water) or that have very short elimination half-
lives.

26. Because body clearance (Cl
T) is equal to kV
D, substitution
into Equation :
At steady state, the drug concentration can be determined
by
Thus, if Cl
Tdecreases, C
∞
avwill
increase.

27. The maximum and minimum drug concentrations (C
∞
maxand C
∞
min)
can be obtained with the following equations:
The time at which maximum (peak) plasma concentration (or t
max)
occurs following a single oral dose is
LargefluctuationsbetweenC
∞
maxandC
∞
mincanbehazardous,
particularlywithdrugsthathaveanarrowtherapeuticindex.Thelarger
thenumberofdivideddoses,thesmallerthefluctuationsintheplasma
drugconcentrations.Forexample,a500-mgdoseofdruggivenevery6
hourswillproducethesameC
∞
avvalueasa250-mgdoseofthesame
druggivenevery3hours,whiletheC
∞
maxandC
∞
minfluctuationsfor
thelatterdosewillbedecreasedbyone-half.Withdrugsthathavea
narrowtherapeuticindex,thedosageintervalshouldnotbelongerthan
theeliminationhalf-life.

28. An adult male patient (46 years old, 81 kg) was given orally 250 mg
of tetracycline hydrochloride every 8 hours for 2 weeks. From the
literature, tetracycline hydrochloride is about 75% bioavailableand
has an apparent volume of distribution of 1.5 L/kg. The elimination
half-life is about 10 hours. The absorption rate constant is 0.9 hr
–1
.
From this information, calculate
(a) C
maxafter the first dose,
(b) C
minafter the first dose,
(c)plasma drug concentration C
pat 4 hours after the 7th dose,
(d)maximum plasma drug concentration at steady-state C
∞
max,
(e)minimum plasma drug concentration at steady-state C
∞
min, and
(f)average plasma drug concentration at steady-state C
∞
av.

29. Bioavailabilitymaybedeterminedduringamultiple-doseregimen
onlyafterasteady-stateplasmadruglevelhasbeenreached.As
discussed,thetimeneededtoreachthesteady-stateplasmalevelis
relatedtotheeliminationhalf-life,t
1/2,ofthedrug.
Theparametersforbioavailabilityofadrugusingplasma-leveldata
fromamultiple-doseregimenaresimilartothoseobtainedwitha
single-doseregimen.Intheformercase,thefirstplasmasamples
aretakenjustbeforetheseconddoseofthedrug.Thereafter,
plasmasamplesaretakenperiodicallyafterthedoseis
administered,inordertodescribetheentireplasmalevel–timecurve
adequately.ParametersincludingAUC,timeforpeakdrug
concentration,andpeakdrugconcentrationarethenusedto
describethebioavailabilityofthedrug.

30. The extent of bioavailability, measured by assuming the
[AUC]
∞
0, is dependent on clearance:
Determination of bioavailability using multiple doses reveals
changes that are normally not detected in a single-dose
study. For example, nonlinear pharmacokinetics may occur
after multiple drug doses, due to the higher plasma drug
concentrations saturating an enzyme system involved in
absorption or elimination of the drug. With some drugs, a
drug-induced malabsorptionsyndrome can also alter the
percentage of drug absorbed. In this case, drug bioavailability
may decrease after repeated doses if the fraction of the dose
absorbed (F) decreases or if the total body clearance (kV
D)
increases.

31. A bioequivalence study may be performed using a multiple-dose
study design. Multiple doses of the same drug are given
consecutively to reach steady-state plasma drug levels. The
multiple-dose study is designed as a steady-state, randomized,
two-treatment, two-way, crossover study comparing equal doses of
the test and reference products in adult, healthy subjects. Each
subject receives either the test or reference product separated by a
"washout" period, which is the time needed for the drug to be
completely eliminated from the body.
To ascertain that the subjects are at steady state, three consecutive
trough concentrations (C
min) are determined. The last morning dose
is given to the subject after an overnight fast, with continual fasting
for at least 2 hours following dose administration. Blood sampling is
then performed similar to the single-dose study

32. Pharmacokineticanalysisincludescalculationforeachsubjectof
thesteady-stateareaunderthecurve(AUC
0–t),t
max,C
min,C
max,and
thepercentfluctuation[100(C
max–C
min)/C
min].Thedataare
analyzedstatisticallyusinganalysisofvariance(ANOVA)onthelog-
transformedAUCandC
max.Toestablishbioequivalence,theAUC
andC
maxparametersforthetest(generic)productshouldbewithin
80–125%ofthereferenceproductusinga90%confidenceinterval.
Forsomesituations,suchashormonereplacementtherapy,a
bioequivalencestudymaybeperformedinpatientsalready
maintainedonthedrug.Inthiscase,awashoutperiodwouldplace
thepatientatsubstantialriskbybeingwithoutdrugtherapy.
Therefore,thepatientcontinuesonhisorherownmedication,and
bloodsamplingisperformedduringadosageinterval(,drug
productA).Oncethisisaccomplished,thepatientbeginstotake
equaloraldosesofanalternatedrugproduct.Again,timemustbe
allowedforthetheoreticalattainmentofC
∞
avwiththeseconddrug
product.Whensteadystateisreached,theplasmalevel–timecurve
foradosageintervalwiththeseconddrugproductisdescribed(,
drugproductB).Usingthesameplasmaparametersasbefore,the
bioequivalenceorlackofbioequivalencemaybedetermined.

33. Multiple-dose bioequivalencystudy comparing the bioavailability of drug
product B to the bioavailability of drug product A. Blood levels for such
studies must be taken after C
∞
avis reached. The arrow represents the start
of therapy with drug product B.

34. The advantages:
(1) the patient acts as his or her own control;
(2) the patient maintains a minimum plasma drug
concentration; and
(3) the plasma samples after multiple doses contain
more drug that can be assayed more accurately.
The disadvantages:
(1) the study takes more time to perform, because
steady-state conditions must be reached; and
(2) sometimes more plasma samples must be
obtained from the patient to ascertain that steady
state has been reached and to describe the plasma
level–time curve accurately.