PK-glossary PK Working Group 2004 PDF

Glossary
Page 1 of 24
Collection of terms, symbols, equations, and

explanations of common pharmacokinetic and
pharmacodynamic parameters and some
statistical functions
Version: 16 Februar 2004

Authors: AGAH working group PHARMACOKINETICS
...\PK-glossary_PK_working_group_2004.pdf
Glossary
Page 2 of 24
Collection of terms, symbols, equations, and explanations of common

pharmacokinetic and pharmacodynamic parameters and some
statistical functions
TABLE OF CONTENTS
Page
TABLE OF CONTENTS .................................................................................................................2

1
Pharmacokinetic Parameters from noncompartmental analysis (NCA) ...............................3

1.1 Parameters obtained from concentrations in plasma or serum...........................................3
1.1.1 Parameters after single dosing..................................................................................3
1.1.2 Parameters after multiple dosing (at steady state)....................................................6
1.2 Parameters obtained from urine ..........................................................................................7
Pharmacokinetic parameters obtained from compartmental modeling................................8

2.1 Calculation of concentration-time curves.............................................................................9
2.2 Pharmacokinetic Equations - Collection of Equations for Compartmental Analysis .........10
Pharmacodynamic GLOSSARY ................................................................................................20

3.1 Definitions ..........................................................................................................................20
3.2 Equations: PK/PD Models..................................................................................................21
Statistical parameters................................................................................................................22
4.1 Definitions ..........................................................................................................................22
4.2 Characterisation of log-normally distributed data ..............................................................23
AGAH Working group PK/PD modelling
Page 3 of 24
PHARMACOKINETIC PARAMETERS FROM NONCOMPARTMENTAL

ANALYSIS (NCA)
1.1
Parameters obtained from concentrations in plasma or serum
1.1.1
Parameters after single dosing
Symbol
Unit /
Dimensio
n/
Definition
Calculation
Dimension
AUC
AUC(0-)
Amounttime/ Area under the concentration-time

volume
curve from zero up to with
extrapolation of the terminal phase
Cz
AUC=AUC (0 - t z ) +
, Cz may be
measured (Cz,obs) or calculated (Cz,calc)

AUC(0-t),
AUCt

According to the linear trapezoidal rule:
volume
curve from zero up to a definite time t
n- 1
AUC (0 - t) = AUC (t i -t i +1 )
wit
i= 1
h t1=0 and tn=t,

Concentrations Ci measured at times
ti, i=1,,n.
AUC (t i
t i +1 )
= 12 (C i + C i+1 ) (t i+1 t i )
or according to the log-linear trapezoidal rule:
AUC(t i
t i +1 )
(C i C i +1 ) (t i +1 t i )
(ln C i ln C i +1 )
(the logarithmic trapezoidal rule is used for the

descending part of the concentration-time curve, i.e. if
Ci>1.001*Ci+1>0)
AUC(0-tz)
AUCextrap %
AUMC
AUMC(0-t)

volume
curve from zero up to the last
%
Amount
2
(time) /
volume
Amount
2
(time) /
volume
concentration LOQ (Cz)

Area under the concentration-time
curve extrapolated from tz to in %
of the total AUC
Area under the first moment of the
concentration-time curve from zero
up to with extrapolation of the
terminal phase
concentration-time curve from zero
up to a definite time t
n- 1
AUMC(0 - t) = AUMC(t i -t i +1 )
i= 1
with t1=0 and tn=t. Concentrations Ci

measured at times ti, i=1,,n.
See AUC(0-t)
AUC extrap % =
AUC-AUC (0-t z )
100
AUC
AUMC = AUMC (0 -
tz )
t z Cz
Cz
2
Cz may be measured (Cz,obs) or calculated (Cz,calc)
AUMC (t i
=
1
6
t i +1 )
(t i+1 t i )(t i +1 (C i + 2C i+1 ) + t i (2C i + C i +1 ))
(linear trapezoidal rule)
C i t i C i +1t i +1 C i C i +1
ln C i ln C i +1
+
with B =
B
t i +1 t i
B2
(log-linear trapezoidal rule)
AUMC(0-tz)
AUMCextrap %
Amount
2
(time) /
volume
%
See AUMC(0-t)
concentration-time curve from zero to
the last quantifiable concentration
AUMC-AUMC
concentration-time curve
AUMC extrap % =
AUMC
extrapolated from tz to in % of the
total AUMC
(0-t z )
100
Symbol
Unit /
Dimension
Page 4 of 24
Definition
Cp or C
Amount/ volume Plasma concentration
Cs or C
Amount/ volume Serum concentration
Cu
Amount/ volume Unbound plasma concentration
CL
Volume/ time or Total plasma, serum or blood

volume/ time/ kg clearance of drug after intravenous
CL / f
Volume/ time or Apparent total plasma or serum

volume/ time/ kg clearance of drug after oral
Calculation
CL =
administration
CLint
CL / f =
administration
Volume/ time or Intrinsic clearance maximum
volume/ time/ kg elimination capacity of the liver
CLH,b
Volume/ time or Hepatic blood clearance, product of

volume/ time/ kg hepatic blood flow and extraction
CLCR
Volume/ time or Creatinine clearance

volume/ time/ kg
D iv
AUC
D po
AUC
CLH = QHEH
ratio
CLm
Volume/ time
Metabolic clearance
Cz, calc
Amount/ volume Predicted last plasma or serum
Cz or Cz, obs
Amount/ volume Last analytically quantifiable plasma
Cmax
D
f
concentration
or serum concentration above LOQ
Amount/ volume Observed maximum plasma or
serum concentration after
administration
Dose administered
Amount
Fraction of the administered dose
systemically available
Measured or Cockcroft & Gault formula
Calculated from a log-linear regression through

the terminal part of the curve
directly taken from analytical data
f =
AUC po D iv
AUC iv D po
Absolute bioavailability, systemic

availability in %
Fraction of the administered dose in
comparison to a standard (not iv)
F = f 100
Relative bioavailability in %
Frel = frel 100
fa
For orally administered drugs: f = fa*(1-EH)
fm
fu
Fraction of the extravascularly

administered dose actually absorbed
Fraction of the bioavailable dose
which is metabolized
Fraction of unbound (not proteinbound or free) drug in plasma or
serum
Half-value duration (time interval
during which concentrations exceed
50% of Cmax)
Terminal rate constant (slowest rate
constant of the disposition)
frel
Frel
HVD
Time
-1
(Time)
ke or kel
(Time)
LOQ
-1
Elimination rate constant from the

central compartment
Amount/ volume Lower limit of quantification
f rel =
AUC DSTD
AUCSTD D
STD = Standard
fu = Cu /C
negative of the slope of a ln-linear regression

of the unweighted data considering the last
concentration-time points LOQ
calculated from parameters of the
multiexponential fit
Symbol
MAT
Unit /
Dimension
Time
Page 5 of 24
Definition
Mean absorption time
Calculation
MAT = MRTev - MRTiv
(ev = extravasal, e.g. im, sc, po)
MDT
Time
Mean dissolution time
MRT
Time
Mean residence time (of the

AUMC
MRT =
unchanged drug in the systemic
AUC
circulation)
Metabolic ratio of parent drug AUC and
AUC parent
MR =
metabolite AUC
AUC metabolite
MR
t1/2
Time
Terminal half-life
tlag
Time
tz
Time
tmax
Time
Lag-time (time delay between drug

administration and first observed
concentration above LOQ in plasma)
Time p.a. of last analytically
quantifiable concentration
Time to reach Cmax
Vss
Vz
Apparent volume of distribution at

Volume
or volume/kg equilibrium determined after
intravenous administration
Volume
or volume/kg
Vss / f
Volume
or volume/kg
Vz / f
Volume
or volume/kg
t 1/ 2
ln 2
z

Vss = CL MRT =
D AUMC
(AUC) 2
Volume of distribution during terminal

phase after intravenous administration
Vz=
Apparent volume of distribution at

equilibrium after oral administration
Vss /f = CL MRT =
Apparent volume of distribution during

terminal phase after oral /
extravascular administration
Vz /f =
Div
AUC z
D AUMC
(AUC) 2
D po
AUC z
po instead of iv !
1.1.2
Parameters after multiple dosing (at steady state)
Symbol
Aave
AUC,ss
Unit /
Dimension
Amount
Average amount in the body at

steady state
Calculation
A ave =
f DM
z
by trapezoidal rule
steady state
%
Cav,ss
Amount
/volume
Cmax,ss
Amount
/volume
Cmin,ss
Amount
/volume
Ctrough
Amount
/volume
DM
Amount
LF
PTF %
Definition

volume
curve during a dosing interval at
AUCss
AUCF%
Page 6 of 24
Percent fluctuation of the

concentrations determined from areas AUCF% = 100 AUC(above C ave ) + AUC(below C ave )
AUC
under the curve
Average plasma or serum
AUC , ss
C av,ss =
concentration at steady state
Maximum observed plasma or serum directly taken from analytical data

concentration during a dosing interval
at steady state
Minimum observed plasma or serum directly taken from analytical data
concentration during a dosing interval
at steady state
Measured concentration at the end of directly taken from analytical data
a dosing interval at steady state (taken
directly before next administration)
Maintenance dose
design parameter
Linearity factor of pharmacokinetics
after repeated administration
Peak trough fluctuation over one
dosing interval at steady state
Accumulation ratio calculated from
AUC,ss at steady state and AUC
after single dosing
Cmax,ss at steady state and Cmax after
single dosing
Cmin,ss at steady state and from
concentration at t= after single dose
RA (AUC)
RA (Cmax)
RA (Cmin)
Theoretical accumulation ratio
Rtheor
TCave
Time
tmax,ss
Time
Time
Time period during which plasma

concentrations are above Cav,ss
Time to reach the observed
maximum (peak) concentration at
steady state
Dosing interval
LF =
AUC , ss
sd = single dose
AUC sd
PTF % = 100
RA
(AUC)
RA
(Cmax) =
RA
C ss,av
AUC ,ss
AUC ,sd
C max,ss
C max,sd
(Cmin) =
R theor
C ss,max - C ss,min
1
1- 2 -
C min, ss
C ,sd
=
1
1 e z
sd = single dose
sd = single dose
, =
t1 / 2
derived from analytical data by linear interpolation

directly taken from study design
1.2
Page 7 of 24
Parameters obtained from urine
Unit /
Dimension
Definition
Ae(t1-t2)
Amount
Amount of unchanged drug excreted

into urine within time span from t1 to t2.
Cur * Vur
Ae(0-
Amount
Cumulative amount (of unchanged

drug) excreted into urine up to infinity
after single dosing
(can commonly not be determined)
Amount
Amount (of unchanged drug) excreted

into the urine during a dosing interval
() at steady state
Amount/
Drug concentration in urine
Symbol
Ae,ss
Aess
Cur
Calculation
volume
CLR
Volume/ time Renal clearance

or volume/
time/ amount
CLR =
Ae(0 )
Ae(0 )
AUC
AUC (0 )
after multiple dose CLR =

fe
Fraction of intravenous administered

drug that is excreted unchanged in
urine
fe =
fe/f
Fraction of orally administered drug

excreted into urine
fe / f =
Fe
Total urinary recovery after intravenous

administration = fraction of drug
excreted into urine in %
tmid
Time
Vur
Volume
Ae(0 )
AUC , ss
Ae
Div
Ae
Dpo
Fe = fe 100
Mid time point of a collection interval

Volume of urine excreted
directly taken from measured lab data
Page 8 of 24
PHARMACOKINETIC PARAMETERS OBTAINED FROM COMPARTMENTAL

MODELING
Symbol
A,B,C or
Ci, i=1,...,n
Unit /
Dimensions
Amount/ volume Coefficients of the polyexponential
Calculation
by multiexponential fitting
equation
-1
Exponents of the polyexponential

equation (slope factor)
-1
Exponent of the i (descending)

exponential term of a polyexponential
equation
, ,
(Time)
(Time)
AUC
Definition
th
Amounttime/
volume
Area under the curve (model)
n
C
AUC = i
i=1 i
extravascular :
iv :
n
ka
AUC = Ci
k a i
i=1
1 1

i k a
Note: Ci is the linear coefficient of the

polyexponential equation
AUMC
Amount(time) / Area under the first moment curve

volume
n
C
AUMC = 2i
i =1 i
extravascular :
iv :
n
ka
AUMC = Ci
k
i =1
a i
1 1
2 2
i k a

C(0)
Amount/ volume Initial or back-extrapolated drug
concentration following rapid

intravenous injection
C (0) =
Ci
i =1

C(t)
CL
fi
Amount/ volume Drug concentration at time point t

Volume/ time
Fractional area, area under the various

phases of disposition (i) in the plasma
concentration-time curve after iv
dosing
f Dose
AUC
iv: f=1
Ci
fi =
i
AUC
with
f
i =1
=1
-1
Zero order rate constant
Design parameter or determined by

multiexponential fitting
-1
Elimination rate constant from the

central compartment
calculated from parameters of the

multiexponential fit
-1
Absorption rate constant
k0
(Time)
ke or kel
(Time)
ka or kabs
(Time)
Km
CL =
Number of compartments in a multicompartmental model
kij
Clearance
See 2.2
Transfer rate between compartment i

and j in a multi-compartmental model
Amount/ volume Michaelis Menten constant
-1
(Time)
by nonlinear fitting
Symbol
MRT
Unit /
Dimensions
Time
Page 9 of 24
Definition
Calculation
Mean residence time
iv: MRT =
AUMC
AUC
extravascular: MRT =
Qi
Amount/Time
Intercompartmental clearance between

central compartment and compartment
i
k0
Amount/Time
Zero order infusion rate
design parameter
th
t 1/ 2, i
Time
Half-life associated with the i

ln2
exponent of a polyexponential equation t1/ 2, i =
i
Time
Infusion duration
Time
Time after drug administration
Vc
Volume or
Apparent volume of the central or
Volume /amount plasma or serum compartment
design parameter
Vc =
f Dose
n
C
i=1
iv: f=1
Vmax
Amount/Time
Maximum metabolic rate
AUMC
1
(tlag + )
AUC
ka
2.1
Page 10 of 24
Calculation of concentration-time curves

Application
iv bolus
Parameter
concentration after bolus administration
Calculation
n
Cp ( t ) = B i e t
i
i=1
short-term iv
infusion
concentration during infusion
B
Cp ( t < T ) = i (1 e t )
i=1 i
peak level
B
Cmax = i (1 e T )
i =1
i
i
concentration after infusion
C p (t ) =
k0
Vc
Bi i t * i t
e 1 e
i =1
n
with t*=min(t,T)
continuous iv
infusion
concentration at steady state
extravascular
C ss =
Ro
CL
ka
(e tl e k tl )
Cp ( t ) = B i
k a i
i=1
tl = t tlag
2.2
Page 11 of 24
Pharmacokinetic Equations - Collection of Equations for Compartmental Analysis
One Compartment Model, IV bolus, single dose, one elimination pathway only
(assumed to be urinary excretion)
D X e U
U - drug amount in urine
dX
= k e X (t )
dt
ke= elimination rate constant

X = drug amount in the body
U =drug amount in the urine
i .v .
dU
= k e X (t )
dt
D = X ( 0) = X (t ) + U (t ) = U ( )
X (t ) = X (0) e k te
D = dose administered
X(t) = amount in plasma at time t after
administration
U(t) = amount in urine at time t
C p (t ) =
Vc =
X (t )
; C p (t ) = C p (0) e k e t
Vc
X (0)
D
=
C p (0) C p (0)
C p (t ) =
D ke t
e
Vd
t1 / 2 =
ln( 2)
ke
Cp= Conc. in plasma after single dose

ke= negative slope of concentration-time
plot in ln-linear scaling
Cp (0)= intercept with y axis
Cp(t) - plasma conc at any time
Urinary excretion
U (t ) = U ( )(1 e ket ) ;
ln(U ( ) U (t )) = ln U ( ) k e t
Sigma-Minus Plot (page 21)

Calc. of ke from urine data based on lnlinear plot of (U () U (t )) versus t, ke is
the negative slope, but you need total
amount U() of drug excreted into urine,
which frequently is not identical to the
dose administered, in contrast to the
assumptions of the model
dU
= k e X ( 0 ) e k e t ;
dt
Other method based on urinary excretion

rate (total amount of drug need not be
known) U/t -sampling intervals
tmid - mean time point of the sampling
interval
ln
U
= ln(k e X (0)) k e t mid
t
dU
CLR = dt
C p (t )
; CLR = k e Vc
U
= CLR Cp (t mid )
t
U t = CL R AUC ( 0 t )
Cp (0)
(1 e ket t )
AUC(0 t ) =
ke
Urinary excretion rate -described by renal

clearance CLR
Cp(tmid) = conc. in plasma at the mean
time point of the urine collection interval,
measured or derived by log-linear
interpolation
CLR = slope of a plot U/t versus
Cp(tmid)
Page 12 of 24
One Compartment Model, IV Inj. and Parallel Elimination Pathways (renal, biliary,
metabolic), single dose
k e = k ren + k bil + k met
kren = rate constant of renal

elimination
kbil = rate constant of biliary
elimination
kmet = rate constant of metabolic
elimination
dX
dU
dB
= k e X (t ) ;
= k ren X (t ) ;
= k bil X (t ) ;
dt
dt
dt
X = amount in plasma
U = amount in urine
B = amount in bile
M = amount of metabolites in
plasma
dM
= k met X (t )
dt
D = X ( 0 ) = X ( t ) + U ( t ) + B( t ) + M ( t ) = U ( ) + B ( ) + M ( )
Plasma concentration
C p (t ) = C p ( 0) e k e t
Drug amount in urine
k ren
D (1 e ket )
ke
U (t ) =
Up to infinite time (t = )
k ren
U ( ) k ren
D ;
=
;
ke
D
ke
ln(U () U (t )) = ln U () ke t
U ( ) =
ke - slope can calc.from the

Sigma Minus Plot (U()-U(t) vs t
fb fraction of bound drug
CLR = k ren Vc
CLR
u
; CLR =
(1 f b )
B( t ) =
k bil
D (1 e ket )
ke
M (t ) =
k met
D (1 e ket ) ; CLmet = k met Vc
ke
dM p
dt
; CLbil
= k bil Vc
= k met X (t ) k eM M p (t )
C M (t ) =
CLtot =
M
k met D
(e k e t e k e t )
M
V (k e k e )
M
c
Biliary excretion can be calc. In

analogous fashion assuming no
reabsorption
Total amounts of metabolites
including further excretion of
M
metabolite into urine ( k e ).

M
C (t) = concentration of the

metabolite in the central
circulation
D
= k e Vc ; CLtot = CLR + CLbil + CLmet
AUC
D : U() : B() : M() = ke : kren : kbil : kmet = CLtot : CLR: CLbil: CLmet
after the end of all elimination

into the different compartments
Page 13 of 24
One Compartment, multiple IV injection (i intervals )

Cn- concentration after nth administration
every hours
(1 e nk )
D
Cn (t ) = e ket
k
Vc
(1 e )
C ss (t) = C 0
e k e t
(1 e
C ss ,max = C0 R =
Fluc. =
Css ,max
Css ,min
= Peak
D
1
Vc 1 e ke
C ss ,min = C0 R e ke =
% Fluctuation =
During steady-state conditions (n=),

C0=concentration immediately after initial
(first) injection = D/Vc
1
R =
1 e k e
= C0 R e k e t
D e ke
= C ss ,max e ke
Vc 1 e ket
C ss ,max C ss ,min
Css ,max
= Trough
Fluctuation depends on the relation

between ke (or t1/2) and , not on the dose
100
= e ke
C
ln ss ,max
C ss ,min
=
ke
ss
AUC
C ss,max =
Useful for calculation of the maintenance

dose
C ss -average ss conc., weighted mean,
value between Cmax and Cmin ;
includes no inform. about fluctuations in
plasma levels + no inform. about
magnitude of Cmax or Cmin
D
CL
DM
D
1
= L ;
k e
Vc 1 e
Vc
DL =
DM
1 e k e
DL = loading dose required to immediately

achieve the same maximum concentration
as at steady state with a maintenance
dose
DM every hours
Page 14 of 24
One Compartment Model, IV Infusion, Zero Order Kinetics

k0
ke
D
X
E
k0- constant infusion rate
dX
= k 0 k e X (t )
dt
C ss =
during constant rate infusion
k0
(1 e ket )
k e Vd
C (t ) =
ss - t = , infusion equilibrium, like ss
k0
k
= 0
k e Vd CLtot
R0 =Css.CL ; Cltot =ke Vc ;

R 0T
D
=
CL tot =
AUC ( 0 T )
AUC
Plasma concentr. at SS , CL at SS
proportional to Css at SS
C ss =
R0
CL
C (t ) =
R0
(1 e ket )
CL
C max =
; C(t ) = C ss (1 e
ket
for example: time to reach 90% SS ?
(ln 0.1)
C (t )
= 0.90 = (1 e k e t ) ; t =
ke
Css
Cmax -occurs at the end of infusion,
setting t= (total time of infusion)
R0
(1 e k eT )
k e Vd
After End of Infusion:

Plasma level after end of infusion with
C(t ) = C max e k e ( t T )
t = time after start of the infusion
Short term Infusion:

k
LD = C ss Vc = 0
ke
Loading dose
Incrementa l LD = Vc (C desired C initial )

Plasma level depends on infusion duration
() and t1/2:
C (t )
100 = (1 e ke ) 100
Css
C
1 < t1/2 < : C (t1 / 2 ) = ss
2
One Compartment Model, Short Term Infusion, Zero Order, multiple dose
C n (t ) = C n 1 ( ) e ket +
C n ( ) =
Cn(t) = concentration after nth infusion in

intervals of
k0
(1 e ket )
k e Vd
1 e nke
ke ( T )
k0
(e
e ke )
1 e ke
k e Vd
n = number of doses
Page 15 of 24
One Compartment Model, Oral Administration With Resorption First Order, single dose
D A a X e E
k
dA
= k a A
dt
dX
dE
= ka A ke X ;
= ke X
dt
dt
f D = A(t) + X(t) + E(t)= E()

C (t ) =
In most cases: k a > k e , this means that
f D ka
(e k e t )
Vd ( k a k e )
ln Cterm (t ) =
e ka t approches zero much faster

k t
than e e - calc. of ke from slope of
terminal phase
k a < k e - Flip-Flop, but you need an
additional iv administration to distinguish
this case
f D ka
k e t ; C(t)->Cterm(t) for t->
Vd ( k a k e )
Cterm (t ) C (t ) =
f D ka
e k at
Vc (ka ke )
ln(Cterm (t ) C (t )) =
t max
BATEMAN-Function
f D ka
(e k e t e k a t )
Vd ( k a k e )
Cterm (t ) =
C (t ) =
F = fraction of dose available for

absorption
A(t ) = f D e kat
ka - feathering-method (can reasonably be

used only if there are at least 4 data points
in the increasing part of the concentrationtime curve)
f D ka
kat
Vd ( k a k e )
substraction of C from C (semilog. (C-C)

versus t - slope -ka)
with t0 - lag time
f D ka
(e k e ( t t 0 ) e k a ( t t 0 ) )
Vd ( k a k e )
k
ln a
ke
ln(k a ) ln(k e )
= =
ka ke
k a ke
C max =
A = unabsorbed drug available at

resorption place
E = sum of the excreted amount of drug
ka = absorp. rate constant
tmax does not depend on the bioavailability f

and, since ke commonly is substancedependent and not preparation-dependent,
reflects ka
f D k a ket max
e
Vd
One Compartment Model, Oral Administration With Resorption First Order, multiple
dose
C n (t ) =
Cn(t) = concentration after the nth consecutive

dosing in intervals ; BATEMAN-Function
expanded by accumulation factor
f D ka
(re e ket ra e k a t )
Vd ( k a k e )
e k et
f D ka
e k at
C ss (t ) =
k e
Vd ( k a k e ) 1 e
1 e k a
t ss ,max =
k (1 e k e )
1
ln a
k a
ka ke
)
k e (1 e
re =
1 e nke
ra =
1 e nk a
; n = for steady
1 e k a
1 e ke
state, in most cases ra 1
tss,max < tmax for ka > ke
Page 16 of 24
Two Compartment Model, IV Inj (without Resorption), single dose

iv
k10
D
X c
E
k12 k 21
X
Xc = amount in central compartment

Xp = amount in peripheral comp.
dX c
= k12 X c + k10 X c k 21 X p
dt
dX p
= k 12 X c k 21 X T
dt
dE
= k10 X c
dt
D = X (0) = X c (0) = X c (t ) + X p (t ) + E (t ) = E ()
E() - Sum of drug eliminated
k 21
(et * 1) e t +
(
)
C (t ) = 0
VC k 21
t *
t
(
e
1
)
e
( )
Concentration in plasma =
Conc. in central compartment
Aiv =
( k 21 ) D
( ) V c
1
k 12 + k 21 + k 10 +
2
1
k 12 + k 21 + k 10
2
; Biv =
( k 21 ) D
( ) Vc
Vc = volume of the central comp.,

>k21>
( k 12 + k 21 + k 10 ) 2 4 k 21 k 10
( k 12 + k 21 + k 10 ) 2 4 k 21 k 10
= k21 k10
+ = k12 + k 21 + k10
Cterm (t ) = B e t
A + B
A+ B
ln C term (t ) = ln B t
k10 =
k12 = + k 21 k10 =
AUC (0 t ) =

k 21
A+ B
A B
+
(1 e t )
disposition rate constants, equal for

iv and oral administration
AUC =
>, for elim. phase first term =0

A,B, , , can determined by
feathering method
Plot ln(Cterm(t)) vs t with slope ,
intercept ln(B)
Plot ln((C(t)-Cterm(t))) vs t with slope
, intercept ln(A)
A,B iv A,B oral
k10=kren+ kmet (+kbil+ kother)
k ren U
=
k10
E
AB( ) 2
( A + B)( A + B )
(1 e t ) +
, = Macro constants (or Hybrid

constants, independent of dose,
A+B proportional to dose
k 12 , k 21 , k10 - Micro constants
C (t ) Cterm (t ) = A e t ln(C (t ) C term (t )) = ln A t
k 21 =
AUC - by integration of the general

equation for C
Page 17 of 24
Two Compartment Model, IV Inj, single dose

iv
k10
D
X c
E
k12 k 21
X
X p (t ) =
D k12 t
e e t

t max, p =
ln ln

Xp = drug amount in the tissues

(peripheral compartment)
dX p
= 0 at tmax,p
dt
Most membranes central
compartment / tissue are crossed by
diffusion by unbound drug only
fb = fraction bound (to protein)
Vc volume of distribution in the
central compartment
Ccf (t max, p ) = C (t max, p ) (1 f b ) =

C p (t max, p ) (1 f b, p ) = C pf (t max, p )
Vc =
D
D
=
C (0) A + B
Xc + X p
X
X
=
= (assumed ) c
Vc
Vc + V p
Vc
Vd , ss = Vss =
Vss =
k
= 1 + 21 Vc
k12
Vss can also be calculated from macro

constants
A 2 + B 2
D
( A + B ) 2
C max, p =
k 21 D
t
t
e max, p e max, p
Vc ( )
dE
dt
C (t )
AUC =
CL
In the strictest sense only true at

equilibrium
Xp
k 21
Vc ; C p =
Vp
k12
k10 X c (t )
= k10 Vc
C (t )
CL = ke Vss ; ke =
Vz =
k 21
k12
Xc
Vc
C ss
V p = Vss Vc =
CL =
(1 + ) X
=
Xc + X p
Other volume terms are

proportionality factors assuming that
Cc = CT, they may take on
unphysiological values. Initially Xc and
Cc high with XT and Cp nearly 0. In the
end frequently CT > Cp. Vd = volume
of distribution of the total organism
not constant in time!
Vss = volume of distribution at
equilibrium, when flows Xc XT
balance: k12Xc = k21XT
k10 Vc
k k
= 10 21
Vss
k21 + k12
k 21
Vc
This is the definition of ke for a twocompartment model
k k
D
= 21 10 Vc = k10 Vc = CL
AUC
k 21
AUC
CL = k10 Vc = ke Vss = Vz =
D
AUC
Vz volume of distribution during

terminal phase, calculated based on
the rate constant
Vz > Vss > Vc during terminal phase
XT > Xc
Page 18 of 24
Two compartment Model single dose infusion (or zero order resorption)
k0
k10
A
X c
E
k12 k 21
X
k0 =
D
T
Infusion of dose D during at

constant rate k0
k 21
(et * 1) e t +
k 0 ( )
C (t ) =
VC k 21
t *
t
(e 1) e
( )
General equation for calc. of C(t)

during and after infusion, t* =
min(,t)
k 0 k 21
k
(1 e t ) + 21
(1 e t )
( )
VC ( )
k0
k
k0 = k10Ass = k10CssVc; C ss =
= 0
k10 Vc CL
during infusion, t*=t

(et*-1)e-t becomes 1- e-t
( k 21 ) (1 e T ) (t T )
e
+
( )
k0
C (t ) =
VC (k 21 ) (1 e T ) (t T )
e
( )
after end of infusion,

t- = time after end
C (t ) =
For a continuing infusion,
Page 19 of 24
Two compartment Model, single dose with Resorption First Order

ka
k10
A
X c
E
k12 k 21
X
(k21 )
(k21 )
t
t
( ) (k ) e + ( ) (k ) e
ka F D
a
a
C(t ) =
(k21 ka )
Vc
kat
e
+
( ka ) ( ka )
k 21
k 21
+
( ) ( ka ) ( ) (k a )
=
k21 ka
( ka ) ( k a )
C-central compartment
with micro constants
C(t) = A et + B e t ( A + B) ekat
C-central compartment
with macro constants
AIV =
D (k 21 )
Vc ( )
Aoral =
ka f
Aiv
(k a )
BIV =
; Boral =
D (k 21 )
Vc ( )
ka f
Biv
(k a )
Vc
D
=
f
f Aiv + f Biv
C p (t ) =
B k 21 t ( A + B) k 21 k a t
A k 21
e
e
e t +
(k 21 )
(k 21 )
(k 21 k a )
Without iv data only Vc/f can be

determined, but based on
knowledge of fAiv and fBiv the
micro constants k10, k21, k12 may
be derived
CT-deep compartment
Two compartment Model, multiple dose with Resorption First Order

Cn (t x ) = A
( A + B)
(1 e n ) t x
1 e n t x
e
+B
e
1 e
1 e
1 e nka
1 e ka
e kat x
Cn concentration at
time tx after the nth
administration at interval
, time after first dosing =
n
Page 20 of 24
PHARMACODYNAMIC GLOSSARY
3.1
Definitions
Symbol
AUEC
Unit / Dimension
Arbitrary unitstime
Definition
Area under the effect curve
Ce
Amount/volume
Fictive concentration in the effect compartment
Cp
Amount/volume
Drug concentration in the central compartment
(effect unit)
Effect
E0
(effect unit)
Baseline effect
Emax
(effect unit)
Maximum effect
EC50
Amount/volume
Imax
(effect unit)
I50
keo
Drug concentration producing 50% of maximum effect

Maximum inhibition
Drug concentration producing 50% of maximal inhibition
Amount/volume
(Time)
Rate constant for degradation of the effect compartment
-1
-1
Zero order constant for input or production of response
kin
(effect unit) (time)
kout
(time)
M50
Amount/volume
50% of maximum effect of the regulator
MEC
Amount/volume
Minimum effective concentration
Sigmoidicity factor (Hill exponent)
n
S
-1
(effect unit)/
First order rate constant for loss of response
Slope of the line relating the effect to the concentration
(amount/volume)
tMEC
Ve
Time
Volume
Duration of the minimum (or optimum) effective

concentration
Fictive volume of the effect compartment
3.2
Equations: PK/PD Models
E=Efixed if C Cthreshold
E=
E=
Page 21 of 24
fixed effect model
E max C
E50 + C
Emax model
Emax C n
sigmoid Emax model
n
E50
+Cn
dR
= k in k out R
dt
Rate of change of the response over time with no

drug present
dR
C
= k in 1
k out R
dt
IC
+
C
50
Inhibition of build-up of response
I
Cn
dR
= k in 1 max
k out R
n
dt
IC50 + C
C
I
dR
= k in k out 1 max
R
+
dt
IC
50 C
Inhibition of loss of response
E C
dR
= k in 1 + max k out R
dt
E50 + C
Stimulation of build-up of response
E C
dR
= k in k out 1 + max R
dt
E50 + C
Stimulation of loss of response
Page 22 of 24
STATISTICAL PARAMETERS
4.1
Definitions
Symbol
AIC
Definition
Akaike Information Criterion
(smaller positive values indicate a better fit)
CI
Confidence interval, e.g. 90%-CI
CV
Coefficient of variation in %
Calculation
AIC = nln(WSSR) +2p
n = number of observed (measured) concentrations,
p = number of parameters in the model
CI = x tn 1, SEM
CV = 100
Median = ~
x
Median, value such that 50% of observed

values are below and 50% above
Mean = x
Arithmetic mean
SD
x
, SD = standard deviation
(n+1)st value if there are 2n+1 values or arithmetic

th
st
mean of n and (n+1) value if there are 2n
values
x=
1
n
i =1
MSC
Model selection criterion
AIC, SC, F-ratio test, Imbimbo criterion etc.
SC
Schwarz criterion
SC = nln(WSSR) +pln(n)
SD
Standard deviation
SD = Var
SEM
Standard error of mean
SSR
SS
Sum of the squared deviations between the

calculated values of the model and the
measured values
Sum of the squared deviations between the
measured values and the mean value C
SEM =
SD
n
n
SSR =
i=1
SS =
i=1
C i , obs - C i , calc
C i , obs - C
Ci ,obs
SS = Ci ,obs 2 - i =1
n
i =1
n = number of observed (measured) concentrations

use of the second formula is discouraged although
mathematically identical
WSS or WSSR Weighted sum of the squared deviations

between the calculated values of the model
and the measured values
WSSR = w i
i=1
C i , obs - C i , calc
Var
Variance
s = SS/(n-1)
X25%
Lower quartile (25%- quantile), value such

that 25% of observed values are below and
75% above
may be calculated as median of values between

minimum and the overall median
X75%
Upper quartile (75%- quantile)
may be calculated as median of values between

the overall median and the maximum
4.2
Page 23 of 24
Characterisation of log-normally distributed data

Symbol
Definition
Xg
Geometric mean of log-normally distributed

data
sdl
Standard deviation to the log-transformed

data
Calculation
1 n
X g = exp * ln(x i )
n
i =1
sd l =
2
n
n

1
1
ln( xi ) 2 ln( xi )
n 1 i =1
n i =1

Scatter
Scatter-Factor
Scatter = e sd
CIg
Confidence interval of log-normally

distributed data
1 n
CI g = exp ln( xi ) tn 1,0.05 SEM ln

n i =1
CVg
Geometric coefficient of variation in %
Per16%
16% percentile of log-normally distributed

data
Per84%
84% percentile of log-normally distributed

data
CVg = 100 eVarln 1 [%]
Per16% =
Xg
Scatter
Per 84% = X g Scatter

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Glossary

Collection of terms, symbols, equations, and

Version: 16 Februar 2004

Collection of terms, symbols, equations, and explanations of common

TABLE OF CONTENTS .................................................................................................................2

Pharmacokinetic Parameters from noncompartmental analysis (NCA) ...............................3

Pharmacokinetic parameters obtained from compartmental modeling................................8

Pharmacodynamic GLOSSARY ................................................................................................20

AGAH Working group PK/PD modelling

PHARMACOKINETIC PARAMETERS FROM NONCOMPARTMENTAL

Parameters obtained from concentrations in plasma or serum

Parameters after single dosing

Amounttime/ Area under the concentration-time

extrapolation of the terminal phase

measured (Cz,obs) or calculated (Cz,calc)

Amounttime/ Area under the concentration-time

h t1=0 and tn=t,

or according to the log-linear trapezoidal rule:

(the logarithmic trapezoidal rule is used for the

Amounttime/ Area under the concentration-time

concentration LOQ (Cz)

with t1=0 and tn=t. Concentrations Ci

Cz may be measured (Cz,obs) or calculated (Cz,calc)

(t i+1 t i )(t i +1 (C i + 2C i+1 ) + t i (2C i + C i +1 ))

(linear trapezoidal rule)

(log-linear trapezoidal rule)

AGAH Working group PK/PD modelling

Amount/ volume Plasma concentration

Amount/ volume Serum concentration

Amount/ volume Unbound plasma concentration

Volume/ time or Total plasma, serum or blood

Volume/ time or Apparent total plasma or serum

Volume/ time or Hepatic blood clearance, product of

Volume/ time or Creatinine clearance

Amount/ volume Predicted last plasma or serum

Amount/ volume Last analytically quantifiable plasma

Measured or Cockcroft & Gault formula

Calculated from a log-linear regression through

Absolute bioavailability, systemic

Frel = frel 100

For orally administered drugs: f = fa*(1-EH)

Fraction of the extravascularly

Elimination rate constant from the

Amount/ volume Lower limit of quantification

negative of the slope of a ln-linear regression

AGAH Working group PK/PD modelling

Mean dissolution time

Mean residence time (of the

Lag-time (time delay between drug

Apparent volume of distribution at

directly taken from analytical data

directly taken from analytical data

Volume of distribution during terminal

Apparent volume of distribution at

Apparent volume of distribution during

AGAH Working group PK/PD modelling

Parameters after multiple dosing (at steady state)

Average amount in the body at

Amounttime/ Area under the concentration-time

Percent fluctuation of the

Maximum observed plasma or serum directly taken from analytical data

Theoretical accumulation ratio