RE: Parallel first order and Michaelis-Menten elimination
Dear Dr. Holford:
Please correct me if I am wrong, but I think the DV may not have been log
transformed. If the DV was log transformed, the residual error model may have
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 model
for log transformed DV, which is equivalent to an additional+proportional
residual model. Please correct me if I am wrong. But would you please clarify a
little bit why you used this error model instead of a regular
additional+proportional residual model?
Thanks!
------------
Kelong Han
PhD Candidate
University of Pittsburgh
School of Pharmacy
Quoted reply history
________________________________________
From: [email protected] [[email protected]] On Behalf Of
Nick Holford [[email protected]]
Sent: Sunday, March 28, 2010 1:44 PM
To: [email protected]
Cc: [email protected]
Subject: Re: [NMusers] Parallel first order and Michaelis-Menten elimination
Leonid,
Thanks for the code example which illustrates one side of a religious debate
which took place a few weeks ago on PharmPK. The essence of this debate was
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 clearance is
more 'natural'. Both groups agree that the two systems are just
reparameterizations and make identical numerical predictions.
Your coding of Vmax for the mixed order elimination process has the implicit
units of mass/time per unit volume e.g. mg/h/L. This is the unit volume belief
system.
I am a unit body believer so I would code this system differently with a very
simple change- substituting A(1) with C1 to multiply the mixed order
expression. 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 process
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 have
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: http://www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
[email protected]<mailto:[email protected]> wrote:
Dear All,
I am working with a Biologic and would like to have a PK model with parallel
first order and Michaelis-Menten elimination. Any suggestion about which
subroutine I am supposed to use? If you can share an example for the control
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: [email protected]<mailto:[email protected]>
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford