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Re: PBPK structural model in NONMEM!

From: M Jamei <masoud.jamei>
Date: Mon, 14 Dec 2009 15:47:55 +0000

Dear Ke

To me one of main issues here is the identifiability of partition
coefficients because you donít have any observations to uniquely estimate
these parameters and there is not an observable relationship between renal
excretion and partition coefficients either. In such cases incorporation of
prior knowledge may be helpful, see:

Langdon G, Gueorguieva I, Aarons L and Karlsson M (2007) Linking preclinica=
l
and clinical whole-body physiologically based pharmacokinetic models with
prior distributions in NONMEM. Eur J Clin Pharmacol 63:485-498. (
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&do=
pt=Citation&list_uids=17345074
).

I noticed you have normalised weight to 25, are you subjects children?
Please note that if this is the case then body composition and blood flow t=
o
organs change by age and weight; however you havenít considered eta for
partition coefficients. Renal function is a big player for your drug and yo=
u
may also need considering maturation of renal function in children:

Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelu=
t
E, Grubb A, Veal GJ, Keir MJ and Holford NH (2009) Human renal function
maturation: a quantitative description using weight and postmenstrual age.
Pediatr Nephrol 24:67-76. (
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&do=
pt=Citation&list_uids=18846389).


In addition to incorporation of physiological knowledge into your model if
you have any physicochemical or in vitro data you can still use such
information. Your case as well as Paul Hutson case (Duration of Absorption
Time From Depot (Gut) as Covariate posted on Friday) are good examples of
joining bottom-up and top-down approaches, see:
http://www.pkuk.org.uk/ContentImages/MasoudJamei.pdf.



Regards

Masoud


2009/12/13 ke fang <fang.coco

> Dear all,
>
> I'm now developing a simple PBPK structural model in NONMEM. The input =
to
> the PBPK model was a i.m. injection, and the only output was the renal
> excretion.. Because the drug was a long acting formulation, so I try to
> model the absorption into a fast phase and a slow phase. Now, here comes =
the
> problem. I don't know how to get DOSE into the model. Here is the control
> stream file:
>
> $PROB WBPBPK POPULATION MODEL
> $INPUT ID TIME CONC=DV AMT WT EVID CMT
> $DATA ..\PBPK.TXT IGNORE=#
> $SUBROUTINES ADVAN6 TOL=3
> $MODEL
> COMP = (LIV) ; 1 - LIVER COMPARTMENT
> COMP = (KID) ; 2 - KIDNEY COMPARTMENT
> COMP = (MUS) ; 3 - MUSCLE COMPARTMENT
> COMP = (INJ) ; 4 - INJECTIONSITE COMPARTMENT RECEIVING DOSE
> COMP = (VEN) ; 5 - VENOUS COMPARTMENT
> COMP = (OUT) ; 6 - KIDNEY EXCRETION COMPARTMENT
> $PK
> ; ------------------------ TWO ABSORBTION PHASE-------------------- ;
> PHSF = 0.714 ; FAST PHASE ABSORPTION FRACTION
> PHSS = 0.286 ; SLOW PHASE ABSORPTION FRACTION
> KF = 0.032334 ; FAST PHASE ABSORPTION ABSORPTION RATE
> KS = 0.00835 ; SLOW PHASE ABSORPTION ABSORPTION RATE
> ; ------------------------- BLOOD FLOWS (Q,L/HR) -------------------- ;
> QVEN = 2.049*WT ;L/H/KG;
> QLIV =QVEN*0.3053*(WT/25) ;L/H/KG;
> QKID =QVEN*0.1398*(WT/25) ;L/H/KG;
> QMUS =QVEN*0.2524*(WT/25) ;L/H/KG;
> QINJ = QVEN*0.2524*(0.5/WT/25) ;L/H/KG;
> ;----------------------------TISSUE VOLUMES (V,L)----------------------;
> VLIV =0.0294*WT ;KG;
> VKID =0.004*WT ;KG;
> VMUS =0.4007*WT ;KG;
> VINJ =0.5 ;KG;
> VVEN =0.06*WT ;KG;
> ;----------------------------PARTITION COEFFICIENTS-------------------;
> PLIV = EXP(THETA(2))
> PKID = EXP(THETA(3))
> PMUS = EXP(THETA(4))
> ;---------------------KIDNEY EXCRETION-------------------;
> TVEXCR=EXP(THETA(1))
> EXCR=TVEXCR*EXP(ETA(1))
> $DES
> ;--------------------COMPARTMENT CONCENTRATIONS-------------------;
> C1 = A(1)/VLIV
> C2 = A(2)/VKID
> C3 = A(3)/VMUS
> C4 = A(4)/VINJ
> C5 = A(5)/VVEN
> DADT(1)=QLIV*(C5-C1/PLIV)
> DADT(2)=(QKID*(C5-C2/PKID)-C2*EXCR)
> DADT(3)=QMUS*(C5-C3/PMUS)
> DADT(4)=(QINJ*(C5-C4/PMUS))
> DADT(5)=(QLIV*C1/PLIV+QKID*C2/PKID+QMUS*C3/PMUS+QINJ*C4/PMUS-QVEN*C5)
> DADT(6)=EXCR
> $ERROR
> Y=A(3)/VMUS+EPS(1)
> ;------------------------------INITIAL
> ESTIMATES--------------------------------;
> $THETA(0,0.5) ; 1-EXCR
> $THETA(0,1.82,10) ; 2-PLIV
> $THETA(0,6.46,10) ; 3-PKID
> $THETA(0,0.486) ; 4-PMUS
> $OMEGA(0.5) ; 1-EXCR
> $SIGMA(1) ; 1-ERROR
> $EST PRINT=5 MAX=9990 POSTHOC SIGDIG=3 METHOD=1
> $COV MATRIX=R
> $TABLE ID TIME CONC WT AMT NOPRINT ONEHEADER FILE=PBPK.FIT
>
> Can anyone give some hint?
> Thanks in advance!
>
> Ke, Fang
>
>

Received on Mon Dec 14 2009 - 10:47:55 EST

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