From: Han, Kelong <*keh45*>

Date: Sun, 28 Mar 2010 14:38:46 -0400

Dear Dr. Holford:

Please correct me if I am wrong, but I think the DV may not have been log t=

ransformed. If the DV was log transformed, the residual error model may hav=

e been coded as

IPRED=LOG(F)

Y=LOG(F)+W*ERR(1)

Dear Dr. Gibiansky:

I think you may have used DV in the original units with an residual error m=

odel for log transformed DV, which is equivalent to an additional+proportio=

nal residual model. Please correct me if I am wrong. But would you please c=

larify a little bit why you used this error model instead of a regular addi=

tional+proportional residual model?

Thanks!

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

Kelong Han

PhD Candidate

University of Pittsburgh

School of Pharmacy

________________________________________

From: owner-nmusers

Of Nick Holford [n.holford

Sent: Sunday, March 28, 2010 1:44 PM

To: nmusers

Cc: chenyuhong

Subject: Re: [NMusers] Parallel first order and Michaelis-Menten eliminatio=

n

Leonid,

Thanks for the code example which illustrates one side of a religious debat=

e which took place a few weeks ago on PharmPK. The essence of this debate w=

as should one normalize PK parameters to a unit volume or to a unit body.

The unit volume believers feel that the rate constant is the 'natural' way =

to describe pharmacokinetics while the unit body believers feel that cleara=

nce is more 'natural'. Both groups agree that the two systems are just repa=

rameterizations and make identical numerical predictions.

Your coding of Vmax for the mixed order elimination process has the implici=

t units of mass/time per unit volume e.g. mg/h/L. This is the unit volume b=

elief system.

I am a unit body believer so I would code this system differently with a ve=

ry simple change- substituting A(1) with C1 to multiply the mixed order exp=

ression. I have also changed VM to VMUB to indicate that the dimensions of =

the Vmax parameter are per unit body i.e. mg/h per body.

DADT(1) = -K10*A(1)-C1*VMUB/(KM+C1)-K12*A(1)+K21*A(2)

It could also be written like this to emphasize that the mixed order proces=

s has the same units as CL (for unit body believers) when C1 tends to 0:

DADT(1) = -C1*(CL+VMUB/(KM+C1) - K12*A(1)+K21*A(2)

I note also that your residual error model implies that the DV has been log=

transformed. This reflects yet another belief system which I think you hav=

e shown has little, if any, practical merit. I prefer to keep the DV in the=

original units.

Best wishes,

Nick

Leonid Gibiansky wrote:

ADVAN6 ADVAN8 or (nm7) ADVAN13

The code is below

Leonid

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

$SUBROUTINE ADVAN6 TOL=9

$MODEL

NCOMP = 2

COMP = (CENTRAL) ;1

COMP = (PERIPH) ;2

$PK

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

V1= THETA(2)*EXP(ETA(2))

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

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

VM= THETA(5)*EXP(ETA(5))

KM= THETA(6)

K10 = CL/V1

K12 = Q/V1

K21 = Q/V2

S1 = V1

S2 = V2

$DES

C1 = A(1)/S1

DADT(1) = -K10*A(1)-A(1)*VM/(KM+C1)-K12*A(1)+K21*A(2)

DADT(2) = K12*A(1)-K21*A(2)

$ERROR

TY = A(1)/V1

IPRED=TY

W = SQRT(THETA(7)**2/TY**2+THETA(8)**2)

Y = IPRED*EXP(W*ERR(1))

$THETA

.....

$OMEGA

.....

$SIGMA

1 FIX ; ~ERR

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

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com<http://www.quantpharm.com>

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

chenyuhong

Dear All,

I am working with a Biologic and would like to have a PK model with paralle=

l first order and Michaelis-Menten elimination. Any suggestion about which =

subroutine I am supposed to use? If you can share an example for the contro=

l stream, that will be a great help.

Thanks,

Yuhong

--

Nick Holford, Professor Clinical Pharmacology

Dept Pharmacology & Clinical Pharmacology

University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand

tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53

email: n.holford

http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

Received on Sun Mar 28 2010 - 14:38:46 EDT

Date: Sun, 28 Mar 2010 14:38:46 -0400

Dear Dr. Holford:

Please correct me if I am wrong, but I think the DV may not have been log t=

ransformed. If the DV was log transformed, the residual error model may hav=

e been coded as

IPRED=LOG(F)

Y=LOG(F)+W*ERR(1)

Dear Dr. Gibiansky:

I think you may have used DV in the original units with an residual error m=

odel for log transformed DV, which is equivalent to an additional+proportio=

nal residual model. Please correct me if I am wrong. But would you please c=

larify a little bit why you used this error model instead of a regular addi=

tional+proportional residual model?

Thanks!

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

Kelong Han

PhD Candidate

University of Pittsburgh

School of Pharmacy

________________________________________

From: owner-nmusers

Of Nick Holford [n.holford

Sent: Sunday, March 28, 2010 1:44 PM

To: nmusers

Cc: chenyuhong

Subject: Re: [NMusers] Parallel first order and Michaelis-Menten eliminatio=

n

Leonid,

Thanks for the code example which illustrates one side of a religious debat=

e which took place a few weeks ago on PharmPK. The essence of this debate w=

as should one normalize PK parameters to a unit volume or to a unit body.

The unit volume believers feel that the rate constant is the 'natural' way =

to describe pharmacokinetics while the unit body believers feel that cleara=

nce is more 'natural'. Both groups agree that the two systems are just repa=

rameterizations and make identical numerical predictions.

Your coding of Vmax for the mixed order elimination process has the implici=

t units of mass/time per unit volume e.g. mg/h/L. This is the unit volume b=

elief system.

I am a unit body believer so I would code this system differently with a ve=

ry simple change- substituting A(1) with C1 to multiply the mixed order exp=

ression. I have also changed VM to VMUB to indicate that the dimensions of =

the Vmax parameter are per unit body i.e. mg/h per body.

DADT(1) = -K10*A(1)-C1*VMUB/(KM+C1)-K12*A(1)+K21*A(2)

It could also be written like this to emphasize that the mixed order proces=

s has the same units as CL (for unit body believers) when C1 tends to 0:

DADT(1) = -C1*(CL+VMUB/(KM+C1) - K12*A(1)+K21*A(2)

I note also that your residual error model implies that the DV has been log=

transformed. This reflects yet another belief system which I think you hav=

e shown has little, if any, practical merit. I prefer to keep the DV in the=

original units.

Best wishes,

Nick

Leonid Gibiansky wrote:

ADVAN6 ADVAN8 or (nm7) ADVAN13

The code is below

Leonid

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

$SUBROUTINE ADVAN6 TOL=9

$MODEL

NCOMP = 2

COMP = (CENTRAL) ;1

COMP = (PERIPH) ;2

$PK

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

V1= THETA(2)*EXP(ETA(2))

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

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

VM= THETA(5)*EXP(ETA(5))

KM= THETA(6)

K10 = CL/V1

K12 = Q/V1

K21 = Q/V2

S1 = V1

S2 = V2

$DES

C1 = A(1)/S1

DADT(1) = -K10*A(1)-A(1)*VM/(KM+C1)-K12*A(1)+K21*A(2)

DADT(2) = K12*A(1)-K21*A(2)

$ERROR

TY = A(1)/V1

IPRED=TY

W = SQRT(THETA(7)**2/TY**2+THETA(8)**2)

Y = IPRED*EXP(W*ERR(1))

$THETA

.....

$OMEGA

.....

$SIGMA

1 FIX ; ~ERR

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

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com<http://www.quantpharm.com>

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

chenyuhong

Dear All,

I am working with a Biologic and would like to have a PK model with paralle=

l first order and Michaelis-Menten elimination. Any suggestion about which =

subroutine I am supposed to use? If you can share an example for the contro=

l stream, that will be a great help.

Thanks,

Yuhong

--

Nick Holford, Professor Clinical Pharmacology

Dept Pharmacology & Clinical Pharmacology

University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand

tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53

email: n.holford

http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

Received on Sun Mar 28 2010 - 14:38:46 EDT