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problem with PK fit in a PKPD model

From: Fatemeh Akhlaghi, PhD <fak4939u>
Date: Fri, 25 Jul 2008 19:04:28 -0400

Dear NMusers group:

I am puzzled by the result of a NONMEM analysis I am working on. I have
modeled plasma conc versus effect data using ADVAN5 (simultaneous link,
comp3=effect) and can get a reasonable fit for the PD but the PK IPRED versus
observed plot has a very unusual S-shape. Fitting the same plasma conc
independently using ADVAN3 with the same error structure does not produce such
pattern. I log transform the plasma concentration data to obtain a better PK
fit. Also I have built a non-linear binding equation into the error structure
of the PKPD model. I have included the code below. Do you know what is
wrong?

Many thanks in advance and I look forward to hear from you.


Fatemeh Akhlaghi


$PROBLEM
;MODEL DESC:PKPDLINKWITH BINDING PARAMETERS
;PROJECT NAME: EXAMPLE1
;PROJECT ID: PKPDLINK MODEL
; MODEL: C = BIEXP; CE = C*KEO.EXP(-KEO.T); E = SIGM_EMX(CE)
; NOTE: MAY BE MORE ETAS HERE THAN REASONABLE
; NOTE: MODEL FOR C CAN BE MORE COMPLEX BY ADDING CMPTS
;
; THE DATA FILE CONTAINS BOTH CP AND EFFECT OBSERVATIONS.
; WHEN DV IS A CP OBSERVATION, CMT = 1 (OR 0),
; WHEN DV IS AN EFFECT OBSERVATION, CMT =2.

$DATA ..\PKPDLINK1ADDDOSE.CSV IGNORE=C
$INPUT ID OCC TIME AMT DV DV1 MDV CMT EVID WT TPRO ALB DOSE HT SEX AST TBIL
UREA CREA WBC DROP=RBC
$SUBROUTINES ADVAN=5
$MODEL
  COMP=(CENTRAL,DEFDOSE,DEFOBS)
  COMP=PERIPH
  COMP=EFFECT
$PK
  K10=THETA(1)
  TVK12=THETA(2)
  K12=TVK12*EXP(ETA(1))
  K13= .001*K10 ; TRIVIAL LOSS TO EFFECT COMPT
  K21=THETA(3)
  TVS1=THETA(4)
  S1=TVS1 ; V1 FOR DRUG
  K30=THETA(5) ; KEO
  E0=THETA(6)*EXP(ETA(2))
  EMAX=THETA(7)
  C50=THETA(8)*EXP(ETA(3))
  HILL=THETA(9)
  TVBMAX=THETA(10)*EXP(ETA(4))
  BMAX=TVBMAX
  KD=THETA(11)
  KNS=THETA(12)
  W=THETA(13)
S3=S1*K13/K30 ; PRESERVES CESS = CPSS

$ERROR
FLAG=0
IF(AMT.GT.0) FLAG=1 ;DOSING RECORD ONLY

CP1=1
IF(F.NE.0) CP1=F

LNCP=LOG(CP1+FLAG) ;TRANFORM THE PREDICTION TO THE LOG OF PRED

Y1=LNCP+W*ERR(1)

CP=0
IF(LNCP.GT.-4) CP=EXP(LNCP)

CB=HT*((CP*BMAX/(CP+KD))+KNS*CP)+CP*(1-HT)
E=E0*(1-(EMAX*(CB**HILL))/((C50**HILL)+(CB**HILL)))
Y2=E+E*(ERR(2))+ERR(3)

Q=1
IF(CMT.EQ.2) Q=0 ; CMT = 3 = EFFECT OBS
Y=Q*Y1+(1-Q)*Y2
F1=Q*LNCP+(1-Q)*E

IPRE=F1

DEL=0
IF(IPRE.EQ.0) DEL=1
W=IPRE+DEL
IRES=IPRE-DV
IWRES=IRES/W

$THETA (0.01,0.5,1) ;K10 1
$THETA (0.1,1,2) ;K12 2
$THETA (0.01,0.05,0.5) ;K21 3
$THETA (0.1,4,10) ;V1 OR S1 4
$THETA (0.1,0.5,) ;K30 5
$THETA (0.1,0.2,) ;E0 6
$THETA (0.01,0.1,) ;EMAX 7
$THETA (0.1,150,) ;EC50 8
$THETA (2,4,6) ;HILL 9
$THETA (200,250,350) ;BMAX 10
$THETA (0.1,0.6,12) ;KD 11
$THETA (0.01,0.1,2) ;KNS 12
$THETA (0.001,0.1,) ;PRO RES ERR 13

$OMEGA BLOCK(3)
 0.001 ;k12
 0.0001 0.001 ;e0
 0.0001 0.0001 0.01 ;ec50

$OMEGA
  0.2 ;BMAX 4

$SIGMA
 0.17 ;[A] SIGMA(1,1)
 0.002 ;[A] SIGMA(2,2)
 0.0001 ;[A] SIGMA(3,3)

$COV PRINT=E

$ESTIMATION METHOD=1 INTER PRINT=10 MAXEVAL=9999 SIGDIG=6 NOABORT

Fatemeh Akhlaghi, PharmD, PhD
Associate Professor in Pharmacokinetics
Biomedical and Pharmaceutical Sciences (BPS)
University of Rhode Island
125 Fogarty Hall, 41 Lower College Road
Kingston, RI 02881, USA

Phone/Fax: (401) 874 9205/(401) 874 2181
Email: fatemeh
Laboratory Website: http://www.uri.edu/pharmacy/faculty/aps/akhlaghi/index
Received on Fri Jul 25 2008 - 19:04:28 EDT

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