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Questions about M3

From: Xiao Hu <Xiao.Hu>
Date: Thu, 29 Apr 2010 13:13:44 -0400

Dear NMusers,

I'm seeking inputs/advice on some M3 related questions. Any comments and
suggestions would be appreciated.

I have some Phase 1 data on a drug, which I want to model with a M3
method. The LLQ is 10 and peak level is about 80 (it's a cytokine and
can't ask assay people to do a better job).

I'm using NONMEM 7, therefore, can use PHI function directly.

Below you can see my initial code (Code 1). I first modeled SIG as a
separate THETA(5). The estimated THETA(5) turned out to be 1.14E6.
Therefore, all the PREDs=0.5 with TYPE==2. I had to admire NONMEM because
it makes (LOQ-IPRE)/SIG close to zero and give me a politically golden
answer (Prob=0.5) on my LLQ data.

Since SIG represents the variance of F, in my second try, I set SIG=SD*SD
and modeled log-tranformed data, because I'm using exponential model on
the ERROR. The code is following the initial code (Code 2).

Here's my questions.

1. Is code 2 a theoretically correct approach? How is SIG generally
modeled based on your experience?
2. Currently, I only included one BLQ post Tmax. The rest were ignored
(MDV=1). If I include one BLQ timepoint before Tmax, the model won't run.
 If I include every BLQ time points after Tmax, the model won't run. Is
this acceptable? What's the general practice?
3. What are the diagnostic tools for BLQ from the M3 method?
4. If I model SIG using all the data, and fix it in the subsequent runs,
which use the same code as Code 1 with SIG fixed, will this be acceptable?

Code 1:
$SUBROUTINES ADVAN2
$PK
   MU_1=THETA(1)
   MU_2=THETA(2)
   MU_3=THETA(3)
   MU_4=THETA(4)
   SD=MU_4
   KA=EXP(MU_1+ETA(1))
   V=EXP(MU_2+ETA(2))
   CL=EXP(MU_3+ETA(3))
   K=CL/V
   S2=V/1000
$ERROR
   SIG=THETA(5)
   LOQ=10
   IPRE=F
   IF(SIG==0) EXIT
   DUM=(LOQ-IPRE)/SIG
   CUMD=PHI(DUM)
   IF(TYPE.EQ.1) THEN
       F_FLAG=0
       Y= F*EXP(SD*ERR(1))
   ENDIF
   IF(TYPE.EQ.2) THEN
       F_FLAG=1
       Y=CUMD
   ENDIF
$THETA
   -1.868;[KA]
   11.9 ;[V]
   10;[CL]
   0.523;[SD]
   0.2
$OMEGA
0.258
0.177
0.227
$SIGMA
1 FIX
$EST METHOD=COND LAP INTERACTION MAXEVAL=9999 PRINT=5 FILE=PK.M3.COND.ext

Code 2
$SUBROUTINES ADVAN2
$PK
   MU_1=THETA(1)
   MU_2=THETA(2)
   MU_3=THETA(3)
   MU_4=THETA(4)
   SD=MU_4
   SIG=SD*SD
   KA=EXP(MU_1+ETA(1))
   V=EXP(MU_2+ETA(2))
   CL=EXP(MU_3+ETA(3))
   K=CL/V
   S2=V/1000; DOSE IN 1000 U, CONC in U, VOLUME IN mL
$ERROR
   LOQ=LOG(10)
   IF(F==0) THEN
   IPRE=0
   ELSE
   IPRE=LOG(F)
   ENDIF
   IF(SIG==0) EXIT
   DUM=(LOQ-IPRE)/SIG
   CUMD=PHI(DUM)
   IF(TYPE.EQ.1) THEN
       F_FLAG=0
       Y= LOG(F)+SD*ERR(1)
   ENDIF
   IF(TYPE.EQ.2) THEN
       F_FLAG=1
       Y=CUMD
   ENDIF
$THETA
   -1.868;[KA]
   11.9 ;[V]
   10;[CL]
   0.523;[SD]
$OMEGA
0.258
0.177
0.227
$SIGMA
1 FIX
$EST METHOD=COND LAP INTERACTION MAXEVAL=9999 PRINT=5 FILE=PK.LOG.COND.ext

Sample Data for code 1:
Sample Data for code 2:

Best regards,

Xiao Hu (Shelley), Ph.D.
Scientist,
Development Pharmacokinetics & Disposition
Biogen Idec, Inc.
14 Cambridge Center
Cambridge, MA 02142
Phone: 617-679-3586
Fax: 617-679-3463
  • application/octet-stream attachment: PKM3.csv
Received on Thu Apr 29 2010 - 13:13:44 EDT

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