RE: Simultaneous PK and Cell Life Span PD modeling
Hi Wei-jian,
I let others help you with the NONMEM coding. However, I would like to ask what
type of data set you have. It seems that you have such a rich data set for both
PK and PD observations that allows you to estimate a total of 14 different
parameters, including 11 associated with variability of every single structural
model parameter. Is it really reasonable to, e.g., expect your plasma
concentration data to provide reliable estimates of both structural model
parameters of a 2-comp model with an absorption component as well as the
variability terms associated with every single parameter of the model?
I would suggest that you start with the simplest model you believe is
reasonable in reflecting the underlying mechanism of the plasma concentration
and effect data and include a single ETA to start with. Once you have the
structural model in place, you could explore the possibility of estimating the
variability terms with the model parameters. This approach should allow you to
get the PK/PD model in place early on, with much shortened computing time.
Toufigh
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] on behalf of Wei-Jian Pan
Sent: Mon 7/16/2007 4:14 PM
To: [email protected]
Subject: [NMusers] Simultaneous PK and Cell Life Span PD modeling
Dear group:
Perez-Ruixo and Jusko et al. published NONMEM code for
a basic cell lifespan model in 2005 (Population Cell
Life Span Models for Effects of Drugs Following
Indirect Mechanisms of Action, J Pharmacokinet
Pharmacodyn. 2005 Dec;32(5-6):767-93), which has PK
parameters modeled first, which are then used for life
span PD modeling.
I was wondering if anyone in this group has attempted
to model PK and the cell life span PD model
simultaneously. Please see followiing part of my
control streams, which yielded the error message: "167
$ MODEL: MORE THAN ONE DEFAULT COMPARTMENT FOR DOSE OR
OBSERVATION". Are there any work-arounds for this?
Many thanks!
Wei-jian
$MODEL
COMPARTMENT=(DEPOT) ; [CMT 1]
COMPARTMENT=(CENTROL, DEFOBS) ; [CMT 2]
COMPARTMENT=(PERIPH) ; [CMT 3]
COMPARTMENT=(RESPONSE) ; [CMT 4]
COMPARTMENT=(DDEPOT) ; [CMT 5; delay]
COMPARTMENT=(DCENTROL, DEFOBS) ; [CMT 6; delay]
COMPARTMENT=(DPERIPH) ; [CMT 7; delay]
$PK CALLFL=-2 ;Call with every event record and at
additional and lagged dose times
;DEFINE PK PARAMETERS
TVKA = THETA(1)
KA = TVKA*EXP(ETA(1))
TVCL = THETA(2)
CL = TVCL*EXP(ETA(2))
TVV2 = THETA(3)
V2 = TVV2*EXP(ETA(3))
TVQ = THETA(4)
Q = TVQ*EXP(ETA(4))
TVV3 = THETA(5)
V3 = TVV3*EXP(ETA(5))
TVF1 = THETA(6)
F1 = TVF1*EXP(ETA(6))
S2 = V2
S3 = V3
;DEFINE PD PARAMETERS
KIN = THETA(7)*EXP(ETA(7))
ALAG6 = THETA(8)*EXP(ETA(8))
ALAG5 = ALAG6
ALAG7 = ALAG6
F4 = KIN*ALAG6
EMAX = THETA(9)*EXP(ETA(9))
IC50 = THETA(10)*EXP(ETA(10))
GAMA = THETA(11)*EXP(ETA(11))
$DES
C2 = A(2)/V2
E1 = EMAX*(C2**GAMA)/((IC50**GAMA)+(C2**GAMA))
C6 = A(6)/V2
E2 = EMAX*(C6**GAMA)/((IC50**GAMA)+(C6**GAMA))
DADT(1)=-KA*A(1)
DADT(2) = KA*A(1)-CL*A(2)/V2-Q*A(2)/V2+Q*A(3)/V3
DADT(3) = Q*A(2)/V2-Q*A(3)/V3
DADT(5) = -KA*A(5)
DADT(6) = KA*A(5)-CL*A(6)/V2-Q*A(6)/V2+Q*A(7)/V3
DADT(7) = Q*A(6)/V2-Q*A(7)/V3
DADT(4) = KIN*(1-E1) - KIN*(1-E2)
$ERROR
CP = A(2)/V2
CONC = CP*EXP(EPS(1))
EFF = A(4)*EXP(EPS(2))
Y = CONC*(1-TYPE) + EFF*TYPE
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