From: Shuying Yang <*shuying.y.yang*>

Date: Thu, 4 Mar 2010 11:18:21 +0100

Dear NMusers

I have collected from several studies PK data from healthy subjects, via IV=

=

and SubCut and patients via both routes and would like to model them all =

together. For all subjects, only one dose level via one administration was =

given. From exploration of raw data, it is observed that there might be som=

e=

difference in bioavailability from SubCut between healthy subjects and =

patients. I tried the model using ADVAN5, the parameterisation is listed =

below.

My questions are:

Is the model with six THETAs and ETAs an identifiable model? NOTE: NONMEM=

=

run with this model is successful, also the estimates for CL,V2,Q and V3 ar=

e=

similar to results with IV data alone.

What is a better way to explore the potential difference in PK between =

healthy subjects and patients with SubCut?

Finally, I also tried to model K12 as K12=0, IF(ROUT.GT.1) =

K12=EXP(THETA(5)+ETA(5)), could anyone help explain why this is wrong? =

NONMEM gave the following error message:

0PRED EXIT CODE = 1

0INDIVIDUAL NO. 1 ID=0.10080000E+04 (WITHIN-INDIVIDUAL) DATA RE=

C=

NO. 2

THETA=

1.10E+00 1.40E+00 5.00E-01 2.50E+00 -1.10E+00 5.00E-01

NUMERICAL DIFFICULTIES OBTAINING THE SOLUTION.

THE COEFFICIENT MATRIX IS ALGORITHMICALLY SINGULAR.

Thanks for the help.

Shuying Yang

Clinical Pharmacology Modelling and Simulation

GlaxoSmithKline

CMT = 1 for SubCut dose record, and CMT=2 for IV dose record

ROUT=1 for IV and ROUT=2 for SubCut

CL = EXP(THETA(1)+ETA(1))

V2 = EXP(THETA(2)+ETA(2))

Q = EXP(THETA(3)+ETA(3))

V3 = EXP(THETA(4)+ETA(4))

K20 = CL/V2

K23 = Q/V2

K32 = Q/V3

K12 = EXP(THETA(5)+ETA(5))

RO = EXP(THETA(6)+ETA(6))

F1=0

IF(ROUT.GT.1) F1=RO/(1+RO)

$THETA

1.0 ; CL

1.2 ; V2

0.5 ; Q

1.5 ; V3

-1.3 ; LOG(KA) /DAY

1.3 ; LOGIT(F1)

$OMEGA 0.05 ;CL

$OMEGA 0.06 ;V2

$OMEGA 0.1 ; Q

$OMEGA 0.05 ;V3

$OMEGA 0.05 ; LOG KA

$OMEGA 0.05 ; LOGIT F1

$SIGMA

0.02; PROPORTIONAL

2000; ADDITIVE

-----------------------------------------------------------

This e-mail was sent by GlaxoSmithKline Services Unlimited

(registered in England and Wales No. 1047315), which is a

member of the GlaxoSmithKline group of companies. The

registered address of GlaxoSmithKline Services Unlimited

is 980 Great West Road, Brentford, Middlesex TW8 9GS.

-----------------------------------------------------------

Received on Thu Mar 04 2010 - 05:18:21 EST

Date: Thu, 4 Mar 2010 11:18:21 +0100

Dear NMusers

I have collected from several studies PK data from healthy subjects, via IV=

=

and SubCut and patients via both routes and would like to model them all =

together. For all subjects, only one dose level via one administration was =

given. From exploration of raw data, it is observed that there might be som=

e=

difference in bioavailability from SubCut between healthy subjects and =

patients. I tried the model using ADVAN5, the parameterisation is listed =

below.

My questions are:

Is the model with six THETAs and ETAs an identifiable model? NOTE: NONMEM=

=

run with this model is successful, also the estimates for CL,V2,Q and V3 ar=

e=

similar to results with IV data alone.

What is a better way to explore the potential difference in PK between =

healthy subjects and patients with SubCut?

Finally, I also tried to model K12 as K12=0, IF(ROUT.GT.1) =

K12=EXP(THETA(5)+ETA(5)), could anyone help explain why this is wrong? =

NONMEM gave the following error message:

0PRED EXIT CODE = 1

0INDIVIDUAL NO. 1 ID=0.10080000E+04 (WITHIN-INDIVIDUAL) DATA RE=

C=

NO. 2

THETA=

1.10E+00 1.40E+00 5.00E-01 2.50E+00 -1.10E+00 5.00E-01

NUMERICAL DIFFICULTIES OBTAINING THE SOLUTION.

THE COEFFICIENT MATRIX IS ALGORITHMICALLY SINGULAR.

Thanks for the help.

Shuying Yang

Clinical Pharmacology Modelling and Simulation

GlaxoSmithKline

CMT = 1 for SubCut dose record, and CMT=2 for IV dose record

ROUT=1 for IV and ROUT=2 for SubCut

CL = EXP(THETA(1)+ETA(1))

V2 = EXP(THETA(2)+ETA(2))

Q = EXP(THETA(3)+ETA(3))

V3 = EXP(THETA(4)+ETA(4))

K20 = CL/V2

K23 = Q/V2

K32 = Q/V3

K12 = EXP(THETA(5)+ETA(5))

RO = EXP(THETA(6)+ETA(6))

F1=0

IF(ROUT.GT.1) F1=RO/(1+RO)

$THETA

1.0 ; CL

1.2 ; V2

0.5 ; Q

1.5 ; V3

-1.3 ; LOG(KA) /DAY

1.3 ; LOGIT(F1)

$OMEGA 0.05 ;CL

$OMEGA 0.06 ;V2

$OMEGA 0.1 ; Q

$OMEGA 0.05 ;V3

$OMEGA 0.05 ; LOG KA

$OMEGA 0.05 ; LOGIT F1

$SIGMA

0.02; PROPORTIONAL

2000; ADDITIVE

-----------------------------------------------------------

This e-mail was sent by GlaxoSmithKline Services Unlimited

(registered in England and Wales No. 1047315), which is a

member of the GlaxoSmithKline group of companies. The

registered address of GlaxoSmithKline Services Unlimited

is 980 Great West Road, Brentford, Middlesex TW8 9GS.

-----------------------------------------------------------

Received on Thu Mar 04 2010 - 05:18:21 EST