Pharmacokinetics: Lecture four

Extravascular administration: Calculating pharmacokinetic parameters from extravascular data

1. Extravascular
Administration
One compartment Model
Anas Bahnassi PhD RPh

2. LECTURE’S OBJECTIVES
•Upon completion of this lecture, the student will able to:
•Calculate plasma drug concentration at any given time after the
administration of an extravascular dose of a drug, based on known or
estimated pharmacokinetic parameters
•Interpret the plasma drug concentration versus time curve of a drug
administered extravascularly as the sum of an absorption curve and an
elimination curve
•Employ extrapolation techniques to characterize the absorption phase
•Calculate the absorption rate constant and explain factors that influence
this constant
•Explain possible reasons for the presence of lag time in a drug’s absorption
•Calculate peak plasma drug concentration, (Cp)max, and the time, (t
max)at
which this occurs
•Explain the factors that influence peak plasma concentration and peak time
•Decide when flip-flop kinetics may be a factor in the plasma drug
concentration versus time curve of a drug administered extravascularly.
Anas Bahnassi PhD 2011
2

3. Anas
Bahnassi
PhD 2011

3
K
a
X
u
1.Equation for determining the plasma concentration at any time t.
2.Determination of the elimination half life (t
½) and rate constant (K or
K
el).
3.Determination of the absorption half life (t
½)abs and absorption rate
constant (K
a).
4.Lag time (t
0), if any.
5.Determination of the apparent volume of distribution (V or V
d) and
fraction of drug absorbed (F).
6.Determination of the peak time (t
max).
7.Determination of the peak plasma or serum concentration, (C
p)
max.
We Need the following info:
X Xa

4. Anas
Bahnassi
PhD 2011

4
0.00
0.50
1.00
1.50
2.00
2.50
0 4 8 12 16 20 24
Concentration (ng/mL)

Hours
Graph

5. Amount Remaining in the
Administration Site
−
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Order
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Bioavailability
Dose
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100% Absorbed

6. Monitoring Drug in Site of
Measurement
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Order
Process
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7. Elimination Half life (t
1/2)
And Elimination Rate Constant(k)
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0
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0.10
1.00
10.00
0 4 8 12 16 20 24
Concentration

Time
t½

8. Anas Bahnassi PhD 2011
8
Calculating Absorption Rate
Constant (ka)
Time (h) Observed Plasma
Concentrations
(Cp)
observed
Extrapolated Plasma
Concentrations
(Cp)
extrapolated
(??????�)
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=??????�
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−??????�
���

Time values
corresponding
to observed
plasma
concentrations
for absorption
phase only
Values only from the
absorption phase
(i.e. all values prior to
reaching maximum
or highest plasma
concentration) (units,
e.g. mgmL
-1
)

Values only from the
extrapolated portion of
the plot of plasma
concentration–time
(units, e.g. (mgmL1)

Differences between
extrapolated and observed
values for each time in the
absorption phase (units,
e.g. mgmL
-1
)
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0
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Method of Residuals
Feathering Method

9. Anas Bahnassi PhD 2011 9
Calculating Absorption Rate
Constant (ka)
Slope=−
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??????
2.303

Method of Residuals
Feathering Method

10. Anas Bahnassi PhD 2011 10
Lag Time (t
0)
Theoretically, intercepts of the terminal linear portion
and the feathered line should be the same; however,
sometimes, these two lines do not have the same
intercepts, Sometimes absorption starts after
administration, this delay may be contributed to:

•Slow tablet disintegration
•Slow and/or poor dissolution
•Incomplete wetting of drug particles
•Poor formula
•Delayed Release formula

11. Anas Bahnassi PhD 2011 11
The presence of a negative lag time may be attributed to
inadequate data points in the absorption phase as well
as in the elimination phase. Another possible reason
may be that the absorption rate constant is not much
greater than the elimination rate constant.
Negative Lag Time (t
0)

12. Analysis of Absorption
Rate Constant
??????
??????≫??????
Quicker
Absorption
Faster Onset
of Action
??????
?????? for a given drug can
change as a result of:

•Changing the formulation
•Changing the dosage form
or the extravascular route
of administration.
•Administration of a drug
with or without food.

13. Anas Bahnassi PhD 2011 13
Apparent Volume of
Distribution(V
d) Cannot be calculated from plasma
drug concentration data alone
WHY?
The fraction of drug absorbed (F) is
not known.
If the drug is 100 percent
absorbed; F=1 then
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0
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If F is not known then it is best to
calculate
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=
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0
(??????
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(
1
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)

14. Anas Bahnassi PhD 2011 14
Calculating Peak Time(t
max)
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When t=tmax ??????
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=??????�
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15. Anas Bahnassi PhD 2011 15
Calculating Peak Time(t
max)
Taking natural log of both sides:

16. Anas Bahnassi PhD 2011 16
Significance of Peak Time(t
max)
•To determine comparative bioavailability and/or
bioequivalence
•To determine the preferred route of drug administration and
the desired dosage form for the patient
•To assess the onset of action.
•Used to determine the comparative bioavailability and/or the
bioequivalence between two products.
•Used to determine the superiority between two different
dosage forms or two different routes of administration
•Correlates with the pharmacological effect of a drug.
Significance of Peak
Concentration(C
max)

17. Anas Bahnassi PhD 2011
17
Plot the data and, using the plot, determine
the following.
a. The elimination half life (t1/2) for each dose.
b. The elimination rate constant (K) for each
dose.
c. The absorption half life, (t1/2)abs, for each
dose.
d. The absorption rate constant (Ka) for each
dose.
e. The observed and computed peak time (tmax)
for each dose.
f. The observed and computed peak plasma
concentrations, (Cp)max, for each dose.
g. The y-axis intercept for each dose.
h. The apparent volume of distribution (V).
i. The fraction of drug absorbed (F).
j. The characteristics of a plot on rectilinear
paper of peak time (tmax) against the
administered dose (then make an important
observation).
k. The characteristics of a plot on rectilinear
paper of peak plasma concentrations, (Cp)max,
i. Lag time if any.
Question

18. [email protected]
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Anas Bahnassi PhD RPh
Pharmacokinetics
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