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Collection of terms, symbols, equations, and explanations of common pharmacokinetic and pharmacodynamic parameters and some statistical functions
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Glossary
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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
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1
1.1
1.1.1
Symbol
Unit / Dimensio n/
Dimension
Definition
Calculation
AUC AUC(0-)
Amounttime/ Area under the concentration-time volume curve from zero up to with
AUC=AUC (0 - t z ) +
Cz
, Cz may be
AUC (0 - t) = AUC (t i -t i +1 )
i= 1
n- 1
wit
AUC (t i
t i +1 )
=1 2 (C i + C i+1 ) (t i+1 t i )
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)
Amounttime/ Area under the concentration-time volume curve from zero up to the last %
See AUC(0-t)
AUCextrap %
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 Area under the first moment of the concentration-time curve from zero up to a definite time t
AUC extrap % =
AUMC
AUMC = AUMC (0 -
t z Cz
Cz
AUMC(0-t)
AUMC (t i
=
1 6
t i +1 )
AUMC(0 - t) = AUMC(t i -t i +1 )
i= 1
n- 1
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
AUMC(0-tz)
AUMCextrap %
See AUMC(0-t) Area under the first moment of the concentration-time curve from zero to the last quantifiable concentration Area under the first moment of the AUMC-AUMC concentration-time curve AUMC extrap % = AUMC extrapolated from tz to in % of the total AUMC
(0-t z )
100
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Symbol
Cp or C Cs or C Cu CL
Unit / Dimension
Definition
Calculation
Amount/ volume Plasma concentration Amount/ volume Serum concentration Amount/ volume Unbound plasma concentration Volume/ time or Total plasma, serum or blood volume/ time/ kg clearance of drug after intravenous
CL =
administration CL / f
Volume/ time or Apparent total plasma or serum volume/ time/ kg clearance of drug after oral
D iv AUC
D po AUC
CL / f =
CLint CLH,b
administration Volume/ time or Intrinsic clearance maximum volume/ time/ kg elimination capacity of the liver
Volume/ time or Hepatic blood clearance, product of volume/ time/ kg hepatic blood flow and extraction
CLH = QHEH
ratio
Metabolic clearance concentration Calculated from a log-linear regression through the terminal part of the curve directly taken from analytical data directly taken from analytical data
Amount/ volume Predicted last plasma or serum Amount/ volume Last analytically quantifiable plasma
D f
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 Absolute bioavailability, systemic availability in % Fraction of the administered dose in comparison to a standard (not iv)
f =
AUC po D iv AUC iv D po
F frel
% -
F = f 100
f rel = AUC DSTD AUCSTD D
STD = Standard
Frel fa fm fu
Relative bioavailability in %
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) Elimination rate constant from the central compartment
fu = Cu /C
HVD
Time
(Time)
-1
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
ke or kel LOQ
(Time)
-1
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Symbol
MAT MDT MRT
Unit / Dimension
Time Time Time
Definition
Mean absorption time Mean dissolution time
Calculation
MAT = MRTev - MRTiv
(ev = extravasal, e.g. im, sc, po)
MR
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
t1/2 tlag
Time
Terminal half-life 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
t 1/ 2
ln 2 z
Time
tz tmax Vss
Time Time
directly taken from analytical data directly taken from analytical data
Apparent volume of distribution at Volume or volume/kg equilibrium determined after intravenous administration
Volume or volume/kg
Vss = CL MRT =
Vz= Div AUC z
D AUMC (AUC) 2
Vz
Volume of distribution during terminal phase after intravenous administration Apparent volume of distribution at equilibrium after oral administration Apparent volume of distribution during terminal phase after oral / extravascular administration
Vss / f
Volume or volume/kg
Vss /f = CL MRT =
D AUMC (AUC) 2
Vz / f
Volume or volume/kg
Vz /f =
D po AUC z
po instead of iv !
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1.1.2
Symbol
Aave
Unit / Dimension
Amount
Definition
Average amount in the body at steady state
Calculation
A ave =
f DM z
Amounttime/ Area under the concentration-time volume curve during a dosing interval at
by trapezoidal rule
steady state
%
Cav,ss
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
Cmax,ss
Cmin,ss
Ctrough
DM LF
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 Accumulation ratio calculated from Cmax,ss at steady state and Cmax after single dosing Accumulation ratio calculated from Cmin,ss at steady state and from concentration at t= after single dose Theoretical accumulation ratio 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 AUC sd
sd = single dose
PTF %
PTF % = 100
RA
=
RA (AUC)
(AUC)
RA (Cmax)
RA
(Cmax) =
sd = single dose
RA (Cmin)
RA
(Cmin) =
sd = single dose
R theor
1 1- 2 -
, =
t1 / 2
derived from analytical data by linear interpolation directly taken from analytical data
Time
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1.2
Symbol
Ae(t1-t2) Ae(0)
Unit / Dimension
Amount Amount
Definition
Amount of unchanged drug excreted into urine within time span from t1 to t2. Cumulative amount (of unchanged drug) excreted into urine up to infinity after single dosing Amount (of unchanged drug) excreted into the urine during a dosing interval () at steady state Drug concentration in urine Cur * Vur
Calculation
Amount
Amount/ volume
CLR =
Ae(0 ) AUC , ss
Fraction of intravenous administered drug that is excreted unchanged in urine Fraction of orally administered drug excreted into urine Total urinary recovery after intravenous administration = fraction of drug excreted into urine in % Mid time point of a collection interval Volume of urine excreted
fe =
Ae Div
Ae Dpo
fe/f Fe
fe / f =
Fe = fe 100
tmid Vur
Time Volume
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Definition
Calculation
by multiexponential fitting by multiexponential fitting by multiexponential fitting
Exponents of the polyexponential equation (slope factor) Exponent of the i (descending) exponential term of a polyexponential equation Area under the curve (model)
th
-1
AUC
Amounttime/ volume
iv :
1 1 k a i
iv :
1 1 2 k 2 a i
C (0) =
Ci
i =1
See 2.2
CL =
Ci
Clearance Fractional area, area under the various phases of disposition (i) in the plasma concentration-time curve after iv dosing Number of compartments in a multicompartmental model
f Dose AUC
with
n
iv: f=1
fi
fi =
i AUC
f
i =1
=1
Zero order rate constant Elimination rate constant from the central compartment Absorption rate constant
Design parameter or determined by multiexponential fitting calculated from parameters of the multiexponential fit by multiexponential fitting by multiexponential fitting by nonlinear fitting
-1
(Time) (Time)
-1 -1
Transfer rate between compartment i and j in a multi-compartmental model Amount/ volume Michaelis Menten constant
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Symbol
MRT
Unit / Dimensions
Time
Definition
Mean residence time
Calculation
iv: MRT =
AUMC AUC
AUMC 1 (tlag + ) AUC ka
extravascular: MRT =
Qi
Amount/Time
Intercompartmental clearance between central compartment and compartment i Zero order infusion rate
th
k0 t 1/ 2, i
Amount/Time Time
design parameter
Half-life associated with the i ln2 exponent of a polyexponential equation t1/ 2, i = i Infusion duration Time after drug administration
Vc = f Dose
Time Time
design parameter
t Vc
Volume or Apparent volume of the central or Volume /amount plasma or serum compartment
C
i=1
iv: f=1
Vmax
Amount/Time
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2.1
iv bolus
Cp ( t ) = B i e t
i
]
i
i=1
short-term iv infusion
peak level
C p (t ) =
k0 Vc
Bi i t * i t e 1 e i i =1
n
with t*=min(t,T)
continuous iv infusion extravascular
C ss =
Ro CL
i a
n ka (e tl e k tl ) Cp ( t ) = B i k a i i=1
tl = t tlag
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2.2
One Compartment Model, IV bolus, single dose, one elimination pathway only (assumed to be urinary excretion)
e D X U
i .v .
U - drug amount in urine ke= elimination rate constant X = drug amount in the body U =drug amount in the urine D = dose administered X(t) = amount in plasma at time t after administration U(t) = amount in urine at time t
dX = k e X (t ) dt
dU = k e X (t ) dt
X (t ) = X (0) e k te
D = X ( 0) = X (t ) + U (t ) = U ( )
C p (t ) =
X (t ) ; C p (t ) = C p (0) e k e t Vc
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
Vc =
C p (t ) =
t1 / 2 =
ln( 2) ke
Urinary excretion
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 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 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)
dU = k e X ( 0 ) e k e t ; dt
ln
dU CLR = dt C p (t )
U = CLR Cp (t mid ) t
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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 X = amount in plasma U = amount in urine B = amount in bile M = amount of metabolites in plasma
dX dU dB = k e X (t ) ; = k ren X (t ) ; = k bil X (t ) ; dt dt dt
dM = k met X (t ) dt
D = X ( 0 ) = X ( t ) + U ( t ) + B( t ) + M ( t ) = U ( ) + B ( ) + M ( ) C p (t ) = C p ( 0) e k e t
U (t ) = k ren D (1 e ket ) ke
Plasma concentration Drug amount in urine
U ( ) =
Up to infinite time (t = ) ke - slope can calc.from the Sigma Minus Plot (U()-U(t) vs t fb fraction of bound drug
CLR = k ren Vc
B( t ) = M (t ) =
CLR u ; CLR = (1 f b )
; CLbil
k bil D (1 e ket ) ke
= k bil Vc
Biliary excretion can be calc. In analogous fashion assuming no reabsorption Total amounts of metabolites including further excretion of metabolite into urine ( k e ). C (t) = concentration of the metabolite in the central circulation
M
dM p dt
M = k met X (t ) k e M p (t )
M k met D (e k e t e k e t ) M V (k e k e )
C M (t ) =
M c
CLtot =
D : U() : B() : M() = ke : kren : kbil : kmet = CLtot : CLR: CLbil: CLmet
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Cn- concentration after nth administration every hours During steady-state conditions (n=), C0=concentration immediately after initial (first) injection = D/Vc 1 R = 1 e k e = Peak
C ss (t) = C 0
e k e t (1 e
k
= C0 R e k e t
C ss ,max = C0 R =
D 1 Vc 1 e ke
C ss ,min = C0 R e ke =
D e ke = C ss ,max e ke Vc 1 e ket
= Trough
% Fluctuation =
100
Fluctuation depends on the relation between ke (or t1/2) and , not on the dose
Fluc. =
= e ke
C ln ss ,max C ss ,min = ke
ss
AUC
D CL
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
C ss,max =
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
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dX = k 0 k e X (t ) dt
k0- constant infusion rate during constant rate infusion ss - t = , infusion equilibrium, like ss
C (t ) =
C ss =
k0 (1 e ket ) k e Vd
k0 k = 0 k e Vd CLtot
C ss =
C (t ) =
R0 CL
R0 (1 e ket ) CL
; C(t ) = C ss (1 e
ket
C max =
R0 (1 e k eT ) k e Vd
C(t ) = C max e k e ( t T )
Short term Infusion: k LD = C ss Vc = 0 ke
Plasma level after end of infusion with t = time after start of the infusion Loading dose
One Compartment Model, Short Term Infusion, Zero Order, multiple dose
C n (t ) = C n 1 ( ) e ket + k0 (1 e ket ) k e Vd
C n ( ) =
1 e nke ke ( T ) k0 (e e ke ) 1 e ke k e Vd
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One Compartment Model, Oral Administration With Resorption First Order, single dose
a e D A X E
dA = k a A dt
dX dE = ka A ke X ; = ke X dt dt
A = unabsorbed drug available at resorption place E = sum of the excreted amount of drug ka = absorp. rate constant F = fraction of dose available for absorption BATEMAN-Function
A(t ) = f D e kat
f D ka (e k e t e k a t ) Vd ( k a k e )
Cterm (t ) =
f D ka (e k e t ) Vd ( k a k e )
f D ka k e t ; C(t)->Cterm(t) for t-> Vd ( k a k e )
ln Cterm (t ) =
terminal phase k a < k e - Flip-Flop, but you need an additional iv administration to distinguish this case ka - feathering-method (can reasonably be used only if there are at least 4 data points in the increasing part of the concentrationtime curve) substraction of C from C (semilog. (C-C) versus t - slope -ka) with t0 - lag time tmax does not depend on the bioavailability f and, since ke commonly is substancedependent and not preparation-dependent, reflects ka
Cterm (t ) C (t ) =
f D ka e k at Vc (ka ke )
f D ka kat Vd ( k a k e )
ln(Cterm (t ) C (t )) =
C (t ) =
f D ka (e k e ( t t 0 ) e k a ( t t 0 ) ) Vd ( k a k e )
t max
ka ln k ln(k ) ln(k ) e a e = = ka ke k a ke
C max =
f D k a ket max e Vd
One Compartment Model, Oral Administration With Resorption First Order, multiple dose
C n (t ) = f D ka (re e ket ra e k a t ) Vd ( k a k e )
Cn(t) = concentration after the nth consecutive dosing in intervals ; BATEMAN-Function expanded by accumulation factor
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
re =
1 e nke
ra =
1 e nk a ; n = for steady 1 e k a
t ss ,max =
k a (1 e k e ) 1 ln k (1 e k a ) ka ke e
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k12 k 21 X
dX c = k12 X c + k10 X c k 21 X p dt dX p = k 12 X c k 21 X T dt
D = X (0) = X c (0) = X c (t ) + X p (t ) + E (t ) = E ()
k 21 (et * 1) e t + ( ) k C (t ) = 0 VC k 21 t * t ( e 1 ) e ( )
Aiv = ( k 21 ) D ( ) V c
; Biv =
( k 21 ) D ( ) Vc
1 k 12 + k 21 + k 10 + 2 1 k 12 + k 21 + k 10 2
( k 12 + k 21 + k 10 ) 2 4 k 21 k 10 ( k 12 + k 21 + k 10 ) 2 4 k 21 k 10
)
)
, = Macro constants (or Hybrid constants, independent of dose, A+B proportional to dose
disposition rate constants, equal for iv and oral administration
= k21 k10
Cterm (t ) = B e t
+ = k12 + k 21 + k10
ln C term (t ) = ln B t
k 21 =
A + B A+ B
k10 =
k 21
A+ B A B +
k12 = + k 21 k10 =
AB( ) 2 ( A + B)( A + B )
B
k ren U = k10 E
AUC (0 t ) =
(1 e t ) +
(1 e t )
AUC =
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k12 k 21 X
X p (t ) =
p
D k12 t e e t
t max, p =
ln ln
Vc =
D D = C (0) A + B
Xc + X p X X = = (assumed ) c Vc Vc + V p Vc
Vd , ss = Vss =
Xc + X p C ss
(1 + ) X =
k 21 k12 Xc Vc
k 21 = 1 + k Vc 12
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 Vss can also be calculated from macro constants In the strictest sense only true at equilibrium
Vss =
A 2 + B 2 D ( A + B ) 2 Xp k 21 Vc ; C p = Vp k12
V p = Vss Vc = C max, p =
CL =
dE dt
k 21 D t t e max, p e max, p Vc ( )
= k10 X c (t ) = k10 Vc C (t ) k10 Vc k k = 10 21 Vss k21 + k12 D
)
This is the definition of ke for a twocompartment model
C (t )
CL = ke Vss ; ke = AUC = Vz = A
= D
Vc
k 21
k k D = 21 10 Vc = k10 Vc = CL AUC k 21
CL
AUC
D AUC
CL = k10 Vc = ke Vss = Vz =
Vz volume of distribution during terminal phase, calculated based on the rate constant Vz > Vss > Vc during terminal phase XT > Xc
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Two compartment Model single dose infusion (or zero order resorption)
k0 k10 A X c E
k12 k 21 X
k0 = D T
p
Infusion of dose D during at constant rate k0 General equation for calc. of C(t) during and after infusion, t* = min(,t)
( k 21 ) (1 e T ) (t T ) e + ( ) k0 C (t ) = VC (k 21 ) (1 e T ) (t T ) e ( )
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k12 k 21 X
p
k 21 k 21 + ( ) ( ka ) ( ) (k a ) = k21 ka ( ka ) ( k a )
C(t) = A et + B e t ( A + B) ekat
D (k 21 ) Vc ( ) ka f Aiv (k a ) D (k 21 ) Vc ( )
AIV =
BIV =
Aoral =
; Boral =
ka f Biv (k a )
Vc D = f f Aiv + f Biv
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
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 )
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
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3
3.1
PHARMACODYNAMIC GLOSSARY
Definitions
Symbol
Unit / Dimension
Arbitrary unitstime Amount/volume Amount/volume (effect unit) (effect unit) (effect unit) Amount/volume (effect unit) Amount/volume (Time)
-1 -1
Definition
Area under the effect curve Fictive concentration in the effect compartment Drug concentration in the central compartment Effect Baseline effect Maximum effect Drug concentration producing 50% of maximum effect Maximum inhibition Drug concentration producing 50% of maximal inhibition Rate constant for degradation of the effect compartment Zero order constant for input or production of response First order rate constant for loss of response 50% of maximum effect of the regulator Minimum effective concentration Sigmoidicity factor (Hill exponent) Slope of the line relating the effect to the concentration Duration of the minimum (or optimum) effective concentration Fictive volume of the effect compartment
AUEC Ce Cp E E0 Emax EC50 Imax I50 keo kin kout M50 MEC n S tMEC Ve
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3.2
E=Efixed if C Cthreshold
E=
E max C E50 + C
Emax C n
n E50 +Cn
E=
dR = k in k out R dt dR C = k in 1 k out R dt IC + C 50 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 E C dR = k in 1 + max k out R dt E50 + C E C dR = k in k out 1 + max R dt E50 + C
Rate of change of the response over time with no drug present Inhibition of build-up of response
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4
4.1
STATISTICAL PARAMETERS
Definitions
Symbol Definition
Akaike Information Criterion (smaller positive values indicate a better fit)
Calculation
AIC = nln(WSSR) +2p
n = number of observed (measured) concentrations, p = number of parameters in the model
AIC
CI CV
CI = x tn 1, SEM
CV = 100
Median = ~ x
SD x
, SD = standard deviation
Median, value such that 50% of observed values are below and 50% above Arithmetic mean
(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
Mean = x
x=
1 n
x
i =1
MSC SC SD SEM
Model selection criterion Schwarz criterion Standard deviation Standard error of mean
SD = Var
SEM = SD n
n
SSR
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
SSR =
i=1
C i , obs - C i , calc
SS
SS =
i=1
C i , obs - C
n Ci ,obs n 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 Var X25%
WSSR = w i
i=1
C i , obs - C i , calc
Variance Lower quartile (25%- quantile), value such that 25% of observed values are below and 75% above Upper quartile (75%- quantile)
s = SS/(n-1) may be calculated as median of values between minimum and the overall median may be calculated as median of values between the overall median and the maximum
X75%
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4.2
Calculation
Xg
sdl
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
CVg
Per16%
16% percentile of log-normally distributed data 84% percentile of log-normally distributed data
Per16% =
Per84%
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