Warm-up

Time (hr) Plasma Calculate t1/2 and k

Concentration
(ng/mL) Calculate C0, the concentration at time 0
10 19.09
14 13.9 k = ln(19.09)-ln(7.97)
20 7.97 20-10

t1/2 = 0.693/k

C0 = Cp ekt Modified equation to get C0

Well come back to these #s

k = 0.0873 /hr
t1/2 = 7.94 hr
C0 = 48.2 ng/mL
Pharmacokinetics
Exam II Review

Charles Dang
 Definitions
t1/2: elimination half-life
k: elimination rate
VD: volume of distribution
R: IV infusion rate (generally constant, 0th
order)
DB, D: total amount of drug in plasma
Cp: concentration of drug in plasma
 Background
0th order

Let the eqn

help you

1st order

Whats happening in the graph:

a) 0th order infusion

b) 1st order infusion
c) 1st order infusion + 1st order elimination
d) 0th order infusion + 1st order elimination
 Background

What happened at A:

a) Transition from infusion only to elimination only

b) Infusion stopped
c) Patient died
 Oral Absorption (not IV !!)
What is happening at B?

B a) absorption only
b) elimination only
c) both absorption and elimination

C
A What happens in between B and C?

Drug getting fully absorbed

i.e. almost no more drug in GI tract
-> nothing left to absorb so
becomes pure elimination
Lets define A,B and C
A absorption
B post absorption
C elimination
Oral Absorption
1st order
absorption

Ignore

1st order elimination

Is it 0th order or 1st order absorption?

Let the equation guide you

 Calculations
General equation for oral dosing
A For simplicity, lump all the
coefficients into one

Can consider absorption and

Cp = Ae-kt Ae-kat elimination separately
elim. abs.
It is counter-intuitive that the
elimination term is subtracting the
absorption term. But the math is
correct. Use as is.

To solve for the constants k, ka, A

we need method of residuals

Recall that we used method of

residuals to solve two compartment
models (Ch 4). It was a mess!
 Residuals Oral Dosing
Ch7, #1. Plasma samples from a
patient were collected after an oral
bolus dose of 10 mg of a new
benzodiazepine solution as follows:

Time (hr) Plasma

Concentration
(ng/mL)
0.25 2.85 3 Phases:
0.5 5.43
0.75 7.75 Absorption
1 9.84
2 16.2
4 22.15
6 23.01 Post absorption
10 19.09
14 13.9 Elimination
20 7.97
 Residuals Oral Dosing
elim. abs.
Ch7, #1. Plasma samples from a Cp = Ae-kt Ae-kat
patient were collected after an oral
bolus dose of 10 mg of a new Cp = 48.2(e-0.0873t e-0.339t)
benzodiazepine solution as follows:

Time (hr) Plasma 48.2 e-0.0873t

Concentration
(ng/mL) Elim Part Abs Part Plug in time
0.25 2.85 47.16 44.31 values for
0.5 5.43 46.14 40.71 elimination part
0.75 7.75 45.15 37.40
1 9.84 Find the
2 16.2 absorption part:
4 22.15 ka = 0.339 abs = elim Cp
6 23.01
10 19.09 Find elimination Find ka based
14 13.9 data first on absorption
20 7.97 k = 0.0873 part. Pick any 2
A = 48.2 data points
 Oral Dosing Contd
So far: k=0.0873 h-1, ka=0.339 h-1, A=48.2 ng/mL
Recall that we used A to simplify the expression:

From here we can find other missing quantities.

For example, if the bioavailability (F) is 80%, the initial
dose is 10mg, what is VD? (careful with units?)
223L
 Graphical method
May be easier than residuals method

100
~50, which is close to our calculated A value of 48.2

10
Doing this method,
the slope = k/2.3
So k = slope*2.3

1
0 5 10 15 20 25
Important quantities
Bioavailability studies

With a known ingested drug amount D0

Cmax indicates rate and extent of absorption

tmax indicates rate of absorption
AUC indicates extent of absorption
Bioavailability
Find Cmax, tmax for the two
dosage forms

APAP 500mg tablet

Cmax is 15mg/mL
Tmax is 0.7h

APAP 500mg liquid

Cmax is 19mg/mL
Tmax is 0.2h

How does Cmax also

indicate the rate of abs?

-Only meaningful when you

compare two drug samples
of same dose. Same 500
mg, but liquid APAP is
absorbed more and must
have been absorbed faster.
Important quantities

tmax =

Plug tmax into t to

get Cmax
lag time makes calculations
more complex. Remove lag
time and calculations will be
back to normal
Lag time
Lag time estimated to be 3hr. Subtract
3hr from the time column.

Time (hr) Plasma Time (hr) Plasma

Concentration Concentration
(mg/mL) (mg/mL)

1 0
2 0
3 0 0 0
4 2.85 1 2.85
5 5.43 2 5.43
7 7.75 4 7.75
9 9.84 6 9.84
Now calculate as usual

Lag time: delay in the start of absorption

e.g. too much food in stomach, low GI motility
Lag time Onset time

MEC

Onset time is time to reach MEC

Lag time has nothing to do with Onset time
 Flip-flop of k and ka
For most drugs given orally, ka > k (absorption proceeds faster than
elimination)
Calculation of k using IV data is best, but invasive
Getting k from oral absorption data, as we have been doing, is less
invasive, but can give incorrect values.
Watch out for:
Drugs that eliminate rapidly (k > 0.69 hr-1)
Isoproterenol
salicyluric acid
In those cases, k and ka values need to be flip-flopped
e.g. you get k = 0.7, ka = 1.72 from oral data calculation
This raises a red flag because the k value is high (>0.69)
Follow up with IV data on the same patient and we find that k is actually
1.72, which means our calculations above need to be flip-flopped (k=1.72
and ka=0.7)
 K and ka by urine data
Recall urine data can be analyzed by
method of average rates (shown here)
sigma minus method (not discussed here)

ke = drug elim constant Notice that the intercept we

through kidneys. get using the method of
ke is part of k: average rates is very similar
k = ke + km + kl to the intercept we get from
plasma data
 Trends
Identify the trends, what if k and km were increased

k,
tmax
Cmax
AUC

ka
tmax
Cmax
AUC same
 Mid-summary
Single Dose orally given drug
Find k, ka by method of residuals or graphing
Many, many other methods to get k, ka
Oral dosing is common, hence many methods used to get
absorption data (k, ka)
If k>0.69, run the drug IV in patient to confirm true
value of k
Calculate tmax, Cmax
Along with AUC, these values most reliably predict
bioavailability
ka does not affect AUC, increases rate and extent of
absorption
k decreases extent of absorption, tmax
 Practice
Time Plasma Calculate
(hr) Concentration k, ka, tmax, Cmax, F
(mcg/mL) given that VD =60L, D0 =500mg
0.25 11.5
0.5 21.0
0.75 29.0 k=0.1 hr-1
1 35.6 ka = 0.6 hr-1
2 51.8 tmax = 3.6 hr
4 58.0 Cmax = 58.2
6 52.1 F = 0.83
10 36.5
16 20.2
24 9.1
 Multiple Doses
Cmax - multiple

Cmax single

Concerns multiple IV doses and also multiple oral doses

Oral Dosing Fluctuations

Multiple dosing goal: to achieve a

steady average concentration

IV infusion much steadier concentration

Oral dosing has wild fluctuations

- Reduced fluctuation when doses are
more frequent
 New Definitions
R: accumulation index
t: time between doses (dose interval)
 Multiple Doses
Cmax - multiple

Cmax single

Accumulation index
NOT IV infusion rate

R = Cmax multiple
Cmax single

t
k, accumulation
t, accumulation
 Equations (IV)
Effect of accumulation Does this equation seem familiar?
It resembles a single IV bolus

The t in these equations means time from the

last dose, NOT the time since 0.

Concentration at time t after steady state

Average steady
State conc. Cmin = Cmax e-kt
 Equations (IV)
Cmin = Cmax e-kt

2. The patient received 1000 mg of an antibiotic every 6 hours by repetitive IV injection.

The drug has an apparent volume of distribution of 20 L and elimination half-life of 3
hours. Calculate (a) the plasma drug concentration Cp at 3 hours after the second dose,
(b) the steady-state plasma drug concentration Cp at 3 hours after the last dose,
(c)Cmax, (d) Cmin, and (e)CSS.

Start with what you know :

D0 = 1000mg
t= 6h
VD = 20L
t1/2 = 3h
 Equations (IV)

2. The patient received 1000 mg of an antibiotic every 6 hours by repetitive IV injection.

The drug has an apparent volume of distribution of 20 L and elimination half-life of 3
hours. Calculate (a) the plasma drug concentration Cp at 3 hours after the second dose,
(b) the steady-state plasma drug concentration Cp at 3 hours after the last dose,
(c)Cmax, (d) Cmin, and (e)CSS.

Start with what you know:

D0 = 1000mg
t= 6h a) Plug values into above equation
n=2
VD = 20L
t = 3h
t1/2 = 3h
Ans:
Cp t=3 after 2nd dose: 31.3mg/L
 Equations (IV)

2. The patient received 1000 mg of an antibiotic every 6 hours by repetitive IV injection.

The drug has an apparent volume of distribution of 20 L and elimination half-life of 3
hours. Calculate (a) the plasma drug concentration Cp at 3 hours after the second dose,
(b) the steady-state plasma drug concentration Cp at 3 hours after the last dose,
(c)Cmax, (d) Cmin, and (e)CSS.

Start with what you know:

D0 = 1000mg
t= 6h b) Plug values into above equation
t = 3h
VD = 20L
Ans:
t1/2 = 3h
Cp t=3h after last dose: 33.3mg/L
 Equations (IV)

2. The patient received 1000 mg of an antibiotic every 6 hours by repetitive IV injection.

The drug has an apparent volume of distribution of 20 L and elimination half-life of 3
hours. Calculate (a) the plasma drug concentration Cp at 3 hours after the second dose,
(b) the steady-state plasma drug concentration Cp at 3 hours after the last dose,
(c)Cmax, (d) Cmin, and (e)CSS.

Start with what you know :

D0 = 1000mg
t= 6h c) Plug values into above equation
Cp0 is really just D0/VD
VD = 20L
Ans:
t1/2 = 3h
Cmax= 66.7mg/L
 Equations (IV)

2. The patient received 1000 mg of an antibiotic every 6 hours by repetitive IV injection.

The drug has an apparent volume of distribution of 20 L and elimination half-life of 3
hours. Calculate (a) the plasma drug concentration Cp at 3 hours after the second dose,
(b) the steady-state plasma drug concentration Cp at 3 hours after the last dose,
(c)Cmax, (d) Cmin, and (e)CSS.
Cmin = Cmax e-kt
Start with what you know :
D0 = 1000mg
t= 6h d) Plug values into above equation
Cmax= 66.7mg/L
VD = 20L
Ans:
t1/2 = 3h
Cmin = 16.7 mg/L
 Equations (IV)

2. The patient received 1000 mg of an antibiotic every 6 hours by repetitive IV injection.

The drug has an apparent volume of distribution of 20 L and elimination half-life of 3
hours. Calculate (a) the plasma drug concentration Cp at 3 hours after the second dose,
(b) the steady-state plasma drug concentration Cp at 3 hours after the last dose,
(c)Cmax, (d) Cmin, and (e)CSS.

Start with what you know :

D0 = 1000mg
t= 6h d) Plug values into above equation
VD = 20L Css value is approximated by the average
t1/2 = 3h value in multiple dosing
F = 1 for IV administration
Ans:
Css, 36.1 mg/L
 Missed Dose (IV)
Same as before, except
Adding one more term

tmiss is the time gone by since the last missed dose. Diagram the problem.

Q: Injections were given every 8 hours. The 3rd dose was missed. What
values of t and tmiss do we use to find the concentration 2 hours after
the 4th dose?
Current time
2h after 4th dose
t=2h
10h after missed dose
tmiss =10h

1st dose 2nd dose 3rd dose 4th dose

 Missed Dose (IV)

A cephalosporin (k = 0.2 hr 1, V D = 10 L) was administered by IV multiple dosing; 100 mg was

injected every 6 hours for 6 doses. What was the plasma drug concentration 4 hours after the 6th
dose (ie, 40 hours later) if (a) the 5th dose was omitted, (b) the 6th dose was omitted, (c) the 4th
dose was omitted?
Questions??
Happy Springtime!

Take good care of yourself and those around you.