Pharmacokinetics

Lecture 6

Urinary excretion data

A patient is diagnosed with a bacterial infection and prescribed Cefuroxime to
be given as an intravenous bolus dose of 750mg. She has requested plasma
levels from the laboratory and they indicated that blood levels at 2 and 4 hours
were 10mcg/ml and 5.5mcg/ml respectively. She calls the pharmacy with the
information and requests you to calculate the following

i) t1/2
ii) Co
iii) Vd
First step is calculating k

If we are given 2 concentrations and 2 time points

We can use the formula

K= (ln C2- ln C1)

t2-t1

We know: C2 = 10mcg/ml and C4 = 5.5mcg/ml .

Substituting the values into the equation:

K= ln 10 – ln 5.5 = 2.303- 1.705 = 0.598

4-2 2 2

K= 0.299 hr-1
Formula for t1/2

t1/2= 0.693/k

t1/2= 0.693/0.299

t1/2= 2.32hrs
Calculating Co

Using Ct= Co e-kt

What do we know- We have a time point and a time

Plus we just calculated k

C2= Co e-kt2

10= Co e-(0.299) (2) = 10= Co e-0.598

10 = Co (0.55) , Co = 10/0.55= 18.18mcg/ml
For volume of distribution

Vd= Amount of drug given (IV)

Cpo

Vd = 750,000 mcg / 18.18 mcg/ml

Vd = 41,254.13 ml

Vd = 41.25 L
A drug with half-life of 5.5 hours is administered by IV injection and the
following data time points are obtained. Calculate
(1) The AUC (t1-∞) (4 marks)
(2) Elimination rate (1 mark)

Time Plasma
levels
1 90.1
2 87.1
4 65.71
8 41.11
12 20.22
24 6
36 1.31
10
20

20
Calculating the elimination rate

T1/2= 0.693 / k

K=0.693/t1/2

K=0.693/5.5

K= 0.126/hr
Using the trapezoid rule
(1) AUC from time 1 to infinity =

Time Plasma t1-t2= (90.1 + 87.1) /2 X (2-1) =

levels +
1 90.1 t2-t4= (87.1 + 65.71)/2 X (4-2) =
2 87.1 +
4 65.71 T4-t8= (65.71 +41.11)/2 X (8-4) =
8 41.11 +
12 20.22 T8-t12=(41.11 + 20.22 )/2 X (12-8) =
24 6 +
36 1.31 T12-t24=(20.22 +6)/2 X (24-12) =
+
T24-t36=(6+1.31)/2 X (36-24) =
+
Cplast/Kel = 1.31/0.126 = 10.40

Therefore AUC = 88.6 +152.81 + 213.64 + 122.66 +

157.32 + 43.86 + 10.40
AUC = 789.29 units/hr
Using the trapezoid rule
(1) AUC from time 1 to infinity =

Time Plasma (90.1 + 87.1) /2 X (2-1) = 88.6

levels +
1 90.1 (87.1 + 65.71)/2 X (4-2) = 152.81
2 87.1 +
4 65.71 (65.71 +41.11)/2 X (8-4) = 213.64
8 41.11 +
12 20.22 (41.11 + 20.22 )/2 X (12-8) = 122.66
24 6 +
36 1.31 (20.22 +6)/2 X (24-12) = 157.32
+
(6+1.31)/2 X (36-24) = 43.86
+
Cplast/Kel = 1.31/0.126 =

Therefore AUC = 88.6 +152.81 + 213.64 + 122.66 +

157.32 + 43.86 + 10.40
Using the trapezoid rule
(1) AUC from time 1 to infinity =

Time Plasma (90.1 + 87.1) /2 X (2-1) = 88.6

levels +
1 90.1 (87.1 + 65.71)/2 X (4-2) = 152.81
2 87.1 +
4 65.71 (65.71 +41.11)/2 X (8-4) = 213.64
8 41.11 +
12 20.22 (41.11 + 20.22 )/2 X (12-8) = 122.66
24 6 +
36 1.31 (20.22 +6)/2 X (24-12) = 157.32
+
(6+1.31)/2 X (36-24) = 43.86
+
Cplast/Kel = 1.31/0.126 = 10.40

Therefore AUC = 88.6 +152.81 + 213.64 + 122.66 +

157.32 + 43.86 + 10.40
AUC = 789.29 units/hr
A known epileptic patient is admitted to accident and emergency after
experiencing a seizure. His doctor promptly administers 200mg of
Phenytoin by IV bolus injection. The physician took a blood sample and
the laboratory determined the initial drug levels to be 50mcg/ml. The
clinical pharmacist looked at population data which suggested the
elimination rate is 0.4/hr. Calculate:

(i) The half-life of the drug (1 mark)

(ii) The plasma drug level at 6 hours. (2 marks)
(iii) If the minimum effective concentration is 10mcg/ml, when
should the next dose be administered? ( 2 marks)
What we know

Dose=200 mg

Cp0 = 50 mcg/ml

k= 0.4/hr

To calculate half life of the drug:

Using formula t1/2 = 0.693/ k

t 1/2 = 0.693/ 0.4/hr

t 1/2 = 1.73 hours

What we know

Dose=200 mg

Cp0 = 50 mcg/ml

k= 0.4/hr

To calculate half life of the drug:

Dose=200 mg , Cp0 = 50 mcg/ml, k= 0.4/hr, t1/2 = 1.73hours

Using formula

Cp= Co e-kt

C6= 50 e-(0.4) (6)

Cp= 50e(-2.4)

Cp= 50 X 0.091

Cp6 = 4.55 mcg/ml

If the minimum effective concentration is 10mcg/ml, when
should the next dose be administered?

We need to find t when Cp= 10mcg/ml

What do we know?

Cp0 = 50 mcg/ml, k= 0.4/hr, t1/2 = 1.73hours, C6=4.55mcg/ml

Cp= Co e-kt

10=50 e-0.4t

10/50 = e-0.4t

0.2= e-0.4t

Ln 0.2=-0.4t ……… -1.61= -0.4t …….. t=1.61/0.4= 4.025 hours

OR Using formula

ln(Cp) = ln (Cp0) - kt
And rearranging to solve for t

t = ( ln (10 mcg/ml) - ln (50 mcg/ml) ) / -0.4/hr

t = 4.025 hrs
A patient is admitted to hospital with a viral infection requiring
treatment with Acyclovir. His physician administers 1000mg IV as a
bolus injection. The plasma concentration at 2 hour is 30mcg/ml and
the elimination rate constant is 0.4/hr.
Calculate:
a) Plasma concentration immediately after the IV bolus dose ( 1 mark)
b) The volume of distribution ( 2 marks)
c) The clearance of the drug ( 2 marks)
What do we know

Dose= 1,000 mg C2 = 30 mcg/ml k = 0.4/hr

We need to find Co

Using formula Cp= Co e-kt

30 = Co e-(0.4) (2)

30 = Coe-(0.8)

30= Co (0.45)………Co= 30/0.45= 66.67mcg/ml

(b) What do we know

Dose= 1,000 mg C2 = 30 mcg/ml k = 0.4/hr Co=66.67mcg/ml

We need to find Vd

Using formula Vd = Dose/Cp0

Vd = 1,000,000 mcg / 66.77 mcg/ml

Vd = 14,976.79 ml
Vd = 14.98 L
(c) (b) What do we know

Dose= 1,000 mg C2 = 30 mcg/ml k = 0.4/hr Co=66.67mcg/ml

Vd= 14.98L

We need to find Cl

Using formula CL = k*Vd

CL= 0.4/hr * 14.98 L

CL= 5.99 L/hr

Clearance from Drug-Eliminating Tissues

• For some drugs, the elimination rate process is more complex and a
noncompartment method may be used to calculate certain
pharmacokinetic parameters such as clearance.

• In this case, clearance can be determined directly from the plasma

drug concentration-versus-time curve by:

D0
C lT 
A U C  
0

Where: D0 is the dose and [AUC]∞ = ∫ ∞ C dt

0 0 p
 CLINICAL APPLICATION

After IV bolus injection, we assumed

One compartment model

Even distribution to highly perfused organs
Calculation of Kel from slope
Determination of Co

This approach is particularly useful for a new or investigational drug when

little pharmacokinetic information is known.

Why would rapid bolus IV injections not be applicable in a practical setting?

.
In practice, rapid bolus injection is often not desirable for
many drugs and a slow IV drip or IV drug infusion is
preferred.

Rapid injection of a large drug dose may trigger adverse drug

reactions (ADR) that would have been avoided if the body
had sufficient time to slowly equilibrate with the drug.

This is particularly true for certain classes of antiarrhythmics,

anticonvulsants, antitumor, anticoagulants, and some
systemic anesthetics.

Immediately after an intravenous injection, the concentrated

drug solution/vehicle is directly exposed to the heart, lung,
and other vital organs before full dilution in the entire body.
Most intravenous drugs are formulated as aqueous solutions,
lightly buffered with a suitable pH for this reason.

A poorly soluble drug may precipitate from solution if injected

too fast.

Suspensions or drugs designed for IM injection only could

cause serious injury or fatality if injected intravenously.

Drugs intended for IM injection have a precaution that

accompanies the packaging to ensure that the drug will not be
injected accidentally into a vein.
Calculation of K from Urinary Excretion Data

• The elimination rate constant k may be calculated from urinary

excretion data.

• In this calculation the excretion rate of the drug is assumed to be first

order.

dD u
 ke DB Where:
dt ke is the renal excretion rate constant.
Du is the amount of drug excreted in
the urine.
Remember:

DB  D B0 e  k t
Calculation of K from Urinary Excretion Data

• The elimination rate constant k may be calculated from urinary

excretion data.

• In this calculation the excretion rate of the drug is assumed to be first

order.

dD u
 ke DB Where:
dt ke is the renal excretion rate constant.
Du is the amount of drug excreted in
the urine.
Remember:

DB  D B0 e  k t
Calculation of K from Urinary Excretion Data

• The elimination rate constant k may be calculated from urinary

excretion data.

• In this calculation the excretion rate of the drug is assumed to be first

order.

dD u
 ke DB Where:
dt ke is the renal excretion rate constant.
dDu Du is the amount of drug excreted in
 k e D 0B e  k t the urine.
dt
Calculation of K from Urinary Excretion Data

• The elimination rate constant k may be calculated from urinary

excretion data.

• In this calculation the excretion rate of the drug is assumed to be first

order.

dD u
 ke DB Where:
dt ke is the renal excretion rate constant.
dDu Du is the amount of drug excreted in
 ke D B e
0 kt
the urine.
dt
dD u  kt
log   log ke D B0
dt 2.3
 Calculation of K from Urinary Excretion Data

log rate of drug excretion versus t on Semilog graph of rate of drug

regular paper. excretion versus time
Calculation of K from Urinary Excretion Data

• The nonrenal rate constant (knr) for any route of elimination other
than renal excretion can be found as follows:

knr  k  ke
Where:
ke is the renal excretion rate constant.
Knr is the nonrenal rate constant.
 Example
• A single IV dose of an antibiotic was given to a 50-kg woman at a
dose level of 20 mg/kg. Urine and blood samples were removed
periodically and assayed for parent drug. The following data were
obtained:

Calculate k and t1/2 ?

• A single IV dose of an antibiotic was given to a 50-kg woman at a
dose level of 20 mg/kg. Urine and blood samples were removed
periodically and assayed for parent drug. The following data were
obtained:

Calculate k and t1/2 ?

Time Du (mg) Du/dt Mg/hr Log du/dt T
(midpoint)

0.25 160 160/0.25 640 2.806 0.125

0.5 140 140/0.25 560 2.748 0.375
1.0 200 200/0.5 400 2.602 0.750
2.0 250 250/1 250 2.398 1.5
4.0 188 188/2 94 1.973 3.0
6.0 46 46/2 23 1.362 5.0
Solution
y = -0.295x + 2.844
R² = 0.999
3

2.5

• Slope = -k/2.303 2

• K = 0.68 hr-1
log Du/dt

1.5

• t1/2 = 0.693/k 1

= 1.01 hr
0.5

0
0 1 2 3 4 5 6
Midtime (hr)
The Sigma-minus Method
• An alternative method for the calculation of the elimination rate
constant k from urinary excretion data is the sigma-minus method,

• or the amount of drug remaining to be excreted method.

• The sigma-minus method is sometimes preferred over the previous

method because fluctuations in the rate of elimination are
minimized.
 The Sigma-minus Method

log( D   D )   kt  log D 
u u u
2.3
where:
D u is the cumulative amount of unchanged drug excreted in the urine.
D∞u is the amount of unchanged drug that is ultimately excreted in the
urine.

The above Equation describes the relationship for the amount

of drug remaining to be excreted (D∞ u – Du) versus time.
 The Sigma-minus Method
• A linear curve is obtained by graphing the logarithm
scale of the amount of unchanged drug yet to be
eliminated, log (D∞u– Du) versus time.

• On semilog paper, the slope of this curve is –k/2.3 and

the y intercept is D∞ u.
 The Sigma-minus Method

Sigma-minus method, or the amount of drug remaining to be

excreted method, for the calculation of the elimination rate
constant.
Graph showing the cumulative urinary excretion of drug as
a function of time.
CLINICAL APPLICATION
The sigma-minus method and the excretion rate method were applied to the
urinary drug excretion in subjects following the smoking of a single marijuana
cigarette.

The urinary excretion curves of 11-nor-carboxy 9-tetrahydrocannabinol

(THCCOOH), a metabolite of marijuana, in one subject from 24 to 144 hours
after smoking one marijuana cigarette are shown on the next slide.

A total of 199.7 mg of THCCOOH was excreted in the urine over 7 days, which
represents 0.54% of the total 9-tetrahydrocannabinol available in the cigarette.

Using either urinary drug excretion method, the elimination half-life was
determined to be about 30 hours.

However, the urinary drug excretion rate method data were more scattered
(variable) and the correlation coefficient r was equal to 0.744 compared to the
correlation coefficient r of 0.992 using the sigma-minus method.
Problems in Obtaining Valid Urinary ExcretionData

Certain factors can make it difficult to obtain valid urinary excretion data.
Some of these factors are as follows:

1. A significant fraction of the unchanged drug must be excreted in the

urine.

2. The assay technique must be specific for the unchanged drug and must
not include interference due to drug metabolites that have similar
chemical structures.

3. Frequent sampling is necessary for a good curve description.

Problems in Obtaining Valid Urinary ExcretionData

4. Urine samples should be collected periodically until almost all of the

drug is excreted. A graph of the cumulative drug excreted versus time
will yield a curve that approaches an asymptote at "infinite" time. In
practice, approximately seven elimination half-lives are needed for 99%
of the drug to be eliminated.

5. Variations in urinary pH and volume may cause significant variation in

urinary excretion rates.

6. Subjects should be carefully instructed as to the necessity of giving a

complete urine specimen (ie, completely emptying the bladder).
How would you determine k and t1/2??
Time Du inf - Du Log Du inf-Du
0.25 824
0.5 684
1 484
2 234
4 46
Time Du inf - Du Log Du inf-Du
0.25 824 2.916
0.5 684 2.835
1 484 2.685
2 234 2.369
4 46 1.663
6 0
 Chart Title

3.5
y = -0.2972x + 3.3852
R² = 0.8517
3

2.5

1.5

0.5

0
1 2 3 4 5
K = 0.2972/2.303

= 0.129/hr

T1/2= 0.693/k

T1/2= 0.693/0.129

T1/2= 5.37 hours

An adult male patient (age 35 years, weight 72 kg) with a urinary tract
infection was given a single intravenous bolus of an antibiotic (dose =
300 mg). The patient was instructed to empty his bladder prior to
being medicated. After dose administration, the patient saved his urine
specimens for drug analysis. The urine specimens were analyzed for
both drug content and sterility (lack of bacteriuria). The drug assays
gave the following results:

T (hours) Amt of drug in urine (mg)

0 0
4 100
8 26

a. Assuming first-order elimination, calculate the elimination half-life

for the antibiotic in this patient.
An adult male patient (age 35 years, weight 72 kg) with a urinary tract
infection was given a single intravenous bolus of an antibiotic (dose =
300 mg). The patient was instructed to empty his bladder prior to
being medicated. After dose administration, the patient saved his urine
specimens for drug analysis. The urine specimens were analyzed for
both drug content and sterility (lack of bacteriuria). The drug assays
gave the following results:

T (hours) Amt of drug in urine (mg)

0 0
4 100
8 26

a. Assuming first-order elimination, calculate the elimination half-life

for the antibiotic in this patient.
Intravenous Infusion

Differs from IV bolus= IV stat dose

Intravenous infusion- rate of drug delivery is constant over a fixed

period of time
Advantages

Precise control of plasma drug concentration to fit the particular need

of an individual patient

Drugs with a narrow therapeutic index- IV infusion maintains an

effective constant plasma concentration

Eliminated wide peaks and troughs in plasma blood levels

May be given with IV fluids that can hydrate, and provide electrolytes
and nutrients

Duration of drug therapy my be maintained or terminated at any time

dCp/dt = 0

Rate of drug input rate

of drug output (infusion
rate) (elimination rate)
In the IV infusion model

The rate of drug input in zero order process

The rate of drug elimination is a first order process

The change in the amount of drug in the body at any time t,

is equal to rate of input- rate of output (elimination)
 Time to 90,95,99% Css
For therapeutic purposes, the time for the plasma drug concentration to reach
more than 95% of the steady-state drug concentration in the plasma is often
estimated.

The time to reach 90%, 95%, and 99% of the steady-state drug concentration,
Css, may be calculated.

IV infusion of the drug for 5 half-lives- the plasma drug concentration will be
between 95% (4.32 t1/2) and 99% (6.65 t1/2) of the steady-state drug
concentration.

Thus, the time for a drug whose t1/2 is 6 hours to reach 95% of the steady-
state plasma drug concentration will be _____________
 Time to 90,95,99% Css

For therapeutic purposes, the time for the plasma drug concentration to reach
more than 95% of the steady-state drug concentration in the plasma is often
estimated.

The time to reach 90%, 95%, and 99% of the steady-state drug concentration,
Css, may be calculated.

IV infusion of the drug for 5 half-lives- the plasma drug concentration will be
between 95% (4.32 t1/2) and 99% (6.65 t1/2) of the steady-state drug
concentration.

Thus, the time for a drug whose t1/2 is 6 hours to reach 95% of the steady-
state plasma drug concentration will be approximately 4.32 t1/2, or

4.32 × 6 hours = 25.92 hours

An antibiotic has a volume of distribution of 10 L and a k of 0.2 h-1. A
steady-state plasma concentration of 10 μg/mL is desired.

What is the infusion rate needed to maintain this concentration ?

An antibiotic has a volume of distribution of 10 L and a k of 0.2 h-1. A
steady-state plasma concentration of 10 μg/mL is desired.

What is the infusion rate needed to maintain this concentration ?

Remember -------

Now lets rearrange: R = Css. Vd. k

An antibiotic has a volume of distribution of 10 L and a k of 0.2 h-1. A
steady-state plasma concentration of 10 μg/mL is desired.

What is the infusion rate needed to maintain this concentration ?

Remember -------

Now lets rearrange: R = Css. Vd. k

R= Css Vd k

R= (10 g/mL)(10)(1000 mL)(0.2 h )

Infusion rate = 20 mg/h

An antibiotic has a volume of distribution of 10 L and a k of 0.2 h-1.
A steady-state plasma concentration of 10 μg/mL is desired.

Assume the patient has a uremic condition and the elimination rate
constant has decreased to 0.1 h-1. To maintain the steady-state
concentration of 10 μg/mL, what rate of infusion is required?

R= Css Vd k

R = (10 mg/mL)(10)(1000 mL)(0.1 h-1)

R= 10 mg/h
A patient was given an antibiotic (t1/2 = 6 hours) by constant IV
infusion at a rate of 2 mg/h. At the end of 2 days, the serum drug
concentration was 10 mg/L. Calculate the total body clearance ClT for
this antibiotic.
A patient was given an antibiotic (t1/2 = 6 hours) by constant IV
infusion at a rate of 2 mg/h. At the end of 2 days, the serum drug
concentration was 10 mg/L. Calculate the total body clearance ClT for
this antibiotic.

Remember: Css= R/Cl

Cl= R/Css

= 2 mg/hr
10 mg/L

= 0.2L/hr = 200ml/hr