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Dosing Regimen Design

Multiple Dosing

Myrna Y. Munar, Pharm.D., BCPS


Associate Professor of Pharmacy
Objectives
Through the preparation for and participation in
this lecture, a successful student should be able to:
Use the Multiple Dosing Function to convert a single
dose equation to a multiple dose equation.
Use the accumulation index to convert a single dose
equation to a steady-state equation and predict the
extent of drug accumulation for a given dosage
regimen.
List the factors that determine if a drug
concentration will stay within a given therapeutic
target window.
Develop and alter a dosage regimen under given
conditions.
Multiple Dosing
Most drugs are given more than
once we need to be able to
understand and predict what will
happen when a dose of drug is
given repeatedly at constant
intervals
Bolus Dosing
140

120
Concentration (mg/L)

100

80

60

40

20

0
0 20 40 60 80 100 120 140

Time (hrs)
Principle of Superposition

Cmax2
Log Plasma Drug Conc

Cmax1
Cmax1 Cmax2

Cmin2
+ Etc for
n doses
Cmin1 Cmin1

Time
Tau
Recall,
After n number of
doses, a pattern
Cmax 2 = Cmax1 + Cmin1
emerges and the n
Cmin1 = Cmax1e kTau numbers of
Cmax 2 = Cmax1 + Cmax1e kTau equations can be
simplified to.
Cmax 2 = Cmax1 (1 + e kTau )
etc...
Before Steady State: Multiple
Dosing Function (MDF)

MDF is used
nk
to convert a
1 e
MDF = k
single dose
equation to a
multiple dose
equation
1 e
Bolus Dosing
140

120
Concentration (mg/L)

100

80

60

40

20

0
0 20 40 60 80 100 120 140

Time (hrs)
Using MDF
Fast Forward from first dose to any
dose after that
Concentration after single dose X MDF =
Concentration at that time at n doses
Equation for single dose x MDF = Equation
at n doses
Recall
e-kt = fraction of drug remaining at time
t
e-k = fraction of drug remaining at the
end of the dosing interval
1-e-kt = fraction of drug removed at time
t
1-e-k = fraction of drug removed at the
end of the dosing interval
Review: Cp=Coe-kt
b=y-intercept Co=y-intercept
Log -k=slope
Y axis m=slope C

X axis Time

m=Y / X -k= lnC / t


m=Y2-Y1/X2-X1 -k=lnC2-lnC1/t2-t1
Y=mX+b lnCp=-kt+Co
Antilog:Cp=Coe-kt
Using MDF
kt
Ct = C 0 e
If given by instantaneous input the
highest concentration occurs at t=0.
F Dose
C0 =
VD
nk

F Dose 1 e kt
Ct = k
e
VD 1 e
At n doses
n k
F Dose 1 e kt
Ct = k e
VD 1 e
Multiple Dosing Function
Bolus Dosing
SS is reached
140

120
Concentration (mg/L)

100

80

60

40

20

0
0 20 40 60 80 100 120 140

Time (hrs)
Using MDF to Determine
Steady State Concentrations
nk
1 e
MDF = k

1 e
When n=large number e-nk approaches 0

1 0 1
MDFn = k k
1 e 1 e
At Steady State=
Accumulation Index/Factor

1
Rac = k
1 e
Relates the concentrations in the dosing
interval at steady state to the values
after a single dose
Accumulation
used to fast forward from first
dose concentrations to steady-
state concentrations
Using Rac
Fast Forward to steady-state
Concentration for single dose X Rac =
Concentration at steady-state
Equation for single dose x Rac = Equation
at Steady-State
Determinants of Accumulation
Frequency of Administration () relative
to
Half-life (t1/2)

1 1
t
2

OR
k
Example
Given t1/2 = 6 hrs & Tau = 6 hrs, what
happens when:
Tau=t1/2
Tau>t1/2; eg. Tau is 5 times greater than t1/2
Tau<t1/2; eg. Tau is 1/3 of t1/2
Calculate Rac

1
Rac = k
1 e
Excel
Application of Accumulation Index (Rac)

Prediction t1/2 (hrs) Tau (hrs) k Rac


Tau = t1/2 6 6 0.1155 2.000294
Tau 5 x > t1/2 6 30 0.1155 1.032283
Tau 1/3 t1/2 6 2 0.1155 4.848237

0.693 0.693
t1/ 2 = ;k =
k t1/ 2
1
Rac = k
1 e
Application of Rac
Prediction: relative to t1/2
When =t1/2: 2
When >t1/2: No or less accumulation
When <t1/2: More accumulation

C C

Tau Tau
t t
Example: t1/2 =6 hours

If is 6 hours Rac=2, CSS 2x first dose


If is 30 hrs(~ >5 times t1/2) Rac 1
no accumulation; all of the drug will
be eliminated from the first dose
before the second is given.
If is 2 hours (1/3 t1/2) the Rac would
be 4.8. Conc, CSS ~ 5x first dose
Application of Rac
Calculation of Loading Dose
LD= MD*Rac
=t1/2 Rac=2 LD=MD x2
>t1/2 Rac1 LD= MD
<t1/2 Raclarge number large LD
Example Drug X
Loading Dose (LD) can be calculated using
Rac, where LD = MD*Rac
Drug X with t1/2 < Tau
t1/2 = 1 hr
Tau = 8 hrs
To achieve target Css, we must give MD = 750
mg/day OR 250 mg q 8 hours
1
Rac = k
1 e
Drug X: t1/2<
MD 750 mg/day OR 250 mg q 8 hrs
=8 hours
t1/2 = 1 hr 1
R ac = k
1 e
1
R ac = 0.693*8
= 1.0
1 e
No accumulation
Drug X
Time to steady-state ~ 5 hours
No need for loading dose
LD= MD*Rac=250 mg (normal MD)
Example Drug Y
Loading Dose (LD) can be calculated using
Rac, where LD = MD*Rac
Drug Y with t1/2 = Tau
t1/2 = 8 hr
Tau = 8 hrs
To achieve target Css, we must give MD = 750
mg/day OR 250 mg q 8 hours

1
Rac = k
1 e
Drug Y: t1/2=
MD 750 mg/day or 250 mg q 8 hrs
=8 hours
t1/2 = 8 hr 1
R ac = k
1 e
1
R ac = 0.087*8
= 2. 0
1 e
Drug Y
Time to steady-state ~ 40 hours
LD= MD*Rac=500 mg
Example Drug Z
Loading Dose (LD) can be calculated using
Rac, where LD = MD*Rac
Drug Z with t1/2 > Tau
t1/2 = 24 hr
Tau = 8 hrs
To achieve target Css, we must give MD = 750
mg/day OR 250 mg q 8 hours

1
Rac = k
1 e
Drug Z: t1/2>
MD 750 mg/day or 250 mg q 8 hrs
=24 hours
t1/2 = 8 hr R = 1
k
1 e
ac

1
R ac = 0.029*8
= 4 .8
1 e
Drug Z
Time to steady-state ~ 5 days

LD= MD*Rac=1200 mg
Excel
Calculation of LD Time to SS in hrs and days:
Prediction t1/2 (hrs) Tau (hrs) k Rac 3*t1/2 (hrs) 5*t1/2 (hrs) MD (mg) LD (mg)
t1/2 < Tau 1 8 0.693 1.003926 3 5 250 250.9816
t1/2 = Tau 8 8 0.086625 2.000294 24 40 250 500.0736
t1/2 > Tau 24 8 0.028875 4.848237 72 120 250 1212.059

0.693 0.693
t1/ 2 = ;k =
k t1/ 2
1
Rac =
1 e k
LD = MD * Rac
Maintenance of
Concentrations within TR
Css,avg
Fluctuation within a dosing interval ()
determined by:

-t1/2
-rate of drug input
Css, max 1
Peak to Trough Ratio (P:T) = k
Css, min e
Peak to Trough Ratio: Cmax
F Dose
C max =
VD
Therefore, at steady state
F Dose 1
Css,max = k
VD 1 e
Peak to Trough Ratio: Cmin

k
Css, min = Css, max e
Peak to Trough Ratio
F Dose 1
k
Css, max VD 1 e
=
Css, min F Dose 1 k
k
e
VD 1 e
1 Peak to trough ratio depends
= -k upon t1/2 and dose interval
e
Peak to Trough Ratio
=t1/2 P:T =2
>t1/2 P:T will be large large
fluctuations
<t1/2 P:T will be small, as 0 there
is no fluctuation like constant infusion
1
P : Tratio = k
Example: t1/2 =6 hours e

=t1/2, eg. =6 hrs, P:T=2, Css,max will be


twice Css,min

>t1/2, eg. =24 hrs, P:T=16, Css,max will be


16x Css,min

<t1/2, eg. =2 hrs, P:T=1.3 , Css,max will be


1/3 larger than Css,min
Rate of Drug Input
PO administration results in a slower
rate of input
Peak conc occur later and are smaller
P:T is also smaller
Equations become complex, but more
accurate
Average Concentration at
Steady-State

AUCss ( 0 )
Css ,avg =

Css,avg
ln conc

tau tau

time
Determinants of Css,avg
F Dose 1 kt
Css ( t ) = k e
VD 1 e

F Dose 1 kt
C
0
ss ( t ) = AUCss ,( 0 ) =
VD
0

k e
1 e

F Dose 1 F Dose F Dose


AUCss ( 0 ) = = =
VD k VD k CL
Determinants of Css,avg
F Dose Dose
F
Css ,avg =
AUCss( 0 )
= CL =
CL

F
Dose/
CL
Dosage Regimen Design
Dose Rate (Dose/)
Rate of drug administered over time
Daily Dose (ie. 1 G Q8, Dose/=3 G/d)
Dose Interval ()
How often given
How small the pieces are
Examples
Dose/ Regimen
1 G/day 6 hours 250 mg Q6
1 G/day 12 hours 500 mg Q12
2 G/day 6 hours 500 mg Q6
2 G/day 12 hours 1 G Q12
When to alter Dose/
Is Css,avg in acceptable range?
Dose
F
Css, avg = =
Drug In
CL Drug Out
Has there been a change in
F
CL
The only thing we can control is Dose/
Determinants of P:T
Css, max 1 CL
= k k=
Css, min e VD

Half-life; k
CL
V
The only thing we control is
When to alter
Is P:T clinically acceptable?
Css, max 1
= k
Css, min e
Has there been a change in
-CL CL
k=
-V VD
The only thing we control is
Examples
Increase Dose Rate

10

250mg Q6
Concentration (mg/L)

Css,max=5.6

P:T=1.9
500mg Q6
Css,avg=4.2

Css,min=3.0
Css,max=2.8
P:T=1.9

Css,avg=2.1

Css,min=1.5

1
0 2 4 6 8

Time (hrs)
Determinants of Css,avg
F Dose Dose
F
Css ,avg =
AUCss( 0 )
= CL =
CL

F
Dose/; increase Dose/, increase
Css,avg
CL
Increase Dose Interval
Concentration (mg/L)

Css,m ax=3.6

Css,m ax=2.77
250mg Q6
P:T=3.3
500mg
Css,avg=2.1 Q12
Css,,m in=1.52
P:T=1.9

Css,m in=1.08

0 2 4 6 8 10 12 14
Time (hrs)
Determinants of P:T
Css, max 1 CL
= k k=
Css, min e VD

CL
VD
Only thing we can control is Tau ()
P:T too small, increase dose interval
i.e. give less often eg. q 6h to q 12h
Decreased Volume

10
Concentration (mg/L)

250mgQ6
Css,m ax=3.6

P:T=3.3 Decreased V
Css,m ax=2.8
Css,avg=2.1
P:T=1.9
Css,m in=1.5

Css,m in=1.1
1
0 1 2 3 4 5 6 7
Time (hrs)
Determinants of Css,avg
F Dose Dose
F
Css ,avg =
AUCss( 0 )
= CL =
CL

F
Dose/
CL
Determinants of P:T
Css, max 1 CL
= k k=
Css, min e VD
CL
VD; decreased VD will increase k (steeper
slope) and increase P:T ratio
Tau ()
Decreased Clearance

250mg Q6 Decreased CL

10
Concentration (mg/L)

Css,max=4.8 P:T=1.3
Css,avg=4.2
Css,min=3.6
Css,max=2.8
P:T=1.9
Css,avg=2.1

Css,min=1.5
1
0 1 2 3 4 5 6 7
Time (hrs)
Determinants of Css,avg
F Dose Dose
F
Css ,avg =
AUCss( 0 )
= CL =
CL

F
Dose/
CL; decreased CL will increase Css,avg
Determinants of P:T
Css, max 1 CL
= k k=
Css, min e VD
CL; decreased CL, will decrease k (flatter
slope), and decrease P:T ratio
VD
Tau ()
When to change Dose Rate
Is Css,avg in the Yes No change
target range? in DR

No
Too Too
Low Is Css,avg too
High
DR high or too
low? DR
P:T fluctuation

Conc.

Shorter
Tau

Longer
Time Tau
When to change Dose
Interval
Is P:T clinically Yes No change
acceptable? in DI

No
Too Too
Small Is P:T too
Great
DI great or too DI
(Give less small? (give more
often)
often)
P:T fluctuation

Conc.

Shorter
Tau

Longer
Time Tau
P:T ratio (fluctuation) too
small?

Conc Peak

Trough

Time
Tau
Next dose
P:T ratio (fluctuation) too
small?
Action is to increase
or lengthen the
dosing interval (tau)
Peak Result is to increase
Conc Increase Tau
P:T ratio
Trough

Time
Next dose
P:T ratio (fluctuation) too
large?

Conc Peak

Trough

Time
Tau
Next dose
P:T ratio (fluctuation) too
large?
Reflects faster k
steeper slope
Reflects shorter t1/2
Conc Peak Action is to decrease
or shorten the
Trough dosing interval (tau)
Result is to decrease
Time P:T ratio
Tau

Next dose