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Re: Duration of Absorption Time From Depot (Gut) as Covariate

From: Leonid Gibiansky <LGibiansky>
Date: Fri, 11 Dec 2009 00:55:00 -0500

Paul,
You need to rewrite the system using differential equations rather than
ADVAN2 and then use

$DES
FLAG=1
IF(T.GE.TOFF) FLAG=0.0001
KA=TVKA*FLAG

In the PK block, this should not work because your TIME is discrete
while nonmem is trying small variation of TOFF parameter to compute the
gradient (which is indeed zero if you do it in the PK block)

On a different note, you are assuming 1 to 1 IVIVC (in-vitro dissolution
= in vivo dissolution). It is rarely the case. You may try to describe
your dissolution profile by some function (Weibull is very flexible) and
then use parametric expression for IVIVC (for example, time scaling) to
insert the dose into the depot compartment (as input rate)

Thanks
Leonid



--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




Paul Hutson wrote:
> I have been asked to look at data that suggest a dependence of AUC and
> Cmax upon transit time in the gut. The elimination rates for the one
> compartment model are quite similar, suggesting that the variability
> lies in bioavailability. Preliminary data suggest that the absorption
> of this drug from the gut is transporter-limited, and may be dependent
> upon the duration of time that the drug is exposed to a specific portion
> of the duodenum or jejunum. Drug is observed at the earliest sampling
> time, so I am not including a Tlag at this point.
>
> I have in vitro dissolution data for this (hopefully) extended release
> formulation, which I am introducing to the gut compartment for the human
> subject PK data as events of AMT and RATE corresponding to each measured
> point in the dissolution curve. Thus I am fixing it as a time-dependent
> inputs over the 12 hour period following the single dose and during the
> plasma sampling. Because of the non-instantaneous input function, I
> understand I cannot use Savik's TRANSIT model (2007).
>
> I have tried the code below to try to turn off Ka after some time TOFF,
> the point at which the drug is estimated to have moved past the section
> of absorption. There is no change in the gradient for TOFF, and the fit
> is not improved over a simple 1 compartment absorption model (ADVAN2).
> I cannot turn off compartment 1 (-1) in my INPUT, since I do not know
> when to turn it off (I am trying to determine this in the model).
> There is extensive first pass of the compound - I do not know of any
> auto-inhibition of metabolism. I suppose that I could try to trip F1 to
> null at some TOFF, but tripping Ka to Null seems more physiologic.
>
> Can anyone suggest a snippet of code that might close Ka based upon a
> covariate THETA corresponding to the time required to move past the
> intestinal segment of absorption?
> Thanks very much.
> Paul
>
> $SUBROUTINES ADVAN2
> ; 1 COMPARTMENT MODEL, NO LAG, NO LIMIT TO ABSORPTION PERIOD
>
>
> $PK
> TVKA=THETA(1); ABSORPTION RATE FROM GUT
> CL=THETA(2)*EXP(ETA(1)); CLEARANCE
> V2=THETA(3)*EXP(ETA(2)); V2
> TOFF=THETA(4)*EXP(ETA(3)); DURATION OF PRESENCE IN ABSORPTION SEGMENT
> K=CL/V2
> DOSE=5; MG TABLET
> AUC=DOSE/CL
> S2=V2/1000
>
> FLAG=1
> IF(TIME.GE.TOFF) FLAG=0.0001
> KA=TVKA*FLAG
>
> $ERROR
> IPRE = F
> W1=F
> DEL = 0
> IF(IPRE.LT.0.001) DEL = 1
> IRES = DV-IPRE; NEGATIVE TREND IS OVERESTIMATING IPRED WRT DV
> IWRE = IRES/(W1+DEL)
> Y=F*(1+ERR(1))+ERR(2)
>
>
> $THETA (0.1,1.23, 50); KAGUT
> $THETA (0.10,97.8,1000); CL
> $THETA (0.1,86.5,1000); V2
> $THETA (0.001, 1, 24); DUR
>
>
> ;$OMEGA 0.3; KA
> $OMEGA 0.5; CL
> $OMEGA 0.3; V2
> $OMEGA 0.6; TOFF
> --
>
> Paul R. Hutson, Pharm.D.
>
> Associate Professor
>
> UW School of Pharmacy
>
> 777 Highland Avenue
>
> Madison WI 53705-2222
>
> Tel 608.263.2496
>
> Fax 608.265.5421
>
> Pager 608.265.7000, p7856
>
Received on Fri Dec 11 2009 - 00:55:00 EST

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