From: Huali Wu <*hualiw*>

Date: Thu, 3 Jul 2008 16:18:29 -0400

Dear Dr. Gibiansky:

Thank you very much for your suggestions.

MATRIX=S did work. But S2 = V2 did not. Also, S2 = V1 is not an error, I

validated that by comparing the simulation results from WinNonlin and NONMEM

without adding any error. I don't understand why but if S2 = V2 will only

give discrepant result.

For the error model, I have tried separate errors for each CMT. But it did

not give good fit of released drug.

Thanks again,

Best regards,

Huali

----- Original Message -----

From: Leonid Gibiansky <LGibiansky

To: "Huali Wu" <hualiw

Cc: <nmusers

Sent: Thursday, July 03, 2008 3:00 PM

Subject: Re: [NMusers] Estimation of standard error

*> Huali and Nick,
*

*> Failure of $COV step sometimes tells about errors in the code. In this
*

*> case, I think the problem is in
*

*> S2 = V1
*

*>
*

*> should it be
*

*> S2 = V2 ?
*

*>
*

*> Also,
*

*> > Y1=F+F*EPS(1)
*

*> > Y2=F+F*EPS(1)
*

*> > Y=R1*Y1+R2*Y2
*

*>
*

*> results in
*

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

*> for both MCT=1 and CMT=2
*

*> so R1 / R2 /Y1 /Y2 part can be omitted. Or you can use separate errors for
*

*> each CMT:
*

*>
*

*> > Y1=F+F*EPS(1)
*

*> > Y2=F+F*EPS(2)
*

*> > Y=R1*Y1+R2*Y2
*

*> --
*

*>
*

*> S2 = V2 should help to get SE. If not, try MATRIX=S on $COV line.
*

*> Leonid
*

*>
*

*> --------------------------------------
*

*> Leonid Gibiansky, Ph.D.
*

*> President, QuantPharm LLC
*

*> web: www.quantpharm.com
*

*> e-mail: LGibiansky at quantpharm.com
*

*> tel: (301) 767 5566
*

*>
*

*>
*

*>
*

*>
*

*> Huali Wu wrote:
*

*>> Dear NMusers:
*

*>> I am trying to fit a data set with concentrations of encapsulated drug
*

*>> and released drug. These concentrations were measured after an hour
*

*>> infusion of encapsulated drug. The problem is that I cannot get standard
*

*>> error estimated from simultaneous fitting of all the data. And I got an
*

*>> error message as below:
*

*>> MINIMIZATION SUCCESSFUL
*

*>> HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION.
*

*>> REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM
*

*>> ONLY
*

*>> AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT.
*

*>> NO. OF FUNCTION EVALUATIONS USED: 968
*

*>> NO. OF SIG. DIGITS IN FINAL EST.: 3.2
*

*>> R MATRIX ALGORITHMICALLY NON-POSITIVE-SEMIDEFINITE
*

*>> BUT NONSINGULAR
*

*>> R MATRIX IS OUTPUT
*

*>> COVARIANCE STEP ABORTED
*

*>> But if I fit the encapsulated drug first and then fit data of both
*

*>> encapsulated drug and released drug by fixing the typical values of
*

*>> parameters associated with encapsulated drug compartment, I can get an
*

*>> estimation of standard errors. And GOF plots look good.
*

*>> So my question is can I use this stepwise strategy to build up my base
*

*>> model? If not, what can I do to get standard error estimated in
*

*>> simultaneous fitting?
*

*>> Any comment or suggestion will be highly appreciated.
*

*>> Below is my code:
*

*>> $SUBROUTINES ADVAN9 TRANS1 TOL=3
*

*>> $MODEL NPAR=8, NCOMP=3, COMP=(CENTRAL,DEFOBS),
*

*>> COMP=(PERIPH1), COMP=(PERIPH2)
*

*>> $PK
*

*>> V1 = THETA(1)*EXP(ETA(1))
*

*>> V2 = THETA(2)*EXP(ETA(2))
*

*>> V3 = THETA(3)
*

*>> VM = THETA(4)
*

*>> KM = THETA(5)
*

*>> Q2 = THETA(6)*EXP(ETA(3))
*

*>> Q3 = THETA(7)
*

*>> Q4 = THETA(8) S1 = V1
*

*>> S2 = V1
*

*>> $ERROR
*

*>> R1=0
*

*>> IF (CMT.EQ.1) R1=1
*

*>> R2=0
*

*>> IF (CMT.EQ.2) R2=1
*

*>> Y1=F+F*EPS(1)
*

*>> Y2=F+F*EPS(1)
*

*>> Y=R1*Y1+R2*Y2
*

*>> IPRED=F
*

*>> IRES=DV-IPRED
*

*>> $DES
*

*>> C1 = A(1)/V1
*

*>> DADT(1) = - C1*VM/(KM+C1)-Q2*A(1)/V1
*

*>> DADT(2) = C1*VM/(KM+C1)+Q2*A(1)/V1 + Q4*A(3)/V3-
*

*>> Q3*A(2)/V2-Q4*A(2)/V2
*

*>> DADT(3) = Q4*A(2)/V2-Q4*A(3)/V3 $THETA (5.27 FIX) (0,
*

*>> 0.5) (0, 3.38) (0.329 FIX) (4.38 FIX) (0.136 FIX) (0, 0.0626) (0, 0.0461)
*

*>> $OMEGA (0.01) (0.01) (0.01)
*

*>> $SIGMA (.1)
*

*>>
*

*>> $EST MAXEVAL=9999 PRINT=5
*

*>> $COV
*

*>> $TABLE ID TIME DV AMT RATE CMT NOPRINT FILE=ENCAP4 ONEHEADER
*

*>> $SCAT (RES WRES) VS TIME BY ID
*

*>> Best regards,
*

*>> Huali
*

*>>
*

*>
*

Received on Thu Jul 03 2008 - 16:18:29 EDT

Date: Thu, 3 Jul 2008 16:18:29 -0400

Dear Dr. Gibiansky:

Thank you very much for your suggestions.

MATRIX=S did work. But S2 = V2 did not. Also, S2 = V1 is not an error, I

validated that by comparing the simulation results from WinNonlin and NONMEM

without adding any error. I don't understand why but if S2 = V2 will only

give discrepant result.

For the error model, I have tried separate errors for each CMT. But it did

not give good fit of released drug.

Thanks again,

Best regards,

Huali

----- Original Message -----

From: Leonid Gibiansky <LGibiansky

To: "Huali Wu" <hualiw

Cc: <nmusers

Sent: Thursday, July 03, 2008 3:00 PM

Subject: Re: [NMusers] Estimation of standard error

Received on Thu Jul 03 2008 - 16:18:29 EDT