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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