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

From: Paul Hutson <prhutson>
Date: Tue, 15 Dec 2009 16:52:36 -0600
Leonid & Jeroen:
Thank you for your suggestions.  I incorporated Jeroen's suggestion of using MTIME below, with a slight modification (KA = TVKA *(1-MPAST(1))), since I want to turn KA off, not on, at TOFF.

I try below to use Leonid's suggestion of a Weibull distribution to describe the dissolution of the oral product, rather than using multiple AMT & RATE inputs corresponding to the dissolution data for the product.  My fit deteriorates both by OBj Func and VPC.  Does the code below appear to be appropriate for introducing the oral drug in A(1) using a Weibull distribution?
Thanks very much
Paul

$SUBROUTINES ADVAN6 TOL=3
$MODEL COMP=(DEPOT, DEFDOSE) COMP=(CENTRAL, DEFOBS)
$PK
callfl=-2
CL=THETA(1)*EXP(ETA(1)); CLEARANCE
V2=THETA(2)*EXP(ETA(2)); V2
TOFF=THETA(3)*EXP(ETA(3)); DURATION OF PRESENCE IN ABSORPTION SEGMENT
K=CL/V2
AUC=AMT/CL
S2=V2/1000

;CLOSE ABSORPTION AFTER SOME TIME TOFF
TVKA=THETA(4)*EXP(ETA(4))
MTIME(1)=TOFF
KA=TVKA*(1.001-MPAST(1)); MPAST(1) = O UNTIL MTIME(1)(TOFF) IS REACHED, THEN IS 1

;DRUG APPEARANCE
PAR1=THETA(5); SCALING CONSTANT FOR TIME
GAMA1=THETA(6); SLOPE FUNCTION FOR WEIBULL
WB1=1-EXP(-((TIME/PAR1)**GAMA1))
RAT1 = AMT*WB1

$DES
DADT(1) = RAT1 - A(1)*KA
DADT(2) = A(1)*KA - A(2)*CL/V2

$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);      CL
$THETA  (0.10,97.8,1000);    V2
$THETA  (0.1,86.5,1000);      TOFF
$THETA  (0.0001, .7, 4); KA
$THETA  176.1 FIXED; PAR1
$THETA    1.033 FIXED ; SLOPE

 
$OMEGA   0.5; CL
$OMEGA   0.3; V2
$OMEGA   0.6; TOFF
$OMEGA   0.3; ka


$SIGMA  .5;         SIG1
$SIGMA  .1;         SIG2

$ESTIMATION METH=1 INT SIGDIGITS=3 MAXEVAL=9999 PRINT=10 NOABORT

Elassaiss - Schaap, J. (Jeroen) wrote:
Leonid, Paul,

Alternatively one may use the MTIME function in NM6 so the algebraic
solutions in eg. ADVAN2 are still applicable:

$PK
....
MTIME(1)=TOFF
KA=TVKA*MPAST(1)

Best regards,
Jeroen

Jeroen Elassaiss-Schaap, PhD
Modeling & Simulation Expert
Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3)
Early Clinical Research and Experimental Medicine
Schering-Plough Research Institute
T: +31 41266 9320


-----Original Message-----
From: 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

    


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--
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 Tue Dec 15 2009 - 17:52:36 EST

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