Transcript LES VOLUMES DE DISTRIBUTION

Volumes of distribution
Update: 06/10/2010
Vol Distrib- 1
Volumes of distribution
• Definition / origin
• Usefulness and clinical use
• Models
Vol Distrib- 2
Distribution vs. volume of
distribution
• Distribution
• actual distribution of the drug to the
relevant target organ and other tissues
• direct measurement (invasive / non invasive)
• Volume of distribution
• a proportionality constant (having a volume
unit) aimed to evaluate the amount of drug
in the body
Vol Distrib- 3
Volumes of distribution
Definition / Origin
Vol Distrib- 5
Volumes of distribution (VD)
Main goal to estimate a VD (1) :
• To assess the amount (A) of drug in the
body from the measurement of plasma
concentrations (cp)
!
The aim is not to evaluate the
physiological space of drug
distribution
Vol Distrib- 6
Volume of distribution
Drug concentration in beaker
Dose = 20 mg
Cp = 10 mg/L
With charcoal in beaker
Dose = 20 mg
Cp = 2 mg/L
n=10
n=2
n=2
n=10
n=8
VD = 2 L
n=8
VD = 10 L
Vol Distrib- 7
Volumes of distribution
• Digoxin : 700 L, Amiodarone 5000 L
!
Volumes of distribution are not the
actual physiological volumes
• They are only proportionality constants
between a plasma concentration and a
drug amount
Vol Distrib- 8
Volume of distribution
•
•
•
•
•
•
Ibuprofen
Gentamicin (ECF)
Antipyrine (TBW)
Diazepam
Digoxin
Azithromycin
0.15 L/kg
0.25 L/kg
0.60 L/kg
1.1 L/kg
7.3 L/kg
31 L/kg
Vol Distrib- 9
The different volumes of
distribution
Aim of the evaluation :
• To know the amount (A(t)) of drug from
plasma concentrations (Cp)
• But the Cp can be measured in
different conditions (steady state,
before equilibrium, during pseudoequilibrium)
 different VD
Vol Distrib- 10
Volumes of distribution
Measurement conditions for Cp and selection of Vd
Cp at t =0
no
yes
Cp constants (equilibrium)
no
yes
Cp pseudo-equilibrium
yes
Vc=cst
Vss=cst
Varea= Cl =cst
z
no
Vt= A(t)=variable
C(t)
Vol Distrib- 11
Two states of equilibrium
Vc
Tissue
Varea
Tissue
Plasma
0
12
Vss
Plasma
24
Pseudo-equilibrium
Steady-state equilibrium
Vol Distrib- 12
Volume of distribution
Total amount (mg)
30
Volume of distribution (L)
Tissue
Varea
20
Plasma
0
12
10
24
Hours
Vc
0
12
24
Vol Distrib- 13
The 4 volumes of distribution
Vc
Time
V(t)
variable
Varea = cst (under pseudoequilibrium conditions)
Vss = cst (under steady state
conditions)
Vol Distrib- 14
Volume of distribution
Varea > Vss > Vc
Vol Distrib- 24
Volume of distribution under
pseudo-equilibrium conditions
Varea
(or Vdb)
Vol Distrib- 25
Varea
Clearance
Varea 
Term inal_slope
Varea 
Clearance
ter m inal _ slope
Vol Distrib- 26
Varea
• Varea is the proportionality constant
relating the plasma concentrations and
the drug amount in the body when
pseudo-distribution (equilibrium) has
been achieved
• V(t) varies with time between 2 extremes
(Vc and Varea)
Vol Distrib- 27
Varea: an example (1)
• A drug is administered at a dose of 1000
µg/kg by IV route
• Varea=144 mL/kg
• Question : What is the drug amount in the
body 3 h post-administration if plasma
concentrations are 1 µg/mL(assuming that
pseudo-distribution is achieved)
Vol Distrib- 28
Varea : example (2)
Amount at 3h = 1.0 µg/mL x 144 mL/kg
144 µg/kg i.e. 14.4% of the dose
µg/mL
1.0
3h
Time
Vol Distrib- 29
Varea
• Varea is not a physiological space
• Varea does not have to be
interpreted in physiological terms
Vol Distrib- 30
Varea
• Varea depends on clearance
• Varea may change whereas the drug
distribution remains unchanged
• In case of renal failure, Varea
decreases because renal clearance
decreases
Vol Distrib- 31
Varea and half-life
t1/2 =
0.693 x Varea
Clearance
Vol Distrib- 32
Volume of distribution and
half-life
t1/2 =
0.693 * VD
Cl
Only drug in the vascular
system can be presented to
the eliminating organ for
elimination, the larger value
of VD, the lower the fraction
of the drug can be eliminated
over time (fractional
elimination rate constant) and
the longer the half-life
Vol Distrib- 33
Influence of change on
volume of distribution
• Important effect on duration of drug effect
• t1/2 is determined by VD and Cl
• Manipulation of VD is an important tool for
changing duration of action
• The higher the VD, the smaller the proportion
of the dose of drug in the circulation and the
less available for clearance
Vol Distrib- 34
Varea for extra-vascular
route
Vol Distrib- 35
Varea : extravascular route
• Actually Varea / F
• depends on bioavailability
• Illicit computation if flip-flop situation
Vol Distrib- 36
Varea in flip-flop conditions
• Given a drug administered by IV and IM
routes at a dose of 1 mg/kg
•
•
•
•
AUCIV = 10 g.h.ml-1
AUCIM = 10 g.h.ml-1
zIV = 0.693 h-1
zIM = 0.0693 h-1 (flip-flop)
= 144 ml/kg
IV = 1000 g/kg-1
10 g.h.ml x 0.693 h-1
Varea
1000 g/kg
= 1440ml/kg
IM =
10 g.h.ml-1 x 0.0693 h-1
Vol Distrib- 37
Steady state volume of
distribution
Vss
Vol Distrib- 39
Vss: background
Why Vss ?
• because under steady-state
conditions, the use of Varea would
overestimate the total amount of
drug in the body
Vol Distrib- 40
Vss : definition
Drug amount in
equilibrium conditions
• Vss =
Css
Dependent
variable
independent
variable
• Use of Vss : to calculate a loading dose
LD = Vss x Css
Vol Distrib- 44
Vss : definition
• Vss =
!
Css =
Amount in equilibrium conditions
Css
Amount at equilibrium
Vss
• is not a valid expression when conceptualizing
dependency and functionality
•! Vss does not control Css
Vol Distrib- 45
Vss and plasma concentration (Css)
• Contrary to common intuition, the most
relevant therapeutic concentration (Css)
is not controlled by Vss but is only
related to clearance
• Css =
Dose (maintenance)
Clearance x dosing interval
! • Clearance =
Dose (maintenance)
Css
which is influenced by distribution
Vol Distrib- 46
Volumes of distribution
Use of the volume of
distribution for dosage regimen
Vol Distrib- 52
The clinical use of Vc
• It is useful to predict the initial
plasma concentration
 to establish the safety or toxicity
of initial concentrations
Vol Distrib- 53
The clinical use of Vss
• Loading dose
• fluctuation of plasma concentrations
during a dosage interval
• predict the ability of dialysis to
remove drug from the body
Vol Distrib- 54
Loading dose (LD)
LD =
maintenance dose
1- e
-
0.693 t
x
z
or
LD =
maintenance dose  accumulation index
Vol Distrib- 55
Clinical use of Vss
Computation of the loading dose (LD)
target Css X Vss
LD =
F
Vol Distrib- 56
Usefulness of the volume of distribution
The loading dose
 required for few drugs
(anesthesiology)
 required for drugs with a very long
half-life and for which therapeutic
effect relies on Css
ex: digitalin (digitoxin)
Vol Distrib- 57
The use of Vss to predict maximum
and trough plasma concentrations
• Control fluctuation seen during a
dosing interval at steady state
Cmax
Cmax - Cmin =
F x Dose
Vss
Cmin
The larger this Vss, the smaller the fluctuation
Vol Distrib- 58
Clearance vs volume of distribution
Computation of dosing
Plasma clearance
Maintenance dose
• required for a majority of drugs
• many factors of variation
 dosage regimen adaptation
Volume of distribution
Loading dose
• required for few drugs
• few factors of variation
 seldom necessary to adapt LD
Vol Distrib- 59