Re: Sequential PD model parameter stays at initial estimation problem
Hi Dear Dr. Holford,
Thank you so much for your response.
What I model is an enzyme drug. The base was not zero and it was the
baseline level of the substrate of the enzyme for each individual measured.
I was just trying to fix the baseline level as constant at the baseline for
each individual and model the effect of enzyme activity on its substrate
concentration by the M-M function. I guess I should not use the model in my
question since an input should be included. I also tried to include kin and
kout to model the baseline level and that way the model was able to
run: DADT(4)=kin-kout*A(4) -Vmax*CP*A(4)/(Km+A(4)).
For the model with kin, kout, if I only use one parameter kin and replace
kout with kin/base, the model was able to run ok. However, if I try to
estimate both kin and kout with the following code:
kin= THETA(1)*EXP(ETA(1))
kout= THETA(2)*EXP(ETA(2))
Vmax= THETA(3)* EXP(ETA(3))
Km = 38.9 ; Enobia Km data
kin=kout*base
F4=kin/kout ;
kin stays at its initial estimation I provided and gradient remains zero.
Is it because kin and kout are related, so NM just fix one and estimate
the other one?
You are right that I was initializing a differential equation by putting a
AMT of 1 in CMT 4 at TIME=0. I will definitely try what you suggest.
Do you have other suggestions to model such enzyme replacement drug? Thanks
again!
Lei
Quoted reply history
On Thu, Nov 10, 2011 at 11:07 PM, Nick Holford <[email protected]>wrote:
> Lei,
>
> Have you checked in a $TABLE file that CP has the expected value and that
> A(4) is indeed initialized at a non zero value of 'base'? You don't
> explicitly define 'base' in your code. If it zero then of A(4) will remain
> at zero and Vmax will have a gradient of zero.
>
> You don't give any clue what kind of PD marker you are trying to model but
> it is rather strange that you don't allow any input of the marker in
> DADT(4). Even if CP remained zero the marker would disappear because there
> is no input.
>
> You seem to be using the very old fashioned NONMEM V method of
> initializing a differential equation by putting a AMT of 1 in CMT 4 at
> TIME=0.
>
> Since NONMEM VI this has become much simpler.
>
> Just use this:
> A_0(4)=base
> Don't set F4 to anything and don't put and AMT into CMT=4.
>
> Nick
>
>
> On 11/11/2011 8:18 a.m., Lei Diao wrote:
>
>> Hi Dear NMusers,
>>
>> I have a sequential PD model and I listed the code here. base is the
>> baseline level of the PD parameter for each individual and was included in
>> the dataset. The problem with this code is that my only parameter to be
>> estimated Vmax stays at the initial estimation whatever I provide and the
>> gradient for THETA1 stays at 0 from the beginning. And the run time is
>> extremely long. If I change F4 to another THETA to be estimated, the same
>> problem still exists.
>>
>> Will anyone please shed some light on this problem?
>>
>> Thanks a lot!
>>
>> Lei
>>
>>
>> $PROBLEM PD model
>> $INPUT ID ETACL ETAV2 ETAKA Weight AMT DV TIME STUDYbase CMT
>>
>> $DATAPD.csv IGNORE=@ WIDE
>>
>> $SUBROUTINES ADVAN6 TOL=3
>>
>> $MODEL NCOMP=4
>> COMP=GUT COMP=CENTRAL COMP=PERI COMP=EFFECT
>>
>> ;---------------
>> $PKSCALE= Weight
>>
>> SCALE2 = Weight ** 0.75; allometric
>>
>> THETACL=1 ; L/day
>> THETAV1= 1; L/kg
>> THETACLRA= 1 ; L/day
>> THETAV2=1 ; L/kg
>> THETAKA= 1 ; 1/day
>> THETAALAG1= 1 ;days
>> THETAF1= 1
>> THETACLHILL= 1
>> THETACLTITER= 1
>> THETACLRAHILL= 1
>>
>> CL= SCALE2 * THETACL * EXP(ETACL)
>>
>> V1= SCALE * THETAV1
>> CLRA= SCALE2 * THETACLRA
>> V2= SCALE * THETAV2 * EXP(ETAV2)
>> KA= THETAKA * EXP(ETAKA)
>> ALAG1= THETAALAG1
>>
>> F1 = THETAF1
>> S2=V1
>> Vmax= THETA(1)* EXP(ETA(1))
>> Km = 100
>> F4=base ; R0 is the baseline for each individual
>>
>> K= CL / V1
>> K23= CLRA / V1
>> K32= CLRA / V2
>>
>>
>>
>> $DES DADT(1)= -KA * A(1)
>> DADT(2)= (KA * A(1)) - ((K + K23) * A(2)) + (K32 * A(3))
>> DADT(3)= K23 * A(2) - K32 * A(3)
>> CP= A(2)/S2
>> DADT(4)= -Vmax*CP*A(4)/(Km+A(4))
>>
>>
>> $ERROR
>> IPRED=F
>> Y= A(4)*(1+ERR(1))+ERR(2)
>> ;---------------
>> $THETA(0,10)
>> $OMEGA (0 FIXED)
>> $SIGMA 0.1 10
>> ;---------------
>> $EST METHOD=0 MAXEVAL=9999 NOABORT PRINT=5
>> $COVARIANCE
>>
>>
> --
> Nick Holford, Professor Clinical Pharmacology
> Dept Pharmacology& Clinical Pharmacology, Bldg 505 Room 202D
> 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]
> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
>
>
--
Lei Diao
Postdoc in PK/PD modeling and simulation
University of Tennessee College of Pharmacy