From: kmanouil@unmc.edu

Subject: Sequential absorption processes with lag time

Date: Thu, 4 Oct 2001 11:58:01 -0500

Dear NONMEM users,

I read discussion ?modeling fast and slow absorption? back to 1995.

Currently, I have similar type of problem.

There is one-compartment model with two absorption compartments linked

together by zero-order rate. A drug dosed in one of depot compartments.

Absorption from the second compartment had delay in a time.

So far I used ADVAN6 with two depot compartments and central compartment.

Despite, the fact that the problem was solved with WinNonlin,

I cannot figure out how to code time delay in NONMEM.

Can you help me with advice?

Konstantine Manouilov

Research Associate

University of Nebraska Medical Center

From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com>

Subject: RE: Sequential absorption processes with lag time

Date: Mon, 15 Oct 2001 13:42:47 +0200

Konstantine,

You can try the following control which implements the sequential zero-order

-- first-order absorption with the lag time.

$PROBLEM Delayed absorption

$INPUT ID TIME AMT RATE CONC=DV

$DATA nmd.txt

$SUBROUTINES ADVAN2 TRANS2

$PK

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

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

D1 = THETA(3) * EXP(ETA(3))

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

ALAG1 = THETA(5) * EXP(ETA(5))

S2 = V

$ERROR CALLFL=0

IPRE = F

Y = IPRE * EXP(ERR(1))

$THETA

(0 3 10); 1 CL

(1 100 ); 2 V

(0 .5 5); 3 D1

(0 1 2); 4 KA

(0 .5 1); 5 ALAG

$OMEGA .1 .1 .1 .1 .1

1 2 3 4 5

$SIGMA .05

$EST MSFO=msf MAX=9990 PRINT=10 POSTHOC

$COV

$TABLE ID TIME AMT IPRE FILE=tab.txt NOPRINT ONEHEADER

$TABLE ID CL V D1 ALAG1 AMT FILE=prm.txt NOPRINT ONEHEADER NOAPPEND FIRST

An example of a (single-individual) data set is given below. It can be used

for simulations (DV variable is dummy). Note RATE = -2 for the dose record

to allow estimating zero-order absorption duration D1.

1 0 10 -2 0

1 0.1 0 0 1

1 0.2 0 0 1

1 0.5 0 0 1

1 1 0 0 1

1 2 0 0 1

1 4 0 0 1

1 8 0 0 1

1 16 0 0 1

1 24 0 0 1

1 48 0 0 1

Best regards,

Vladimir

------------------------------------------------------------------------

Vladimir Piotrovsky, Ph.D.

Research Fellow

Advanced Modelling and Simulations

Global Clinical Pharmacokinetics and Clinical Pharmacology (ext. 5463)

Janssen Research Foundation

B-2340 Beerse

Belgium

Email: vpiotrov@janbe.jnj.com