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Duration of Absorption Time From Depot (Gut) as Covariate

From: Paul Hutson <prhutson>
Date: Thu, 10 Dec 2009 23:00:28 -0600
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

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 - 00:00:28 EST

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