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:

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 andCmax 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 absorptionof this drug from the gut is transporter-limited, and may be dependentupon 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 releaseformulation, 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-instantaneousinput 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 absorptionmodel (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, p7856This message and any attachments are solely for the intended recipient. If you are not the intended recipient, disclosure, copying, use or distribution of the information included in this message is prohibited --- Please immediately and permanently delete.

--

Paul R

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