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

Received on Thu Apr 29 2010 - 13:13:44 EDT

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

- application/octet-stream attachment: PK_M3_log.csv