Pharmacokinetics

• Pharmacokinetic techniques attempt to mathematically

define the time course for the drug in the body by assaying
for drug and metabolites in readilly accesible fluids such as
blood and urine.
• Concentration vs. time relationships are investigated in
relation to dosing and route of administration.
• Specific analytical methods allow to quantify drugs and
metabolites in biological samples.
• The goal is to quantitatively account for the amount of drug
which has entered the body (bioavailable dose) and to
estimate the rate by which the drug is eliminated from
the body.
 Key pharmacokinetic questions:
What is the dose-concentration relationship?
What are the concentrations after repeated drug
administrations?
What is the influence of the route of administration?

What is the influence of drug formulation?

What is the extent and importance of inter-individual
variability in pharmacokinetics and which factors have
an influence. Can we predict (account for) this variability?
 Pharmacokinetics techniques

• The mathematical descriptions use PK variables (PK

parameters) for modelling of the time-course of a drug
in the plasma or other fluids (concentration versus time
curves).
• PK parameters are than used to calculate appropriate
dosing.
Concentration is
a function of time
after dosing and
of PK-parameters V,
k which are
characteristic of the
drug and organism.
 Pharmacokinetic parameters
• apparent volume of distribution Vd
• total clearance CL
• elimination half-life t1/2
• bioavailability F
• absorption rate constant ka
 how PK parameters are obtained experimentally
 which PK processes describe
 how PK parameters are used to calculate dosing regimen
 what are the sources of inter-patient variability of PK
parameters
 Apparent Volume of Distribution (Vd)
Describes the extent of distribution of the drug in the body.
Vd is calculated assuming a uniform drug distribution
in the body at the concentration same as that in the plasma
 Apparent Volume of Distribution (Vd)
• Definition: The apparent volume
of distribution indicates into how large
a volume the drug distributes if it were
at the same concentration as that in plasma
(or in other reference fluid which is sampled
- blood, serum).
 Apparent Volume of Distribution (Vd)
• This apparent volume of distribution is not a physiological
volume.
• It won't be lower than blood or plasma volume but it can
be much larger than body volume for some drugs.
• It is a mathematical factor relating the amount of drug
in the body and the concentration of drug in the measured
compartment, usually plasma.
Vd = AMOUNT OF DRUG IN THE BODY
CONCENTRATION IN THE PLASMA
Units of Vd : volume (L, L/kg of body weight)
Estimation of Vd after i.v. dosing
C0hDose
L. = Dose / DistributionVolume At later times after
Vd = Dose / C0h administration:
Amount in the body =
Dose - Amount eliminated

Loading dose = CP x VD
 Use of Vd :
1/ Initiating treatment: Vd in conjunction with
a target concentration CTherapeutic can be used to
compute a loading dose DL:
DL = VD . CTherapeutic

The loading dose is the first higher dose which rapidly fills
the distribution volume with the drug.
Therapeutic concentrations are achieved quickly.
This is important in acute conditions (status epilepticus,
status asthmaticus, bacteraemia) and if the drug has a long
t1/2 (digoxin, amiodarone).
 Loading dose 500 mg + maintenance dosing (150 mg every 8 h)

Conc
.

maintenance dosing (150 mg every 8 h)

8h 16h 24h 32h 40h Time

 Use of Vd:
EXAMPLE:
J.K. (body weight = 90 kg) was admitted to the ICU for
pneumonia caused by Gram-negative bacteria. Calculate
the loading dose of tobramycin for this patient to achieve
the target concentration of 4 mg/l.
Tobramycin VD is 0.2 L/kg of body weight.

Loading Dose = ?
Loading Dose = 0.2 L/kg . Body weight (kg) . Concentration
Loading Dose = 0.2 . 90 . 4 = 72 mg
 Use of Vd :
2/ Evaluation of the drug distribution pattern
(total body water, only plasma plus extracellular
water, only plasma, high binding in tissues)
Vd 0.05 L/kg the drug remains in the blood (heparine)
Vd 0.1-0.3 L/kg distribution from blood into extracellular
fluid (gentamicin - polar drugs).
Vd 0.6 L/kg distribution from blood into intracelular and
extracellular fluid (methotrexate)
Vd >>0.6 L/kg distribution intracellularly and high binding
in tissues (amiodarone - 350 L/kg)
 Use of Vd:
3/ To assess feasibility of using hemoperfusion
or dialysis for drug removal from the body:
The larger the Vd , the smaller fraction of the dose
is in the plasma, the less is plasma concentration
of the drug and the less efficient is any drug
removal through extracorporeal mechanisms
(hemodialysis and hemofiltration).
Age related interindividual variability of Vd

• Vd per unit of body weight (L/kg) for water-

soluble drugs is higher in neonates compared to
adults
– 5 mg/kg gentamicin: Cmax = 16-20 mg/L in adults
Cmax = 10-11 mg/L in neonates
• Vd per unit of body weight (L/kg) for lipid-soluble
drugs is higher in the elderly (diazepam)
 The effect of obesity on Vd
• Water-soluble drugs have a limited distribution into fat and
their Vd is better correlated with the ideal body weight than
with total body weight (Vd is less than it would by predicted
using the total body weight).
– Aminoglycosides are hydrophilic antibiotics commonly used
to treat Gram-negative onfections. The need for dosing adjustment
in obesity has been established in gentamicin, tobramycin, and
amikacin.
– Aminoglycosides distribute primarily into the intravascular space
and moderately into the interstitial space. Therefore,
aminoglycosides typically display only a slightly larger volume
of distribution (in liters) in obese patients than in lean patients.
 Drug elimination :
Biotransformation + Excretion

Drug elimination refers to the irreversible removal

of the drug from the body by all routes of elimination.

Clearance quantitatively describes the process of drug

elimination from the body or an organ regardless of the
mechanism.
 Clearance (CL)
Definition : Clearance of a drug is the ratio of the rate
of elimination to the concentration of drug in plasma.

CL = Rate of eliminination [mg / h ]

C of drug in plasma [mg /L ]

Unit: Volume/Time [L/h] or adjusted for body weight

[l/h/kg]
 Clearance (CL)

Rate of eliminination = CL x C
(Amount / Unit of time) = (Volume / Unit of time) x C

Another possible way of understanding clearance:

Clearance is the volume of plasma completly cleared
of the drug per unit of time by all routes - by the liver,
the kidney…).
 Clearance (CL)
The higher is CL, the faster is the decrease
of the concentration, the shorter is the half-life.

Vd

High clearance Low clearance

Concentration

Time
 Clearance (CL)
The higher is Vd, the slower is the decrease of the
concentration, the longer is the half-life.

Vd
Vd High Vd
Low Vd

Concentration

Time
 Clearance (CL)
Clearance has an additive character: It is the sum
of clearences in all eliminating organs.

CL = CLRENAL + CLHEPATIC +CLpulmonary ...other

renal + nonrenal
 How is the clearance obtained experimentally?

CL= Dose /AUC

(i.v. admin.)
CL= F× Dose /AUC
(perenteral adm.)
AUC = Area under the
curve

The AUC is estimated as a sum of trapezoids

 The principle of linear
pharmacokinetics
Linear (first-order) pharmacokinetics:
For most drugs, clearance is constant over the plasma
concentration range used in clinical practice.
Elimination is not saturable (non-capacity-limited)
and the rate of drug elimination is directly
proporcionate to its concentration:

Rate of elimin. = CL × Concentration

 The principle of linear
pharmacokinetics
Rate of elimin. = CL × Concentration

After repeated dosing, at equilibrium

(at the steady-state):

Rate of dosing = Rate of elimin. = CL × Concentration

(2 × Rate of dosing) = CL × (2 × Concentration)
 Nonlinear pharmacokinetics
Nonlinear pharmacokinetics: (capacity-limited,
dose or concentration dependent, saturable)
CL varies depending on the concentration of a drug.
Rate of elimination = Vmax . C /Michaelis- Menten/
Km + C
CL = Vmax
Km + C

ethanol, phenytoin, theofylline

Nonlinear pharmacokinetics

Linear kinetics

Nonlinear kinetics
 The importance of Clearance
Total clearance determines the average steady-state
concentration of a drug during continuous drug
administration (multiple intermittent dosing or
constant rate i.v. infusion):
at the steady-state:
Rate of dosing = Rate of elimination = CL . Css
Continuous i.v. infusion: Css = Rate of infusion/ CL
 Repeated oral dosing (continuous intermittent
dosing)
Conc
Caverage,ss

Oral dosing

t
Time

Caverage,ss = (F. Dose/t) / CL

 Use of clearance:
1/ Total clearance, when multiplied by a target steady-state
concentration, can be used to calculate the dosing rate
required to maintain plasma CSS,Therapeutic i.e. the maintenance
dose.
Maintenance dose restores the amount of the drug which has
been eliminated per unit of time (i.v. infusion) or between
doses (intermittent dosing).
Rate of dosing = CSS,TARGET . CL
Rate of dosing ….. Rate of i.v. infusion (mg/h)
……(F . Oral dose) / Dosing interval
…… i.v. dose / Dosing interval
 Calculation of the maintenance dose
J.K.was admitted to the ICU for pneumonia caused by
Gram-negative bacteria. Calculate the maintenance dose
(i.v.-infusion in 6 h intervals) of tobramycin for this patient
to achive the target average concentration of 4 mg/l.
Clearance of tobramycin was estimated to be 70 ml/min.

Rate of dosing = Dose / Interval

Rate of dosing = Rate of elimination = CL.cT
Rate of dosing = 4.70.60 / 1000 = 16.8 mg/h
Dose = Rate of dosing . Interval = 6 . 16.8 = 101 mg
 Use of clearance:
2/ The numerical value of total clearance and its two
principal components (hepatic and renal clearances)
provide important insights into the elimination processes
and into the potential needs for dosage adjustments in
case of liver or kidney impairment.
 Organ clearance: Hepatic clearance CLh
Q… hepatic blood flow per 1 min: 1.5 L/min,

Q . Cin LIVER Q . Cout

bile
Amount excreted in bile = Amount extracted= Q.(Cin- Cout)
CLh = rate of elimin. / Cin = Q . (Cin- Cout) / Cin
CLh= Q × E hepatic extraction ratio
 Hepatic extraction ratio (E)

E = (Cin- Cout) / Cin

A/ High extraction: Cout  0, E  1 (>0.7)

After oral administration, drug is efficiently extracted by the

liver and less is available in the systemic circulation - high
first-pass effect.
The elimination of the drug from the systemic circulation is
flow limited: Clearance = Q × E = Q.
 Hepatic extraction ratio (E)

E = (Cin- Cout) / Cin

B/ Low extraction: Cout  Cin , E  0 (<0.3)

Small first-pass, high systemic availability after oral

administration, hepatic clearance is sensitive to change in E
(inhibition and induction of metabolism).
 Organ clearance: Renal clearance CLR

Renal clearance = rate of elimination of the drug per unit

of its concentration in the plasma entering the kidneys.

Renal drug clearance is correlated with kidney function:

endogenous creatinine clearance or serum creatinine
concentration.
 Renal clearance CLR
GFR , C in plasma
KIDNEY GFR 100 -150
ml/min

URINE
VU , CU

VU = volume collected / urine collection period

Amount excreted = VU × CU
CLR = rate of elim. / C in plasma = VU × CU/ C in plasma
 Factors affecting clearance

• Clearance and, therefore, maintenance dose

requirements can be affected by a range of factors,
including age, renal disease, hepatic disease,
genetic factors and drug interactions (inhibition
or induction of the activity of drug-metabolizing
enzymes)
 Elimination half-life (t1/2)
Definition: Elimination half-life is the time it takes
the drug concentration in the blood to decline to one
half of its initial value.

It is a secondary parameter :
The elimination half-life is dependent on the ratio
of two primary parameters Vd and CL:

t1/2 = 0.7 × Vd / CL

Unit : time (min, h, day)

 How is t1/2 obtained experimentally?
Semi-log graph of Log concentration vs time

t 1/2 = 0.7 / kel

kel can be estimated
as the slope of the
Log (concentration)
vs. Time
relationship by
means of the linear-
regression analysis
 Use of t1/2: stopping treatment
t1/2 can be used to predict how long it will take
for the drug to be eliminated from the plasma (five
half-lives)
1. 2. 3. 4. 5.
10
50 75 87.5 94 97
Conc. (mg/L)

7.5 5 percent eliminated %

5 t1/2 = 2 hours
2.5
2.5 1.25
0.625
0
0 2 4 6 8 10
time (h)
 Conversely, t1/2 descibes the kinetics
of approaching the steady state
t1/2 can be used to predict how long it will take from
the start of dosing to reach steady-state levels during
multiple dosing or continuous i.v. infusion.

No. of t1/2 Concentration achieved

(% of steady conc.)
1 50
2 75
3 87.5
4 94
5 97
 Multiple i.v. bolus dose administration :
the drug accumulates in the plasma until the steady state is
achieved after 5 t1/2
 Important!
During continuous (infusion) or continuous
intermittent dosing (oral dosing):
The steady-concentration depends on the rate
of dosing (the dose/dosing interval) and the clearance.
Time required to achieve steady-state depends on the
half-life and is independent of the rate of dosing and
the clearance.
 Use of t1/2:
The relationship between t1/2 and dosing interval t can
be used:

1/ to predict the degree of accumulation of a drug in the

blood. The longer t1/2 and the shorter t, the more drug
accumulates.

2/ to predict the degree of fluctuation of a drug

concentration within a dosing interval. The longer t1/2
and the shorter t, the less the concentration fluctuates
(changes) between succesive doses at the stady-state.
 t1/2 6 h

The relationship between t 24 h

t1/2 and dosing interval t

determines accumulation of
t1/2 24 h Css,max
the drug in the blood (diference
between the concentration at
the steady state vs that after Css,min
the first dose) and fluctuation
(difference between Cmax and
Cmin at the steady-state). t1/2 96 h (4 dny)
 Use of t1/2:
t1/2 can be used to predict how long it will take a drug
concentration to decline from one specific value to
another.

t = t1/2 × ln(C1/C2) / 0.7

It can be usefull in overdoses and dosage adjustments.

 Pharmacokinetics after extravascular
administration: bioavailability
Most of the routes of administration are extravascular;
for example i.m., s.c., and most importantly oral.
With this type of drug administration the drug isn't
placed in the systemic circulation but must be absorbed
through at least one membrane.
This has a considerable effect on drug pharmacokinetics
and may cause a reduction in the actual amount of drug
which is absorbed and reaches the systemic circulation.
 Pharmacokinetics after extravascular
administration: bioavailability F
Bioavailability indicates a measurement of the rate and
extent (amount) to which the therapeutically active drug
reaches the general circulation.

Absolute bioavailability (0 < F < 1) descibes the fraction

of the dose which reaches systemic circulation:

Bioavailable dose = F × Dose, after i.v. administration F = 1.

Absolute bioavailability (F)
F determines
the AUC and
maximum
concentration but
not the time when
the Cmax is reached
(Tmax)
 Bioavailability
Absolute bioavailability F is the absolute fraction of
dose which is available from a drug formulation in
general circulation. It is measured by comparing AUC
after i.v. and extravascular administration.

CL = Dose / AUCi.v. = (F × Dose) /AUCoral

F = AUCoral / AUCi.v.
 Bioavailability

Conc. AUCiv

AUCpo

Time
 Relative bioavailability
Relative bioavailability is a relative amount of the dose
if two formulations (other than i.v., most frequently
oral) are compared.
 Bioequivalence
Bioequivalence study: new drug formulation (a generic
copy) of a known active drug is compared to the
reference (original formulation or another marketed
formulation) in a study with healthy volunteers.
Two drug formulations are bioequivalent if the extent and
rate of bioavailability of a drug is comparable (within
certain limits). Not only the AUC (the extent of bio-
availability) but Cmax and Tmax (the rate of bioavailability
must be similar).
The effect of changing ka (absorption rate constant)
F and Dose are constant

If ka decreases,
the Cmax decreases
and Tmax shifts
towards later
times.
Pharmacokinetic modelling: Compartmental models
One-compartment model
The organism is replaced by several
Dose DX
compartments (boxes with uniform
drug concentration which changes
with time).
X,Vd
The boxes have its volume
ke Vd.Transfer of the drug to, between,
EX and out of compartments is described
by rate constants. For simple models,
C(t) = C0 . e- ke . t concentration of the drug can be
expressed as a function of time and
C =D/V parameters of the model.
0 d
Pharmacokinetic modelling: Compartmental
models
Dose DX Two-compartment model

k12
V1 V2
k21
ke
EX
 Fitting of parameters of the model to the
assayed concentrations of the drug
by nonlinear regression (PC)
50
45
40
35
Conc. (mg/l)

30
25
20
15
10
5
0
0 2 4 6 8 10
Time (h)