Problem set 2

Problems for Chapter 6 f. The y-axis intercept.

Compare:
Question 1 g. The observed peak time (tmax) with the calcu-
Table P2.1 gives the plasma drug concentrations lated peak time.
(Cp) that were obtained following the oral admin- h. The observed and the calculated peak plasma
istration of 1 g dose of a drug. concentrations (Cp)max.
Plot the data and, using the plot, determine
the following. Question 2
a. The elimination half life (t1/2) and the elimi- Promethazine (Phenergan) is a widely used anti-
nation rate constant (K). histaminic, antiemetic and sedative drug. Zamen
b. The absorption half life, (t1/2)abs. et al. (1986) undertook a study to determine the
c. The absorption rate constant (Ka). dose proportionality of promethazine from the
d. The observed and calculated peak time (tmax). tablet dosage form. Following the administration
e. The observed and calculated peak plasma con- of one tablet containing either 25 or 50 mg of
centrations, (Cp)max. promethazine, plasma concentrations were mea-
sured (Table P2.2).
Plot the data and, using the plot, determine
the following.
a. The elimination half life (t1/2) for each dose.
Table P2.1
b. The elimination rate constant (K) for each
Time (h) Plasma concentrations (mg%)
dose.
c. The absorption half life, (t1/2)abs, for each dose.
0.25 3.00 d. The absorption rate constant (Ka) for each
dose.
0.50 4.60
e. The observed and computed peak time (tmax)
1.00 5.70 for each dose.
1.50 5.60 f. The observed and computed peak plasma con-
centrations, (Cp)max, for each dose.
2.00 4.80
g. The y-axis intercept for each dose.
3.00 3.20 h. The apparent volume of distribution (V).
4.00 2.00 i. The fraction of drug absorbed (F).
j. The characteristics of a plot on rectilinear paper
5.00 1.20 of peak time (tmax) against the administered
6.00 0.75 dose (then make an important observation).
k. The characteristics of a plot on rectilinear pa-
7.00 0.46
per of peak plasma concentrations, (Cp)max,

117
 118 B a si c P ha r m a c ok i n e t ic s

When a tablet containing 250 mg procaina-

Table P2.2
mide is administered orally to a normal healthy
subject:
Time (h) Mean plasma concentrations (ng mL1)a
· the absorption rate constant (Ka) ¼ 2.8 h1
25 mg tablet 50 mg tablet · the intercept of the plasma concentration time
(lot 1821448)b (lot 1821148)b profile ¼ 1.665 mg mL1
0.5 0.12 ! 0.45 0.26 ! 0.75 · the fraction of dose absorbed (i.e. reaching the
general circulation) ¼ 85.54%.
1.0 2.20 ! 1.76 3.62 ! 3.05
Determine the following from the available
1.5 5.38 ! 4.26 6.65 ! 4.15
information.
2.0 6.80 ! 4.42 10.74 ! 3.67

3.0 6.91 ! 3.42 12.54 ! 6.22 1. Peak time (tmax) and peak plasma concentra-
tion [(Cp)max] following the administration of
4.0 6.32 ! 2.90 11.20 ! 4.42 a 250 mg and 500 mg tablet.
6.0 4.25 ! 2.00 8.54 ! 3.04 2. Whether the administered oral dose (i.e. 250 mg
tablet) will provide the peak plasma concentra-
8.0 3.60 ! 1.53 6.48 ! 2.43
tion high enough to control arrhythmia.
10.0 2.72 ! 1.27 4.85 ! 1.66 3. If not, how many tablets (250 mg strength) will
12.0 2.30 ! 1.35 4.05 ! 2.07 be required to control arrhythmia?
4. Determine the absorbable amount of drug
24.0 0.67 ! 0.94 1.70 ! 1.64
remaining at the site of administration (Xa)
a
Mean ! SD of 15 determinations. and the amount of drug in the body and/or
b
Products made by Wyeth Laboratory. blood (X) at a time when the rate of
absorption is equal to the rate of elimination for
extravascularly administered dose of 500 mg
via tablet.
against the administered dose (make an im- 5. Determine the rate of absorption and the rate of
portant observation). elimination, at peak time, following the admin-
l. Lag time (to), if any. istration of a 250 mg and a 500 mg tablet.
6. Indicating the appropriate graphical coordi-
nates (rectilinear or semilogarithmic), sketch
Problem-solving exercise
the profiles of rate of absorption against the
Procainamide is used for the treatment of ventric- dose administered and rate of elimination
ular tachyarrhythmia. It is administered intrave- against dose administered. What will be the
nously, orally and intramuscularly, and its relationship between the rate of absorption
therapeutic range is 4 to 8 mg mL1. When a and the rate of elimination at peak time?
750 mg dose is administered intravenously to a 7. Is it possible to determine the absorption rate
normal healthy subject: constant (Ka) and the peak time from the
knowledge of peak plasma concentration,
· the elimination half life ¼ 3 h
the apparent volume of drug distribution, the
· the apparent volume of distribution ¼ 140 L or
elimination half life and the amount of drug
2 L kg1
remaining at the site of administration at peak
· % excreted in urine ¼ 65%
time? Only if the answer is yes, show all the
· % metabolite (N-acetylprocainamide) ¼ 35%.
steps involved in the calculation.
Please note that the elimination half (t1/2), the 8. In a 70 kg patient with renal impairment, the
elimination rate constant (K), the apparent vol- elimination half life (t1/2) of procainamide is
ume of distribution (V) and the systemic clear- reported to be 14 h (range, 9–43 h). Following
ance (Cls) of a drug are independent of the route the administration of a 250 mg procainamide
of administration. tablet to this subject, the absorption rate
 Problem set 2 119

constant and the intercept on the y-axis of the b. Employing the feathering or residual or curve
plasma concentration–time profile were stripping method:
reported to be 2.8 h1 and 1.556 mg mL1,
(t1/2)abs ¼ 0.425 h.
respectively. Assume no change in volume
of distribution from the 2 L kg1 value in nor-
mal subjects. Determine the systemic (Cls), c: Ka ¼ 1:630 h  1 :
renal (Clr) and metabolic (Clm) clearances fol-
lowing the administration of this 250 mg pro- d. Observed tmax ¼ 1 h (graphical method)
cainamide tablet. Also determine tmax, the calculated t max ¼ 1:05 hðequation methodÞ:
time of peak plasma level. Will these values
change for a 750 mg dose administered intra- e. (Cp)max ¼ 5.70 mg % (graphical method)
venously? In a normal subject, peak time was ðCp Þmax ¼ 5:796 mg %ð5:796 mg 100 mL  1 Þ
observed to be 0.97 h. Determine the percent-
ðequation methodÞ:
age difference in peak time in normal and
renally impaired subjects, with respect to
f. The y-intercept of the plasma concentration
the normal value of a 750 mg dose intrave-
versus time profile is 14 mg %.
nously.
g. The observed tmax is simply the time of the
9. What will be the peak time in this renally
highest recorded plasma drug concentration;
impaired patient following the administra-
therefore, it will be exactly equal to one of the
tion of a 500 mg tablet of an identical formu-
time points at which blood was collected. The
lation.
calculated tmax is not restricted to a time at
10. What will be the procainamide peak plasma
which blood was collected; moreover, its value
concentration in this renally impaired sub-
will be based on the curve that best fits all the
ject following the administration of a
data points. Calculated tmax will, therefore, be
500 mg tablet of an identical formulation.
more accurate.
11. Show the relationship between the area un-
h. The observed (Cp)max is simply the highest
der the plasma concentration–time curve
recorded plasma drug concentration and, as
ðAUCÞ¥0 and the systemic clearance of a drug for tmax, it will occur at one of the time points
in a renally impaired patient. at which blood was collected. The calculated
(Cp)max is not restricted to a time at which
blood was collected but is based on the phar-
macokinetic fit to all the plasma drug concen-
Answers tration versus time data; it will, therefore, be
more accurate.
The problem set provides plasma concentration Note: Peak plasma concentration is always di-
versus time data following the administration of a rectly proportional to the dose administered,
drug by an extravascular route (oral). Once again, regardless of the route of administration or
it is assumed that the administered drug follows the health of the subject (healthy or renally
the first-order process and exhibits the character- impaired) as long as a first-order process is
istics of a one-compartment model. The follow- occurring. Therefore, administration of a
ing are our answers to these questions and it is 500 mg dose of the same drug via identical for-
possible that your answers may differ from these mulation, dosage form and route of adminis-
for the reasons discussed in Problem set 1. tration will give a y-intercept of 7 mg % and a
peak plasma concentration of 2.898 mg %
(2.898 mg 100 mL1). The peak plasma concen-
Question 1 answer tration in a renally impaired subject will be
higher than in a normal subject; nonetheless,
a. t1/2 ¼ 1.4 h it will be directly proportional to the adminis-
K ¼ 0:495 h  1 : tered dose.
 120 B a si c P ha r m a c ok i n e t ic s

Question 2 answer f. 25 mg tablet, (Cp)max ¼ 6.91 ng mL1 (graphical

method)
This question involves two different doses of an
50 mg tablet, (Cp)max ¼ 12.54 ng mL1 (graphical
identical drug (promethazine) in an identical dos-
method).
age form (tablet), via an identical route of admin-
Is the peak plasma concentration for a 50 mg
istration (oral) of an identical formulation (made
dose approximately twice that of 50 mg dose?
by the same manufacturer). Plasma concentra-
Note the units of concentration (ng mL1;
tion versus time data were plotted on suitable
1 mg ¼ 1000 mg; 1 mg ¼ 1000 ng).
semilogarithmic graph paper. As mentioned
25 mg tablet,(Cp)max ¼ 6.476 ng mL1 (6.476mg L)
above, greater variation can occur in the values
(calculated method)
in parts a–d because of the technique employed.
50 mg tablet, (Cp)max ¼ 11.63 ng mL1 (calcu-
This variation, in turn, will be reflected in the
lated method).
answers for the peak time, peak plasma concen-
Once again, note the approximate directly
tration and the intercept of the plasma concen-
proportional relationship between the peak
tration versus time profile.
plasma concentration and the administered
a. 25 mg tablet, t1/2 ¼ 5.25 h dose.
50 mg tablet, t1/2 ¼ 5.50 h. The intercept values for the plasma concentra-
(Do not be concerned about the 0.25 h differ- tion versus time profiles are as follows:
ence [insignificant] in the elimination half life 25 mg tablet, intercept ¼ 9.8 ng mL1.
of the drug; this reflects the graphical method For 50 mg tablet, intercept ¼ 18.0 ng mL1.
employed.)
g. 25 mg tablet, intercept ¼ 9.8 ng mL1 (graphi-
b. 25 mg tablet, K ¼ 0.132 h1 cal method)
50 mg tablet, K ¼ 0.126 h1. 50 mg tablet, intercept ¼ 18.0 ng mL1 (graph-
(Ignore the small difference in the elimination ical method).
rate constants.) These two values are reasonably close for
c. Use the feathering or residual or curve- graphical estimates.
stripping method to determine from the feath- h. Notice that V cannot be calculated for an ex-
ered or residual line of (Cp)diff against time on a travascular dose without knowledge of F, the
semilogarithmic graph paper. As mentioned bioavailable fraction. The best that one can do
above, there may be greater variation in these is to calculate the ratio V/F:
values because of the technique employed.
This variation, in turn, will be reflected in V=F ¼ X0 Ka =ðIÞðKa  KÞ
the answers for the peak time, peak plasma
concentration and the intercept of the plasma where I is the y-axis intercept.
concentration versus time profile. For 25 mg dose, V/F ¼
25 mg tablet, t1/2 ¼ 0.625 h (25)(1.109)/(9.8)(1.109  0.132) ¼ 2.90 L
50 mg tablet, t1/2 ¼ 0.700 h. For 50 mg dose, V/F ¼
(50)(0.990)/(18.0)(0.990  0.126) ¼ 3.18 L.
d. 25 mg tablet, Ka ¼ 1.109 h1 Again, reasonably close for graphical esti-
50 mg tablet, Ka ¼ 0.990 h1. mates.
e. The observed and computed peak time for i. For reasons explained above in (h), F cannot be
each dose: calculated with the information at hand.
25 mg tablet, tmax ¼ 3.00 h (graphical method)
j. Your plot should show no significant changes
50 mg tablet, tmax ¼ 3.00 h (graphical method)
in tmax as a function of dose.
25 mg tablet, tmax ¼ 2.178 h (calculated method)
k. Within the limits of accuracy of the graphi-
50 mg dose, tmax ¼ 2.385 h (calculated method).
cally derived answers, your plot should show
Note that doubling the dose did not alter the direct proportionality between dose and
peak time. (Cp)max.
 Problem set 2 121

l. The extrapolated line and the feathered line 2. The therapeutic range for the drug is 4–8 mg
intersect virtually at the y-axis, indicating the mL1. This, therefore, suggests that 250 mg dose
absence of any lag time. is insufficient to produce the pharmacological
effect and a larger dose will be needed. Further-
Problem-solving exercise answer more, the relationship between the peak plasma
1a. lnðKa =KÞ lnð2:8 h  1 =0:231 h  1 Þ concentration and the dose administered is di-
t max ¼ ¼ rectly proportional (linear pharmacokinetics).
Ka  K 2:8 h  1  0:231 h  1
Therefore, following the administration of a
2:4949 500 mg dose peak plasma concentration will
t max ¼
2:569 h  1 be 2.440 mg mL1. This dose will also be inade-
quate to provide a procainamide plasma concen-
tmax ¼ 0.971 h or 58.25 min for a 250 mg dose.
tration within therapeutic range.
Please note that since peak time is independent
3. Administration of four to six tablets of 250 mg
of the dose administered, for a 500 mg tablet, the
strength or three tablets of 500 mg strength
peak time will be identical (i.e. 0.971 h or
or two tablets of 750 mg strength, however,
58.25 min). However, if an identical dose or
will yield procainamide plasma concentration
even a different dose of procainamide is ad-
of 4.88 mg mL1 for the 1000 mg dose and
ministered through a different extravascular
7.32 mg mL1 for a 1500 mg dose (linear phar-
route (e.g intramuscular), different dosage
macokinetics) (within the therapeutic range).
form (e.g. solution, capsule, controlled release
tablet) or different formulation (e.g. tablet 4. When the rate of absorption (KaXa) is equal to
made by a different manufacturer or the same the rate of elimination (KX), t ¼ tmax; in other
manufacturer with a different formulation), words, rate of absorption and rate of elimina-
the peak time may be different. This is because tion become equal only at peak time:
the absorption rate constant may change with ðXa Þt ¼ FX0 e  Ka t
route of administration, dosage form and for-
mulation. The absorbable fraction F is 0.8554, or 85.54%.
When t ¼ 0; eKat ¼ 1.0; and Ka ¼ 2.8 h1.
b. (Cp)max is given by Therefore, for a 250 mg dose, the absorbable
amount of drug at the site of administration
ðCp Þmax ¼ Iðe  Kt max  e  Ka t max Þ at t ¼ 0 is (Xa)t=0 ¼ 0.8554 $ 250 mg $ 1
¼ 213.85 mg.
where I is the y-axis intercept of the line ex- When t ¼ tmax,
trapolated from the terminal linear segment of F(Xa)0 ¼ 213.85 mg.
the plasma concentration versus time curve on At tmax, (Xa) ¼ F(Xa)0eKatmax, where tmax
semilogarithmic coordinates. We know from 0.970 h and Ka ¼ 2.8 h1.
the available information that the absorption So at tmax, (Xa) ¼ 213.85 mg $ e2.8 $ 0.970
rate constant (Ka) and the elimination rate ¼ 213.85 mg $ e2.716
constant (K) are 2.8 h1 and 0.231 h1, respec- ¼ 213.85 mg $ 0.066138
tively, and the calculated peak time is 0.971 h. At tmax, (Xa) ¼ 14.14 mg (the absorbable
The intercept of the plasma concentration ver- amount of drug remaining at the site of admin-
sus time data for a 250 mg tablet is reported to istration at peak time).
be 1.665 mg mL1. Substituting these values in Therefore, for the 500 mg dose (linear pharma-
the equation will provide (Cp)max: cokinetics), the absorbable amount of drug
remaining at the site of administration at peak
(Cp)max ¼
time is 24.28 mg.
1.665 mg mL1(e0.231$0.971  e2.8$0.971)
1 0.2243
The amount of drug in the blood (X)max at peak
(Cp)max ¼ 1.665 mg mL (e  e2.7188) time:
1
(Cp)max ¼ 1.665 mg mL (0.7990  0.06595)
(Cp)max ¼ 1.220 mg mL1 for a 250 mg dose. (X)max ¼ (Cp)max) $ V
 122 B a si c P ha r m a c ok i n e t ic s

Peak plasma concentration for a 250 mg tablet By linear pharmacokinetics, the amount of
is 1.22 mg mL1 and the apparent volume of drug eliminated at peak time is 57.82 mg for
distribution is 140 000 mL. Therefore, the the 500 mg tablet.
amount of drug in the blood/body at peak At peak time, rate of absorption (KaXa) ¼ rate of
time: elimination (KX):
(X)max ¼ 1.22 mg mL1 $ 140 000 mL ¼ Ka(Xa)max ¼ KXmax.
170.8 mg For the 250 mg tablet:
For 500 mg dose (applying linear pharmacoki- rate of absorption ¼ Ka(Xa)max ¼ 2.8 h1 $
netics), the amount of drug in the blood/body 14.09 mg ¼ 39.45 mg h1
at peak time, (X)max, is: rate of elimination ¼ K(Xa)max ¼ 0.231 h1 $
2.44 mg mL1 $ 140 000 mL ¼ 341.6 mg. 170.80 mg ¼ 39.45 mg h1.
For the 500 mg tablet:
5. These calculations show that, following the rate of absorption ¼ 2.8 h1 $ 28.18 mg ¼
administration of a 250 mg tablet and 500 mg 78.90 mg h1
tablet, the amount of drug ultimately reaching rate of elimination ¼ 0.231 h1 $ 341.6 mg ¼
the general circulation is 213.85 mg and 78.90 mg h1.
427.7 mg, respectively (85.54% of dose; note Calculations provided here support and con-
that the fraction reaching the general circula- firm the theory that only at peak time do the
tion is independent of the dose administered). rate of absorption and the rate of elimination
At peak time for the 250 mg tablet, the amount become equal, regardless of the dose adminis-
of drug remaining at the site of administration tered, chosen extravascular route, chosen dos-
and the amount of drug in the blood/body are age form, chosen formulation of a dosage form
14.09 mg and 170.80 mg, respectively. At peak and health of the subject (normal or renally
time for the 500 mg tablet, the amount of drug impaired). However, the time at which rates be-
remaining at the site of administration and the come equal can be different.
amount of drug in the blood/body are
6. A graph on rectilinear coordinates of rate of
28.18 mg and 341.6 mg, respectively.
absorption against dose administered is given
Therefore, the amount of drug eliminated at in Fig. P2.1. The relationship between the rate
peak time for a 250 mg tablet is 213.85 mg of absorption and the rate of elimination at
(14.09mg + 170.80 mg) ¼ 28.91 mg. peak time is shown in Fig. P2.2.

12

10
–dXa /dt (mg h–1)

0
0 2 4 6 8 10 12
X 0 (mg)

Figure P2.1
 Problem set 2 123

12

10

(–dXa/dt)tmax (mg h–1)

8

0
0 2 4 6 8 10 12
(–dX/dt)tmax (mg h–1)

Figure P2.2

7. The following approach will permit determi- renally impaired patient is 21.42% of the
nation of the absorption rate constant and normal value. Calculate the percentage
peak time. As shown above, only at peak time change in the elimination half life (3 h in nor-
does the rate of absorption equal the rate of mal subject and 14 h in this renally impaired
elimination: Ka(Xa)max ¼ KXmax. subject) of this drug in this renally impaired
patient and compare the answer with the per-
Rearranging this equation gives:
centage change in the systemic clearance.
KXmax
Ka ¼ Cls $ % excreted ¼ 6930 mL h1 $ 0.65
ðXa Þmax
¼ 4504.5 mL h1 (4.50 L h1).
Clm ¼ Cls $ % metabolite ¼ 6930 mL h1
Once the absorption and elimination rate con-
$ 0.35 ¼ 2425.5 mL h1 (2.42 L h1).
stants are known, calculation of peak time is
possible by using the equations in Answer 4. These clearance values are dose independent
Since 65% of the dose is excreted in urine as and, therefore, will not change for a 750 mg
procainamide and 35% as N-acetylprocaina- intravenous dose.
mide (metabolite), for a 750 mg intravenous Peak time will be:
bolus dose, the amount excreted at time infin-
ity is dose $ % excreted. lnðKa =KÞ lnð2:8 h  1 =0:0495 h  1 Þ
t max ¼ ¼
For procainamide, the amount excreted is Ka  K 2:8 h  1  0:0495 h  1
750 mg $ 0.65 ¼ 487.50 mg.
4:0354
For N-acetylprocainamide, the amount excret- t max ¼ ¼ 1:467 h:
2:7505 h  1
ed is 750 mg $ 0.35 ¼ 262.5 mg.
8. We know that: The value of tmax is also dose independent and,
therefore, will not change for a 750 mg intrave-
K ¼ 0.693/t1/2 ¼ 0.693/14 h ¼ 0.0495 h1.
nous dose. In a normal subject, peak time was
Cls ¼ V $ K
observed to be 0.97 h. The percentage difference
Cls ¼ 140 000 mL $ 0.0495 h1 ¼ 6930 mL h1
in peak time in renally impaired subjects with
(6.930 L h1).
respect to the normal value is:
Normal value is 32.34 L h1. Note that
systemic clearance of procainamide in this (1.467  0.97)/0.97 ¼ 0.512 ¼ 51.2%
 124 B a si c P ha r m a c ok i n e t ic s

1.2

1.0

AUC (µgL–1h) 0.8

0.6

0.4

0.2

0.0
0 2 4 6 8 10 12
–1
Cls(mLh )

Figure P2.3

This increase in tmax indicates slower elimina- Note that the relationship between the peak
tion for the renally impaired patient. plasma concentration and the dose admin-
istered is directly proportional (linear phar-
9. Since peak time is independent of the dose
macokinetics). This means that for a 500 mg
administered, peak time for a 500 mg tablet
tablet the peak plasma concentration will be
in this renally impaired subject will be iden-
2.842 mg mL1.
tical to that for a 250 mg tablet (1.467 h).
11. Since
10. (Cp)max is given by:
FX0
ðAUC¥0 Þ ¼
Cls
ðCp Þmax ¼ Iðe  Kt max  e  Ka t max Þ
the AUC will be inversely proportional to sys-
The available information is that Ka and K are temic clearance (Fig. P2.3). If renal clearance
2.8 h1 and 0.0495 h1, respectively; peak time represents a significant fraction of systemic
has been calculated to be 1.467 h. The inter- clearance, ðAUC¥0 Þ will increase with decreas-
cept of the plasma concentration–time data for ing renal function.
a 250 mg tablet was reported to be 1.556 mg Additional reflections. Compare the calculated
mL1. Substituting these values in the equa- values of peak time and peak plasma concen-
tion will provide the following: tration for the 250 and 500 mg doses in normal
and renally impaired subjects. Is there a pro-
(Cp)max ¼ longation in peak time (i.e. longer peak time)
1.556 mg mL1(e0.0495 $ 1.467  e2.8 $ 1.467) and elevation in peak plasma concentration in
(Cp)max ¼ 1.556 mg mL1(e0.0726  e4.107) the renally impaired subject following the ad-
(Cp)max ¼ 1.556 mg mL1 (0.9299  0.0164) ministration of the same dose? Do these calcu-
(Cp)max ¼ 1.421 mg mL1 for a 250 mg dose. lations agree with the theory?