Multiple Exposure Models

Sukamto S M

Single exposure
Single Bolus IV Inj.
(Instant Abs)
C

Single IV Inf. or
Cont. Lung Exp.
(Zero-Ord. Abs.)

T
k0

Single Oral Dose

(1st Order Abs.)
C

FD

Multiple exposures

C = CD1 + CD2 + CD3

CD1

CD2

CD3
t

D1

D2

D3

Multiple Instant Absorption Exposures

(bolus IV or pseudo-instantaneous
absorption)
3

Multiple exposures

C = CD1 + CD2 + CD3

C
CD1

D1

CD2

D2

CD3

D3

Multiple Zero-Order Absorption Exposures

(IV infusion, prolonged lung exposures, etc.)
4

Multiple exposures

C = CD1 + CD2 + CD3

C
CD2

CD1

CD3

t
D1

D2

D3

Multiple 1st-Order Absorption Exposures

(oral, im, ip, sc, etc.)
5

Introduction

= time period between

exposures

Examples:
Medicine taken three times a day every 8 hr (
= 8 hr)
Occupational air exposure every day during 8 hr
work shift ( = 24hr, T = 8hr)
Consumption of contaminated fish once per
week ( = 1 week or 7 days)
6

Introduction
Two

main factors/parameters that

must be considered in multiple
exposures
The size of the drug dose
The frequency of drug administration
()

In

this kind of regimen, the drug

level must be maintained
between MEC and MTC.
In multiple exposure models,
7

Example

Multiple bolus iv injections of lidocaine (drug for treating

heart attack patients, V = 1.1 L/kg, t1/2,elim = 1.8 hr,
Ctherapeutic = 1.5-6 mg/L, Ctoxic > 6 mg/L). A 92 kg patient
enters the emergency room at 7:50 pm suffering from a
heart attack.
D1: A bolus iv injection of 200 mg lidocaine is administered
at 8:00 pm.
D2: A second bolus iv injection of 250 mg lidocaine is
administered at 8:30 pm.
D3: A third bolus iv injection of 300 mg lidocaine is
administered at 9:30 pm.
Determine whether this patients plasma lidocaine levels
are within the therapeutic or toxic range at each of the
following time points:
8
Just before 9:30 pm injection

Answer

Given:
V= 1.1 L/kg * 92kg = 101 L
k = 0.693/1.8hr = 0.39 hr-1
Just before 9:30 pm injection:
C =C D1 1.5 hr +C D2 1.0 hr =

200 mg -0.39hr-1 1.5 hr 250 mg -0.39hr-1 1.0 hr

e
+
e
101 L
101 L

C = 1.1 mg/L + 1.7 mg/L = 2.8 mg/L (within

therapeutic range)
9

Answer
Immediately after 9:30 pm injection:
=C 1.5 hr +C 1.0 hr +C 0 hr
C
D1
D2
D3
C=

200 mg -0.39 hr-1 1.5 hr 250 mg -0.39 hr-1 1.0 hr 300 mg -0.39 hr-1 0 hr
e
+
e
+
e
101 L
101 L
101 L

C = 1.1 mg/L + 1.7 mg/L + 3.0 mg/L= 5.8 mg/L

(very near toxic range)
At 2:00 am:
C = 0.19 mg/L + 0.29 mg/L + 0.51 mg/L= 0.99
mg/L
(below therapeutic range)10

Combination of bolus IV
injection and IV infusion

C = Cbolus + Cinfus ion

C0,bolus= Cs s ,infus ion

Cinfus ion
Cbolus
Dinfus ion

Dbolus

During the infusion period for this case:

C = Cbolus + Cinfusion = Css e-kt + Css (1-e-kt) = Css =
11
constant

Toxicology tests are performed in 250 g rats to determine the

effects of a new antibiotic (V = 0.5 L/kg, t1/2,elim = 2.6 hr). The
drug is iv infused over an 8hr period at a rate of 1.0 mg/hr. In
addition, a 3.75 mg dose of the drug is given by bolus iv
injection at the start of the infusion.
Estimate the initial plasma drug concentration just after the bolus
iv injection is administered.
Answer
C0 = D/V = 3.75 mg/0.125 L = 30 mg/L

Estimate the plasma drug concentration at 2, 8, and 12 hr after

the start of the infusion.
Answer
Css,infusion = 30 mg/L; k = 0.693/2.6 = 0.27 hr-1
Plasma drug concentration at 2 hr after the start of infusion
12
C = Csse-kt + Css(1 e-kt) = [30(e-0.27*2)] + [30(1 e-0.27*2)] = 17.48 + 12.52

Toxicology tests are performed in 250 g rats to determine the

effects of a new antibiotic (V = 0.5 L/kg, t1/2,elim = 2.6 hr). The drug
is iv infused over an 8hr period at a rate of 1.0 mg/hr. In addition,
a 3.75 mg dose of the drug is given by bolus iv injection at the
start of the infusion.
Plasma drug concentration at 8 hr after the start of infusion

C = Csse-kt + Css(1 e-kt) = [30(e-0.27*8)] + [30(1 e-0.27*8)] = 3.46 +

26.54 = 30 mg/L

Plasma drug concentration at 12 hr after the start of infusion

C = Csse-kt = 30*e-0.27*4 = 10.19 mg/L

13

One-Compartment Instantaneous
Absorption
(Bolus IV or pseudo-instant Absorption)

14

One-Compartment Instantaneous
Absorption (Bolus IV or pseudo-instant
Absorption)
Css,max
CN,max

Cs s ,ave

Css,min

CN,min

Nth
Dose

SteadyState

t
D

Steady-State
Cs s
C

D
D
D
D
50% to steady

At t1/2, elim
state
At 2t1/2, elim 75% to steady
state
At 7t1/2, elim 99% to steady
state
At 10t1/2, elim 99.9% to

15

The maximum concentration for any given exposure interval

occurs at t = 0
-Nk

1e
C N,max =FD
V 1 e-k

1
C ss,max=FD
V 1 e-k

The minimum concentration for any given exposure interval

occurs at t =
-Nk
1

e
C N,min =FD
e-k =C N,max e-k
V 1 e-k

1
C ss,min =FD
e-k =C ss,maxe-k
V 1 e-k
The average concentration
during at steady-state can
be defined by
C ssdt'
C ss,ave = 0
= FD = FD
Vk CL
dt'
16
0

To calculate concentration
after the Nth dose:

for 0 t

Finally, consider what happens if the exposures

stop occurring after the Nth dose or after steadystate has been reached:

C
Nth
Dose

t
D

Concentrations can be predicted for any time after exposures

stop by using the final CN equation with t = time after last
dose
1 e-Nk -kt'
FD
C N,final =
e
for t' 0
V 1 e-k
17

Exposures stop after steady-state is

reached:

C
SteadyState

t
D

Concentrations can be predicted for any time after

exposures stop by using the final Css equation with t =
time after last dose

1
C ss,final =FD
e-kt' =C ss,maxe-kt'
V 1 e-k

for t' 0

18

The following general relationships

then apply:
If < t1/2,elim, there is a lot of chemical buildup => higher
concentrations
If > t1/2,elim, there is little chemical buildup => lower
concentrations
FD

=>
C (more chemical absorbed during
each interval)
t1/2,elim
=>
each interval)

C (less chemical eliminated during

k
=>
each interval)

C (more chemical eliminated during

often)

C (chemical enters the body less

=>

19

Example Calculations - Ethosuximide is an

anticonvulsant drug given orally that follows psuedoinstantaneous absorption kinetics, with V = 0.72 L/kg,
t1/2,elim = 45 hr, and F=100%. Estimate the following for
a 52 kg woman taking 1000 mg of ethosuximide once
per day.

a)

Plasma concentration 4 hr after fifth dose:

b)

Number of days needed to reach 99% of steady-state

conditions:

c)

Maximum steady-state concentration:

d)

Minimum steady-state concentration:

e)

Average steady-state concentration:

f)

Concentration 48 hr after stopped taking drug at

k = 0.639/t1/2,elim
= 0.639/45hr = 0.0154 hr-1
steady-state
conditions:

V = 0.72 L/kg * 52 kg = 37.4 L

N=5
t = 4 hr
= 24 hr
20

Plasma concentration 4 hr after fifth dose:

-1

1 e-Nk -kt' 1.0 1000 mg 1 e-5 0.0154hr

FD
C=
e =
-1
V 1 e-k
37.4 L
1 e- 0.0154hr

24 hr
24 hr

e- 0.0154hr

-1

4 hr

=68.5 mg/L

Number of days needed to reach 99% of

steady-state conditions:
7t1/2,elim = 7 (45 hr) = 315 hr = 13.1 days
Maximum steady-state
concentration:

1.0 1000 mg
1
1
C ss,max=FD
=
=86.5 mg/L
-1
-0.0154
hr
24
hr
V 1 e-k
37.4 L
1 e

Minimum steady-state concentration:

C ss,min =C ss,maxe-k = 86.5 mg/L e-0.0154hr

-1

24 hr

=59.8 mg/L
21

Average steady-state concentration:

1.0 1000 mg
C ss,ave= FD =
=72.3 mg/L
Vk 37.4 L 0.0154hr-1 24 hr

Concentration 48 hr after stopped taking

drug at steady-state conditions:
C =C ss,maxe-kt' = 86.5 mg/L e-0.0154hr

-1

48 hr

=41.3 mg/L

Note that the therapeutic plasma concentration range for

ethosuximide is 40-100 mg/L, so that this dosage schedule
keeps plasma levels within the desired range at steady-state.

22

One-Compartment Zero-Order
Absorption
(IV infusion, continuous lung
exposure)

23

Css,max
CN,max

Css(t')
Css,min

CN (t')
CN,min

SteadyState

Nth
Dose
t
ko

ko

ko

ko

ko

ko

ko

ko

ko

ko

ko

The concentration during the exposure period (0

t T) of the Nth interval or at steady-state is
given by

for 0 t
where t = time since the start of the most recent exposure T 24

The concentration during the postexposure period

(T t ) of the Nth interval or at
steady-state is given by:

for T t

25

The maximum concentration during

each interval occurs when t = T
-Nk
1

e
ko
C N,max =
1 e-kT
Vk
1 e-k

1
C ss,max= ko 1 e-kT
Vk
1 e-k

C ss,ave= FD = FD
Vk CL
The minimum concentration during each
interval occurs at t = 0
C N,min

1 e- N1 k -k -T
ko
-kT
=
1e
e
-k
Vk
1e

1
C ss,min = ko 1 e-kT
e-k -T
Vk
1 e-k

26

If exposures stop after the Nth dose, then

concentrations after exposures stop are given
by

for t
T

If exposures stop after steady-state is

reached, then concentrations after
exposures stop are given by

for t
T

where t is the time since the start of the last exposure period
Concentrations during the final exposure period are the same
as given previously for the exposure period of the Nth

27

One-Compartment First-Order
Absorption (oral, im, ip, sc, etc)

28

Css,max
CN,max

Css(t')
Css,min

CN (t')
CN,min

SteadyState

Nth
Dose
t
D

The concentrations during the Nth interval is

given by:

for 0 t
29

The maximum concentration during each interval occurs when t =

tmax
-Nk
-Nka

ka
C N,max =FD
V ka k

1 e
1e
e-kt'max
e-kat'max
1 e-k
1 e-ka

ka
C ss,max=FD
V ka k

1
1
e-kt'max
e-kat'max
1 e-k
1 e-ka

Where tmax =

Ln [(ka/k) * (1-e-k)/1-e-ka)]
ka - k

The minimum concentration during each

interval occurs at t = 0
1 e-Nk
1 e-Nka
ka
FD
C N,min =

V ka k 1 e-k
1 e-ka

C ss,min =FD ka
V ka k

1
1

1 e-k
1 e-ka

C ss,ave= FD = FD
Vk CL

30

If exposures stop after the Nth dose, then

concentrations after exposures stop are
given by

for t 0

where t is the time since the last dose

If exposures stop after steady-state is
reached, then concentrations after
exposures stop are given by

for t 0

where t is the time since the last dose

31

An experimental artificial flavor additive is being tested

by administering a 200 mg oral dose twice a day (every
12 hr) in 3 kg rabbits. Previous single dose
toxicokinetic experiments indicate V = 2.4 L/kg, F =
77%, t1/2,elim=8.6hr, and t1/2,abs = 1.3 hr. Using the
repetitive dosing one-compartment first-order
absorption equations, estimate:
a) The maximum and minimum concentrations for the
4th oral dose.
b) The number of days it should take to reach 99.9% of
steady-state.
c) The maximum, minimum, and average plasma
concentrations at steady-state.
d) The plasma concentration at 6 hr and at 24 hr after
the last dose if dosing is stopped after steady-state
conditions have been reached.
32

An experimental artificial flavor additive is being tested by

administering a 200 mg oral dose twice a day (every 12 hr) in 3
kg rabbits. Previous single dose toxicokinetic experiments
indicate V = 2.4 L/kg, F = 77%, t1/2,elim=8.6hr, and t1/2,abs = 1.3
hr. Using the repetitive dosing one-compartment first-order
absorption equations, estimate:
The maximum and minimum concentrations for the 4th oral
dose.

33

An experimental artificial flavor additive is being tested by

administering a 200 mg oral dose twice a day (every 12 hr) in 3
kg rabbits. Previous single dose toxicokinetic experiments
indicate V = 2.4 L/kg, F = 77%, t1/2,elim=8.6hr, and t1/2,abs = 1.3
hr. Using the repetitive dosing one-compartment first-order
absorption equations, estimate:
The maximum and minimum concentrations for the 4th oral
dose.

The number of days it should take to reach 99.9% of steadystate

Answer

10*t1/2,elimination = 10*8.6 = 86 hr ~ 3.6 days

34

10*t1/2,elimination =
10*8.6 = 86 hr ~
3.6
dayzzzz......zzzz.....z
zzzz..zzzz..zzzz.zzz...
zzz...zzz..zzzzz.zzzz..
..zzzz.....zzzz.......zzz
zzz....zzzzz

35

Kuis
Pemberian obat oral secara umum mengikuti kinetika absorpsi
orde nol
2) Obat generik bermerek adalah obat generik yang nama
dagangnya sama dengan nama zat aktifnya
3) Bioavailabilitas relatif membandingkan obat A yang diberikan
dengan rute non-IV dan obat B yang diberikan dengan rute IV
4) Metabolisme lintas pertama melibatkan organ hati
5) Obat dengan aturan pakai 4 x 1 memiliki nilai 5 jam
6) Untuk menentukan aturan pakai obat, maka nilai t 1/2 obat
memainkan peran penting
7) Sebuah obat dengan t1/2 = 2 jam, maka untuk mencapai 99%
kadar tunak waktu yang dibutuhkan adalah 20 jam
8) Penambang yang bekerja di pertambangan dari pukul 8 sampai
pukul 12 selama 5 hari seminggu memiliki nilai T = 4 jam
9) Jika nilai > t1/2 , maka akan terjadi akumulasi obat dalam tubuh
10)Notasi Css,final menunjukkan nilai konsentrasi plasma setelah obat
dihentikan dan kadar tunak belum tercapai
1)

36

37