RE: [NMusers] 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


-----Original Message-----
From: owner-nmusers_at_globomaxnm.com on behalf of Wei-Jian Pan
Sent: Mon 7/16/2007 4:14 PM
To: nmusers_at_globomaxnm.com
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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Received on Tue Jul 17 2007 - 03:36:34 EDT