**From: MATTHEW.HUTMACHER@monsanto.com
Subject: Q:$DES with a lagged zero-order bolus dose**

Date: 24 Jun 1998 16:45:53 -0500

I am trying to use ADVAN6 to model a zero-order bolus dose with a lag time. I am having difficulty figuring out how to do this. (I know I could do this with ADVAN3 but there are other modeling issues which require the differential equation solver.)

The code I have been using (obviously wrong) is like the following:

$INPUT ID AMT EVID TIME DV=LCON RATE (rate=-2 duration)

$SUBROUTINE ADVAN6 TRANS1 TOL=5

$MODEL COMP=(CENTRAL,DEFDOSE,DEFOBS)

CALLFL=-2 (for lagged dose call to PK)

D1 =THETA(1)*EXP(ETA(1))

K12 =THETA(2)*EXP(ETA(2))

K21 =THETA(3)*EXP(ETA(3))

K =THETA(4)*EXP(ETA(4))

V =THETA(5)*EXP(ETA(5))

ALAG1 =THETA(6)*EXP(ETA(6))

S1=V

$DES

Z=0

IF (T.LE.DOSTIM) Z=1

DADT(1)=Z*???-(K12+K)*A(1)

DADT(2)=K12*A(1)-K21*A(2)

I can't seem to figure out how to code the differential equations? Any advice would be appreciated.

**From: alison@c255.ucsf.EDU (ABoeckmann)
Subject: Re: Q:$DES with a lagged zero-order bolus dose**
Date: 29 Jun 1998 18:30:39 -0400

With ADVAN6, dosing is handled the same as with ADVAN3 (or any other ADVAN routine). Include a dose record with the AMT and the RATE data items, setting RATE to -2. This indicates that D1 will be modelled in $PK, as was done. In the $DES block, code only the compartmental kinetics.

PREDPP itself adds an extra term to DADT(1) giving the total rate of infusion into the compartment (in this case, AMT/D1) when appropriate:

starting when time = ALAG1, and ending when the given AMT has been entered into the system.