Re: Using MIXture model to fit 1 compartment vs 2 compartment model
Thank you, Joachim. You express my concern better than I could have. Unfortunately I could not find in the literature the compartmental priors to use in $PRIOR, only non-compartmental hooey. I am thankful to Rob ter Heine who pointed out a nice population PK study of similar patients receiving continuous veno-venous hemofiltration (CVVH) being presented this year at PAGE (#2526).
I also appreciate Maciej Swat's point that my coding was faulty, and that
CL2=THETA(1)*THETA(3)*ETA(1) led to poorly identifiable thetas, and should be simplified to CL2=THETA(3)*ETA(1), and similarly for TVV2. This also allowed me to re-introduce the parameter-specific etas.
Paul Hutson
Quoted reply history
On 5/15/2012 3:48 AM, Joachim Grevel wrote:
> Dear Paul and friends within the NONMEM community,
>
> You touch on a fundamental issue with your questions. The issue is, what to
> do with prior knowledge. Do we just fit the data at hand as well as we can,
> or do we want to embed the data at hand in a larger knowledge space. I for
> my part have once and for all made up my mind. I will not fit any more data
> and disregard prior knowledge. For me each drug only exists in its biologic
> context, and for each drug there is a body of knowledge that needs to be
> respected and represented. I do not hunt anymore for the perfect fit, nor do
> I adhere to a strict set of rules. Models need to represent both, prior
> knowledge and current data. I now often resort to representing prior
> knowledge via the $PRIOR functionality and I have gained experience in the
> use of informative priors.
>
> To answer your specific question: I would not go the route you have chosen
> using $MIX. Instead I would represent the two compartment model with
> informative priors and I would let your scares new data modify those priors,
> to a certain extent to arrive at meaningful individual predictions. Your
> very limited data set is obviously not fit to revise the knowledge base of
> the drug (CVVH - what is that?), but it may be sufficient to obtain
> individual predictions (to relate dialysis flow rate to individual clearance
> estimates?).
>
> The technicalities of setting up informative priors have been discussed in
> this forum recently.
>
> Good luck,
>
> Joachim
>
> Joachim Grevel, PhD
> Scientific Director
> BAST Inc Limited
> Loughborough Innovation Centre
> Charnwood Building
> Holywell Park, Ashby Road
> Loughborough, LE11 3AQ
> Tel: +44 (0)1509 222908
>
> -----Original Message-----
> From: [email protected] [mailto:[email protected]] On
> Behalf Of Paul Hutson
> Sent: 14 May 2012 16:50
> To: [email protected]
> Subject: [NMusers] Using MIXture model to fit 1 compartment vs 2 compartment
> model
>
> I have a small data set of 4 samples each from 15 patients getting CVVH for
> renal failure that was handed to me. Some subjects appear to be modeled
> best by a 1 compartment model, other by a 2 compartment model.
> I have tried the ctl stream below using MIX to allow NONMEM to fit to either
> a 1 or 2 cmpt model, and it appears to work well (Note there is high
> covariance in CL, V1, and Q,V2, so their respective ETAs are shared).
>
> However, I have two questions to the group:
> 1. Is this the optimal way to allow NONMEM to fit to a 1 vs 2 compt model?
>
> 2. Is this appropriate? That is, the drug likely is best modeled by (at
> least) a 2 compartment model, yet only a fraction (~20%) of these sparse
> data sets appear best fit by a 2 compt model. Given that the sampling was
> not optimized to detect/characterize a 2 compartment model, should I settle
> and report a one compartmental model, or describe a 2 cmpt when possible?
> Perhaps is it an angels on a pinhead issue, as my primary objective is to
> describe any effect of dialysate flow on clearance.
>
> $INPUT ID TIME CLCK=DROP AMT RATE SS II DV LGDV WGT HGT DURD FLOW CMPD EVID
> $DATA Zosyn.CSV IGNORE=# IGNORE(CMPD=2) $SUBROUTINES ADVAN6 TOL=3 $MODEL
> NPARAMS=7 NCOMP=2 COMP=(CENTRAL DEFDOSE)
> COMP=(TISSUE)
> ; 2 COMPARTMENT MODEL
> ; CMPD 1 = Piperacillin
> ; CMPD 2 = Tazobactam
>
> $MIX
> NSPOP=2
> P(1)=THETA(7)
> P(2)=1-THETA(7)
> P1C = THETA(7)
> $PK
> CALLFL=1
> EST=MIXEST
> CL1=THETA(1)*EXP(ETA(1));
> TVV1=THETA(2)*EXP(ETA(1));
> CL2=THETA(1)*THETA(3)*EXP(ETA(2))
> TVV2=THETA(2)*THETA(4)*EXP(ETA(2))
>
> FLG=1
> IF (MIXNUM.EQ.2) FLG=0
> CL=FLG*CL1 + (1-FLG)*CL2
> V1 = FLG*TVV1 + (1-FLG)*TVV2
> Q=THETA(5)*(1-FLG)
> V2 = THETA(6)**(1-FLG); V2 cannot be 0 for 1 compt due to K21=Q/V2 divide by
> 0 fault
> S1=V1
>
> K10 = CL*(FLOW/35)/V1
> K12 = (Q/V1)*(1-FLG)
> K21 = (Q/V2)*(1-FLG)
>
> $DES
> DADT(1) = -A(1) * (K10 + K12) + A(2) * K21
> DADT(2) = A(1) * K12 - A(2) * K21
>
> --
> Paul R. Hutson, Pharm.D.
> Associate Professor
> UW School of Pharmacy
> T: 608.263.2496
> F: 608.265.5421
--
Paul R. Hutson, Pharm.D.
Associate Professor
UW School of Pharmacy
T: 608.263.2496
F: 608.265.5421