From: Luann Phillips <*Luann.Phillips*>

Date: Wed, 20 Jul 2011 09:44:42 -0400

Xiao Hu,

I think it may be a problem with identifiability. It can't separate the

definition of K23 from K20 unless there are measurements during

elimination for hemo. patients off dialysis and on dialysis.

Thoughts:

(1) Try making K20=0 for hemodialysis patients

Assumes: no elimination except during hemodialysis via K23

(2) Estimate a different theta for K20 in hemodialysis patients since it

should be different for them (bi-modal distribution)

Assumes: very small elimination from central & with additive elimination

from hemodialysis via K23.

Regards,

Luann Phillips

Director, PK/PD

Cognigen Corporation

Xiao Hu wrote:

*> Dear NM users,
*

*>
*

*>
*

*>
*

*> I’m working on a PK model in renal disease patients with hemodialysis.
*

*> The drug in healthy subjects is well described with a first-order
*

*> absorption and one-compartment disposition model. A third hemodialysis
*

*> compartment was added; CMT=3 or -3 were included in the data set to turn
*

*> this compartment on and off. However, the 3rd compartment did not seem
*

*> to be turned off, based on the fact that the same results were obtained
*

*> whether I excluded the EVID==2 record or not (corresponding to CMT==3 or
*

*> -3). Both ADVAN6 and ADVAN7 provided the same results as well. The
*

*> code and partial data set are shown below. I’m wondering if you can
*

*> point me to the right direction. I’d really appreciate your input. Thanks!
*

*>
*

*>
*

*>
*

*> Best regards,
*

*>
*

*> Xiao
*

*>
*

*>
*

*>
*

*> $INPUT C ID DAT2=DROP TIME GROUP DV AMT MDV TYPE CMT EVID
*

*>
*

*>
*

*>
*

*> $DATA .\DATA\FINAL\105RI101ESRDPK.CSV
*

*>
*

*> IGNORE=C IGN(GROUP.NE.5) ;IGN(EVID.EQ.2)
*

*>
*

*>
*

*>
*

*> $SUBROUTINES ADVAN7 ;ADVAN6 TOL=8
*

*>
*

*>
*

*>
*

*> $MODEL
*

*>
*

*> COMP=(DEPOT,INITIALOFF,DEFDOSE)
*

*>
*

*> COMP=(CENTRAL,DEFOBS,NOOFF)
*

*>
*

*> COMP=(HEMODIA,INITIALOFF)
*

*>
*

*>
*

*>
*

*> $PK
*

*>
*

*> K12=THETA(1)
*

*>
*

*> K20=THETA(2)
*

*>
*

*> K23=THETA(3)
*

*>
*

*> K32=0
*

*>
*

*> V2=THETA(4)*EXP(ETA(1))
*

*>
*

*> S2=V2
*

*>
*

*> $ERROR
*

*>
*

*> Y=F*EXP(EPS(1))
*

*>
*

*> IPRE=F
*

*>
*

*>
*

*>
*

*> ;$DES
*

*>
*

*> ;DADT(1)=-K12*A(1)
*

*>
*

*> ;DADT(2)=K12*A(1)-K23*A(2)-K20*A(2)
*

*>
*

*> ;DADT(3)=K23*A(2)
*

*>
*

*>
*

*>
*

*> $THETA
*

*>
*

*> (0,0.1) ;THETA1 K12
*

*>
*

*> (0,0.05) ;THETA2 K20
*

*>
*

*> (0,.102) ;THETA3 K23
*

*>
*

*> (0,200000) ;THETA6 V2
*

*>
*

*>
*

*>
*

*> $OMEGA
*

*>
*

*> 0.2
*

*>
*

*> $SIGMA
*

*>
*

*> 0.2
*

*>
*

*>
*

*>
*

*> $ESTIMATION MAXEVAL=9999 METH=COND PRINT=5 MSFO=ESRD.MSF FILE=ESRD.EXT
*

*>
*

*> C,ID,DATE,TIME,GROUP,CONC,AMT,MDV,TYPE,CMT,EVID
*

*>
*

*> ,102001,2010/05/04,8:35,2,0,6.3e+07,1,1,1,1
*

*>
*

*> ,102001,2010/05/04,8:35,2,0,0,1,1,-3,2
*

*>
*

*> ,102001,2010/05/04,14:39,2,177,0,0,1,2,0
*

*>
*

*> ,102001,2010/05/04,20:35,2,190,0,0,1,2,0
*

*>
*

*> ,102001,2010/05/05,08:35,2,144,0,0,1,2,0
*

*>
*

*> ,102001,2010/05/05,20:35,2,145,0,0,1,2,0
*

*>
*

*> ,102001,2010/05/06,08:37,2,135,0,0,1,2,0
*

*>
*

*> ,102001,2010/05/07,08:41,2,139,0,0,1,2,0
*

*>
*

*> ,102001,2010/05/08,08:35,2,177,0,0,1,2,0
*

*>
*

*> ,102001,2010/05/11,08:35,2,82.2,0,0,1,2,0
*

*>
*

*> ,102002,2010/06/30,8:00,2,0,1.25e+08,1,1,1,1
*

*>
*

*> ,102002,2010/06/30,8:00,2,0,0,1,1,-3,2
*

*>
*

*> ,102002,2010/06/30,14:03,2,416,0,0,1,2,0
*

*>
*

*> ,102002,2010/06/30,21:00,2,727,0,0,1,2,0
*

*>
*

*> ,102002,2010/07/01,08:21,2,1040,0,0,1,2,0
*

*>
*

*> ,102002,2010/07/01,20:00,2,1070,0,0,1,2,0
*

*>
*

*> ,102002,2010/07/02,08:06,2,719,0,0,1,2,0
*

*>
*

*> ,102002,2010/07/03,08:00,2,580,0,0,1,2,0
*

*>
*

*> ,102002,2010/07/04,08:00,2,518,0,0,1,2,0
*

*>
*

*> ,102002,2010/07/07,08:00,2,127,0,0,1,2,0
*

*>
*

*> ,102002,2010/07/10,08:00,2,35.2,0,0,1,2,0
*

*>
*

*> ,102002,2010/07/14,08:08,2,30,0,0,2,2,0
*

*>
*

*> ,102002,2010/07/17,08:00,2,30,0,0,2,2,0
*

*>
*

*> ,102002,2010/07/21,08:00,2,30,0,0,2,2,0
*

*>
*

*> ,102002,2010/07/23,15:05,2,30,0,0,2,2,0
*

*>
*

*> ,102002,2010/07/28,08:21,2,30,0,0,2,2,0
*

*>
*

*> ,102003,2010/08/06,8:35,3,0,1.25e+08,1,1,1,1
*

*>
*

*> ,102003,2010/08/06,8:35,3,0,0,1,1,-3,2
*

*>
*

*> ,102003,2010/08/06,14:35,3,132,0,0,1,2,0
*

*>
*

*> ,102003,2010/08/06,20:35,3,189,0,0,1,2,0
*

*>
*

*> ,102003,2010/08/07,08:35,3,210,0,0,1,2,0
*

*>
*

*> ,102003,2010/08/07,20:35,3,246,0,0,1,2,0
*

*>
*

*> ,102003,2010/08/08,08:35,3,221,0,0,1,2,0
*

*>
*

*> ,102003,2010/08/09,08:35,3,236,0,0,1,2,0
*

*>
*

*> ,102003,2010/08/10,08:35,3,180,0,0,1,2,0
*

*>
*

*> ,102003,2010/08/13,08:35,3,55.9,0,0,1,2,0
*

*>
*

*> ,102004,2010/08/31,7:40,3,0,1.25e+08,1,1,1,1
*

*>
*

*> ,102004,2010/08/31,7:40,3,0,0,1,1,-3,2
*

*>
*

*> ,102004,2010/08/31,13:52,3,309,0,0,1,2,0
*

*>
*

*> ,102004,2010/08/31,19:40,3,252,0,0,1,2,0
*

*>
*

*> ,102004,2010/09/01,07:40,3,224,0,0,1,2,0
*

*>
*

*> ,102004,2010/09/01,19:43,3,265,0,0,1,2,0
*

*>
*

*> ,102004,2010/09/02,07:40,3,306,0,0,1,2,0
*

*>
*

*> ,102004,2010/09/03,07:40,3,328,0,0,1,2,0
*

*>
*

*> ,102004,2010/09/04,07:40,3,206,0,0,1,2,0
*

*>
*

*> ,102004,2010/09/07,07:40,3,37.6,0,0,1,2,0
*

*> *

Received on Wed Jul 20 2011 - 09:44:42 EDT

Date: Wed, 20 Jul 2011 09:44:42 -0400

Xiao Hu,

I think it may be a problem with identifiability. It can't separate the

definition of K23 from K20 unless there are measurements during

elimination for hemo. patients off dialysis and on dialysis.

Thoughts:

(1) Try making K20=0 for hemodialysis patients

Assumes: no elimination except during hemodialysis via K23

(2) Estimate a different theta for K20 in hemodialysis patients since it

should be different for them (bi-modal distribution)

Assumes: very small elimination from central & with additive elimination

from hemodialysis via K23.

Regards,

Luann Phillips

Director, PK/PD

Cognigen Corporation

Xiao Hu wrote:

Received on Wed Jul 20 2011 - 09:44:42 EDT