From: "Ralph Quadflieg" <email@example.com>
Date: 28 Sep 1998 14:16:27 -0400
Dear NONMEM users,
I am a new NONMEM user and I have some difficulties in writing a control file for my pk problem:
I would like to model 3 data sets (3 different settings) with a 4 compartment model (depot, central, peripher1, peripher2).
a) the depot comp. should be the dosing compartment with a first order process to the central comp. (is not known) a bioavailability factor (is not known, oral appl.) and a lagtime parameter (is not known)
b) the central comp. should be the dosing comp. with two different constant rates (are known) and a bioavailability factor = 1 (iv infusion)
I thought that this should be a problem for ADVAN6 and TRANS1 with a MODEL record like this:
NCOMPARTMENTS = 4
COMP = (DEPOT)
COMP = (CENTRAL, DEFOBS)
COMP = (PER1)
COMP = (PER2)
LINK DEPOT TO CENTRAL = 1
LINK CENTRAL AND PER1 = 3
LINK CENTRAL AND PER2 = 5
LINK CENTRAL TO OUTPUT = 7
KA = THETA(1) * EXP(ETA(1))
V2 = THETA(2) * EXP(ETA(2))
CL23 = THETA(3) * EXP(ETA(3))
V3 = THETA(4) * EXP(ETA(4))
CL24 = THETA(5) * EXP(ETA(5))
V4 = THETA(6) * EXP(ETA(6))
CL20 = THETA(7) * EXP(ETA(7))
F1 = THETA(8) * EXP(ETA(8))
ALAG1 = THETA(9) * EXP(ETA(9))
S1 = V1
k23 = CL23/V2
k32 = CL23/V3
k24 = CL24/V2
k42 = CL24/V4
k20 = CL20/V2
and a corresponding data file with RATE CMT EVID PCMT data items.
But there are problems due to the MODEL block, which I cannot solve (especially the LINK statement).
I am a bit confused about the different possibilities of working with the LINK statements within the MODEL block or within th PK block, I should say.
The MODEL is established with differential equations, but with this control file the run takes a lot of time. (around one hour).
I would be pleased if there was somebody who can help me.
Thank you in advance
University of Bonn
An der Immenburg 4
Tel.: ++49 228 218997
Fax.:++49 228 735268
From: firstname.lastname@example.org.EDU (ABoeckmann)
Subject: Re: 4Comp.mod.
Date: 28 Sep 1998 16:13:20 -0400
Ralph Quadflieg asked about a 4 compartment model.
The error messages arise because LINK clauses in $MODEL are used only with a user-written PK routine *and* with either ADVAN5 or ADVAN7.
With $PK, he should omit the LINK clauses.
1) With ADVAN6 8 or 9, use a $DES block to define the differential equations, using the K's defined in $PK.
2) Since the kinetics are linear, ADVAN5 or ADVAN7 can be used. NMTRAN will understand that these statments in $PK imply the links between compartments, providing that the lower case k's are changed to upper case K's:
K23 = CL23/V2
K32 = CL23/V3
K24 = CL24/V2
K42 = CL24/V4
K20 = CL20/V2
Note that the following are also needed:
K12=KA and a model for V1.
Here is a better approach.
With NONMEM V, the analytic solution to the 4 compartment problem has been supplied as ADVAN12. This will give faster run times than the general ADVAN routines 5,6,7,8,9.
Omit the $MODEL block. Use the original $PK block (with uppercase k's as noted above).
With ADVAN12 TRANS1, the statement
is not needed, but
It is also possible to use ADVAN12 with TRANS4. This is a very similar parameterization, with slightly different notation.
See Users Guide VIII, ADVAN12 and TRANS4 entries (or nmhelp advan12, nmhelp trans4), for the details.