1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Questions to Consider
•
•
•
4.
5.
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
concentrations at anytime after the 1st dose.
Calculate the absorption rate – ka.
Comparison of Observed and Estimated [ ].
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Exam Questions and Problem Sets
will ask practical,
application questions
Recommend that you
take this data and attempt
to reproduce the calculations
on your own.
Graph Patient Data
10
Using semi-log paper, or Excel
graph the data following
oral administration of
400 mg of moxifloxacin
10.0
Concentration (mg/L)
6
3
1.0
0.1
0
4
8
12
Hours
16
20
1
0.6
0.4
0.2
0.1
0
4
8
10
14 18
22 24
24
Graph Patient Data
What model best
describes this profile?
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
Hours
16
20
24
Terminal elimination
phase is log-linear…
1 Compartment Model
with first order
absorption (ka)
and first order
elimination (K)
Graph Patient Data
What model best
describes this profile?
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
Hours
16
20
24
Graph Patient Data
What model best
describes this profile?
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
Hours
16
20
24
kH = kM1 + kM2
KNR = 20% excreted into
bile as unchanged drug.
Graph Patient Data
What model best
describes this profile?
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
Hours
16
20
24
K = ke + kH + kNR
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Questions to Consider
•
•
•
4.
5.
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
concentrations at anytime after the 1st dose.
Calculate the absorption rate – ka.
What do you calculate first?
Comparison of Observed and Estimated [ ].
Cmax, Tmax, AUC, K, T½, V or Cl
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Questions to Consider
•
•
•
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
What do at
you
calculate
first?
concentrations
anytime
after the
1st dose.
Cmax, Tmax,
? Does rate
the maximum
4. Calculate
the absorption
– ka.
5. concentration
Comparison of actually
Observedoccur
and Estimated
[ ].
at 2 hours
(Tmax)? Cmax and Tmax are
sampling time (data) dependant.
1-Compartment Oral Dosing
Does the maximum concentration actually occur at 2 hours?
Cmax and Tmax are sampling time (data) dependant and observed.
Could the true maximum concentration occur at 2.5 hr??
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
Hours
16
20
24
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Questions to Consider
•
•
•
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
concentrations
anytime
after the
1st dose.
What do at
you
calculate
first?
4. Calculate the absorption rate – ka.
AUC, K and T½ can be easily calculated
5. Comparison of Observed and Estimated [ ].
from available data. K from slope of log [ ]
vs. time or Excel. AUC, trapezoidal rule.
1-Compartment Oral Dosing
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
Hours
16
20
24
Since the concentrations between 4 and 24 hr appear log-linear,
ANY pair of points in the terminal phase can be used
to calculate K and half-life, AFTER CONVERSION to LOG.
In Excel this would likely result in K being calculated by
log-linear regression (SLOPE) of all points (4, 8, 12 and 24 hr).
1-Compartment Oral Dosing
Using the concentrations at
4 and 24 hours calculate K
(x1 = 4 hr and x2 = 24 hr)
(y1 = log (C4) = 0.248)
(y2 = log (C24) = -0.357)
Slope = (y2 – y1) / (x2 – x1)
= (-0.357 – 0.248)/(24-4)
= (- 0.605) / (20)
= -0.0302
- K = slope x 2.303
= - 0.0302 x 2.303
K = 0.06961 hr-1
T½ = 0.693 / K
= 0.693 / 0.06961
= 9.955 hours
1-Compartment Oral Dosing
Slope = (y2 – y1) / (x2 – x1)
= (-0.357 – 0.248)/(24-4)
= (- 0.605) / (20)
= -0.0302
- K = slope x 2.303
= - 0.0302 x 2.303
K = 0.06961 hr-1
T½ = 0.693 / K
= 0.693 / 0.06961
= 9.955 hours
1-Compartment Oral Dosing
Concentration (mg/L)
10.0
Selection of the points
from the terminal phase
for calculation of K.
Accurate calculation of K (T½)
and all other parameters which
depend on K (AUC, Cl, etc)
demand that the points used
to calculate K be found
in the terminal phase
after absorption is complete.
1.0
0.1
0
4
8
12
Hours
16
20
24
When is absorption complete?
1-Compartment Oral Dosing
If absorption occurs as a
first order process
(constant percentage
per unit time),
When does
absorption stop?
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
Hours
16
20
24
If we deal with ka as
we would K,
Assume ka = 0.693,
then T½ka = 1 hour.
This means that following
a 400 mg dose,
half of the dose (200 mg)
will be absorbed
in the first hour
And half of the remaining
dose (100 mg) in the second.
Concentration (mg/L)
1-Compartment Oral Dosing
10.0
If absorption occurs as a
first order process
(constant percentage per
unit time), When does
absorption stop?
1.0
Amount absorbed during
each hour following the dose
can be estimated as:
6.25 mg/hr
25 mg/hr
100 mg/hr
0.1
0
4
8
12
Hours
16
20
24
Time
(hr)
1
2
3
4
5
6
Amount
(mg)
200
100
Peak
50
25
12.5
6.25
1-Compartment Oral Dosing
Amount absorbed during
each hour following the dose
can be estimated as:
Concentration (mg/L)
10.0
1.0
6.25 mg/hr
25 mg/hr
100 mg/hr
0.1
0
4
8
12
Hours
16
20
24
Time Amount
(hr)
(mg)
1
200
2
100
Peak
3
50
4
25
5
12.5
6
6.25
so … when does absorption
stop for this formulation?
(i) At the Tmax – 2.6 hrs
(ii) Prior to the peak
(iii) ~ 1 hr after the peak
(iv) Technically – never
(v) It depends
10.0
Concentration (mg/L)
1-Compartment Oral Dosing
1.0
0.1
0
4
8
12
Hours
16
20
24
Selection of the points
from the terminal phase
for calculation of K.
In Excel®, selection of points
in the terminal phase can be
completed with statistics.
Evaluate the correlation coefficient (r)
& the number of points.
A change in r value signals the
end of absorption, with confirmation
by “visual inspection”.
10.0
Concentration (mg/L)
Selection of the points
1-Compartmentfrom
Oral
Dosing
the terminal phase
for calculation of K.
Notice that as you select more points
to be used in the calculation of K,
the K value begins to shrink,
the T½ begins to increase and
the correlation coefficient (r)
becomes smaller.
1.0
0.1
0
4
8
12
Hours
16
20
24
As you use more points
in the absorption phase
Best
choice?
4 points?
or
5 points?
1-Compartment Oral Dosing
5
points?
r
-0.9999
K
0.069 hr-1
T½
10.04 hr
1-Compartment Oral Dosing
AUC
trapezoid
AUC
(0-24hr)
AUC
(LP-)
AUC
(0-)
1-Compartment Oral Dosing
AUC Analysis
following Oral Absorption
At time zero, even
immediately following
ingestion of the dose,
the plasma concentration
is 0 mg/L.
Back extrapolation to t=0
is not appropriate,
and should not be done
It will not aid in
the calculation of volume.
1-Compartment Oral Dosing
AUC Analysis
following Oral Absorption
AUC
(0-24hr)
AUC should be calculated
by trapezoidal rule
between all
concentrations.
The sum of these
partial areas will equal
AUC 0-24hr or AUC 0-LP
1-Compartment Oral Dosing
AUC Analysis
following Oral Absorption
AUC
(0-24hr)
26.623 mg*hr/L
AUC from the last
measured concentration
should be calculated by
the pharmacokinetic
method ([ ]LP/K).
= (0.44 mg/L) / 0.069 hr-1
= 6.377 mg*hr/L
= AUC LP-
1-Compartment Oral Dosing
AUC Analysis
following Oral Absorption
AUC
(0-24hr)
26.623 mg*hr/L
AUC
(24hr-)
6.377 mg*hr/L
Total AUC (0-) is the sum
= 26.623 + 6.377 mg*hr/L
= 33.000 mg*hr/L
1-Compartment Oral Dosing
AUC
trapezoid
AUC
(0-24hr)
AUC
(LP-)
AUC
(0-)
1-Compartment Oral Dosing
AUC
trapezoid
AUC
(0-24hr)
AUC
(LP-)
AUC
(0-)
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Plasma Conc
Questions to Consider
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
•
•
•
4.
5.
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
Now calculate
Clearance.
concentrations
at anytime
after the 1st dose.
Calculate the
absorption
rate – ka.
Use
the formula:
Comparison
and Estimated [ ].
Clof Observed
= Dose / AUC
T
Does this formula
make any assumptions?
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Plasma Conc
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
Clearance
Cl = Dose / AUC
= 400 mg / 33.00 mg*hr/L
= 12.12 L/hr
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Plasma Conc
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
Clearance
Cl = Dose / AUC = K * V
Assumption?
that the entire dose of 400 mg
was absorbed.
If not what happens to V?
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Plasma Conc
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
Clearance
Cl = Dose / AUC = K * V
Clearance
Following oral absorption
Cl = F x Dose / AUC
where F is the fraction absorbed.
So…how much was absorbed?
Calculation of Clearance
Clearance
Cl = Dose / AUC
= 400 /33.00
= 12.12 L/hr
Agrees with
Estimate Using
Excel®
=12.12 L/hr
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Plasma Conc
Questions to Consider
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
•
•
•
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
Now calculate Volume.
concentrations at anytime after the 1st dose.
can be done
through the rate
use of– two
4.This
Calculate
the absorption
ka. equations:
Cl = Dose
/ AUC andand
Cl =Estimated
KxV
5. Comparison
of Observed
[ ].
This allows: K x V = Dose / AUC
and so Volume = Dose /(K x AUC)
but again F? Volume = F x Dose /(K x AUC)
Calculation of Volume
Volume
Volume = F x Dose /(K x AUC)
But because we do not know F
we will assume a value of 1
(completely absorbed).
Volume/F = Dose /(K x AUC)
=400 / (0.069 x 33.00)
V/F = 175.69 L
Volume
Volume = F x Dose /(K x AUC)
But because we do not know F
Volume/F = Dose /(K x AUC)
V/F = 175.69 L
Notes:
A volume of 175 L is
calculated when F = 1.
If F = 0.9 (90%) V = 158.12
If F = 0.8 (80%) V = 140.55
If F = 0.7 (70%) V = 122.98
If F = 0.6 ….
… but what is F and
how would this be
determined?
Calculation of Volume
Volume
Volume = F x Dose /(K x AUC)
But because we do not know F
Volume/F = Dose /(K x AUC)
V/F = 175.69 L
Notes:
A volume of 175 L is
calculated when F = 1.
If F = 0.9 (90%) V = 158.12
If F = 0.8 (80%) V = 140.55
If F = 0.7 (70%) V = 122.98
If F = 0.6 ….
… but what is F and
how would this be
determined?
Calculation of Volume
Volume
Volume = F x Dose /(K x AUC)
or because we do not know F
Volume/F = Dose /(K x AUC)
V/F = 175.69 L
Notes:
A volume of 175 L is
calculated when F = 1.
If F = 0.9 (90%) V = 158.12
Monograph (CPS) and
literature indicates that
the fraction absorbed
is approximately 90%.
Another way???
Calculation of Volume
Volume
Volume = F x Dose /(K x AUC)
or because we do not know F
Volume/F = Dose /(K x AUC)
V/F = 175.69 L
Notes:
A volume of 175 L is close
to that determined by back
extrapolation and calculation
of a concentration of
2.3 mg/L at time zero.
This appears to have worked
because (i) absorption was
relatively quick and
(ii) elimination relatively
slow (T½=10 hr).
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Plasma Conc
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
Questions to Consider
•
•
•
4.
5.
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
concentrations at anytime after the 1st dose.
Calculate the absorption rate – ka.
Comparison of Observed and Estimated [ ].
Concentration-time Equation
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
Hours
16
20
24
Equation must include F
and ka in addition to
parameters found in the
IV equation.
Profile for a 1 compartment
model with first order input
and first order elimination.
Concentration-time Equation
How do you calculate ka?
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Plasma Conc
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
Questions to Consider
•
•
•
4.
5.
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
concentrations at anytime after the 1st dose.
Calculate the absorption rate – ka.
Comparison of Observed and Estimated [ ].
Determining the Absorption Rate
How can we find the
rate constant associated
with absorption - ka
from the rising
concentration time data?
Determining the Absorption Rate
Absorption phase
generally associated
with absorption of the drug,
but what is going on here?
Absorption? Elimination?
Terminal phase
generally associated
with elimination of the drug.
But what is going on here?
Absorption? Elimination?
Determining the Absorption Rate
Absorption
&
Elimination
How can we look only at absorption?
Terminal phase
generally associated
with elimination
of the drug.
Determining the Absorption Rate
Absorption & Elimination
How can we look only at absorption?
We need to be able to subtract
the elimination rate,
to strip away one rate constant
to reveal only the other.
This is called the
method of residuals
…sometimes called
feathering the curve or
curve stripping.
Determining the Absorption Rate
Since the terminal phase
is <pure>,
associated with
only 1 rate constant we
can back extrapolate the
terminal phase to find
extrapolated
concentrations
at each of the times where
concentrations were
observed during
absorption.
Same method used with
IV 2C models.
Determining the Absorption Rate
Estimation of
Absorption Rate
Using method
of residuals
1. Back extrapolate
terminal phase
using best r-value
to guide selection.
2. Determine difference
between obs. [ ] & back
extrapolated [ ].
3. Plot differences
4. Slope estimates ka.
Determining the Absorption Rate
Concentration (mg/L)
10.0
Estimation of Absorption
Rate Using method
of residuals
1. Back extrapolate terminal phase
using best r-value to guide selection.
1.0
Recall we had a K value of 0.069 hr-1
based on the last 5 points or 0.0696 hr-1
using the 4 and 24 hr concentrations.
0.1
0
4
8
12
Hours
16
20
24
Using the selected K value and a point
that is in the terminal phase (8, 12 or 24
hr), calculate the concentrations at 0,
0.25, 0.5, 1.0, 1.5 and 2 hr.
Determining the Absorption Rate
Estimation of Absorption
Rate Using method
of residuals
1. Back extrapolate terminal phase
using best r-value to guide selection.
Recall we had a K value of 0.069 hr-1
based on the last 5 points or 0.0696 hr-1
using the 4 and 24 hr concentrations.
Using the selected K value and a point
Completed using the K value of 0.069 hr-1 that is in the terminal phase (8, 12 or 24
determined from the last 5 points generate hr), calculate the concentrations at 0,
0.25, 0.5, 1.0, 1.5 and 2 hr.
concentrations at every time point.
Determining the Absorption Rate
Estimation of Absorption
Rate Using method
of residuals
1. Back extrapolate terminal phase
using best r-value to guide selection.
2. Determine the difference between
the observed [ ] & back extrap. [ ].
Example: at 0.25 hr the back extrap
conc is 2.27 mg/L and the observed
concentration was 0.88 mg/L.
The difference is:
Diff. = 2.27 – 0.88
= 1.39 mg/L
Determining the Absorption Rate
Estimation of Absorption
Rate Using method
of residuals
1. Back extrapolate terminal phase
using best r-value to guide selection.
2. Determine the difference between
the observed [ ] & back extrap. [ ].
3. Plot differences. Diff. must be
plotted as log of concentrations.
Determining the Absorption Rate
Concentration (mg/L)
10.0
Estimation of Absorption
Rate Using method
of residuals
1. Back extrapolate terminal phase
using best r-value to guide selection.
1.0
2. Determine the difference between
the observed [ ] & back extrap. [ ].
3. Plot differences. Diff. must be
plotted as log of concentrations.
0.1
0
4
8
12
Hours
16
20
24
4.
Slope estimates ka through
conversion by –2.303.
Slope = -1.027; ka = 2.365 hr-1
Determining the Absorption Rate
Estimation of
Absorption Rate
Using method
of residuals in Excel
1. Back extrapolate
terminal phase
using best r-value
to guide selection.
Using the K value
determined from the
last 5 points generate
concentrations at
every time point.
Determining the Absorption Rate
Estimation of
Absorption Rate
Using method
of residuals in Excel
1. Back extrapolate
terminal phase
using best r-value
to guide selection.
2. Determine difference
between obs [ ] & back
extrapolated [ ].
Determining the Absorption Rate
Estimation of
Absorption Rate
Using method
of residuals
1. Back extrapolate
terminal phase
using best r-value
to guide selection.
2. Determine difference
between obs [ ] & back
extrapolated [ ].
3. Plot differences. Diff.
must be plotted as log
of concentrations.
Determining the Absorption Rate
Estimation of
Absorption Rate
Using method
of residuals
1. Back extrapolate
terminal phase
using best r-value
to guide selection.
2. Determine difference
between obs [ ] & back
extrapolated [ ].
3. Plot differences
4. Slope estimates ka.
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Plasma Conc
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
Questions to Consider
•
•
•
4.
5.
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
concentrations at anytime after the 1st dose.
Calculate the absorption rate – ka.
Comparison of Observed and Estimated [ ].
Concentration-time Equation
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Observed
Plasma Conc
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
Calculate expected concentrations to see how close the observed
and expected concentrations are using our parameter estimates.
Dose = 400 mg; T½ = 10.04; K = 0.06902 hr-1; ka = 2.365 hr-1
Volume = 175.69 L with F = 1.
Concentration-time Equation
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Concentration (ng/mL)
2.50
2.00
1.50
1.00
0.50
0.00
0
4
8
12
16
20
Observed
Expected
Plasma Conc Plasma Conc
(mg/L)
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
0.00
1.00
1.55
1.97
2.05
2.02
1.78
1.35
1.02
0.45
24
Hours
Agreement is good. Concentrations deviate by -0.11 to -0.15 mg/L
in the first hour. This would indicate good estimation of K, with
some error in ka. But volume and F are really still a combined
term. What is the true F in this patient?
1-Compartment Oral Dosing
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0.0
0.25
0.5
1
1.5
2
4
8
12
24
Parameters to
Plasma Conc
Investigate Further
(mg/L)
0.00
0.88
1.40
1.86
1.98
1.99
1.77
1.34
1.02
0.44
Questions to Consider
•
•
•
What model & equation best describes profile?
Calculate Cmax, Tmax, AUC, K, T½, V &Cl
Write an equation that will calculate
Effect concentrations
of ka on profile
at anytime after the 1st dose.
4.SR
Calculate
the absorption rate – ka.
products.
5. Comparison of Observed and Estimated [ ].
F, Bioavailability and its calculation