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From: Lowe, Phil <phil.lowe_at_novartis.com>

Date: Wed, 7 Sep 2016 09:08:19 +0000

Hi Chris,

I’ve done it, many years ago, for a drug-drug interaction to estimate an inhibition constant for one drug on the clearance of the other. It was never published, I was just playing around in my spare time to learn how to use NONMEM. I’d developed a naïve pool model first in WinNonlin and SAAM II which helped finding appropriate equations and with initial estimates.

As Nick suggested one can use ADVAN5 or 7 for linear systems (use matrix calculations) which are faster than differentials (slower computers 16 years ago). Use the first compartments for one drug, the subsequent for the other. If Kij (see below) is not defined in the control file, it is set to a default of zero.

All the best, Phil.

___________________________________________________________________

| |

| ADVAN5 ADVAN7 |

|_________________________________________________________________|

MEANING: Choice of Pharmacokinetic Model for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [ADVAN=]ADVAN5

SAMPLE:

$SUBROUTINE ADVAN5

DISCUSSION:

ADVAN5 and ADVAN7 are routines in PREDPP's library which implement the

general linear model. The general linear model is used for systems in

which a drug is distributed between compartments according to linear

processes. ADVAN7 may be used when the eigenvalues of the rate con-

stant matrix are known to be real (which is true for many pharmacok-

inetic systems such as mammillary models). It is generally faster

than ADVAN5.

A $MODEL record is required to describe the compartments and their

attributes. The $PK record (or, if a user-supplied PK routine is

used, the $MODEL record) describes how the compartments are linked.

TRANS routines that may be used: TRANS1

Suppose there are m compartments in the system, including the output

compartment.

Basic PK parameters with TRANS1:

Kij (rate constant from compartment i to compartment j)

Ki0 (alternate name for Kim)

The letter T may be used as a separator between the two compartment

numbers, e.g., KiTj. The letter T is optional when there is no

ambiguity, but required when there are two possible interpretations

of the numbers that follow K. E.g., with 12 compartments, K111 is

ambiguous. It should be coded K1T11 or K11T1, depending if it sym-

bolizes the rate constant from compartment 1 to compartment 11 or

from compartment 11 to compartment 1.

Additional PK parameters:

For each compartment n in the system (n=1, ..., m):

Sn - Scale for nth compartment

S0 - Alternate name for scale for output compartment

For each dosable compartment n in the system:

Fn - Bioavailability for nth compartment

Rn - Rate for nth compartment

Dn - Duration for nth compartment

ALAGn - Absorption lag for nth compartment

Other additional PK parameters:

F0 - Output fraction (also called Fm, FO)

XSCALE - X parameter

Received on Wed Sep 07 2016 - 05:08:19 EDT

Date: Wed, 7 Sep 2016 09:08:19 +0000

Hi Chris,

I’ve done it, many years ago, for a drug-drug interaction to estimate an inhibition constant for one drug on the clearance of the other. It was never published, I was just playing around in my spare time to learn how to use NONMEM. I’d developed a naïve pool model first in WinNonlin and SAAM II which helped finding appropriate equations and with initial estimates.

As Nick suggested one can use ADVAN5 or 7 for linear systems (use matrix calculations) which are faster than differentials (slower computers 16 years ago). Use the first compartments for one drug, the subsequent for the other. If Kij (see below) is not defined in the control file, it is set to a default of zero.

All the best, Phil.

___________________________________________________________________

| |

| ADVAN5 ADVAN7 |

|_________________________________________________________________|

MEANING: Choice of Pharmacokinetic Model for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [ADVAN=]ADVAN5

SAMPLE:

$SUBROUTINE ADVAN5

DISCUSSION:

ADVAN5 and ADVAN7 are routines in PREDPP's library which implement the

general linear model. The general linear model is used for systems in

which a drug is distributed between compartments according to linear

processes. ADVAN7 may be used when the eigenvalues of the rate con-

stant matrix are known to be real (which is true for many pharmacok-

inetic systems such as mammillary models). It is generally faster

than ADVAN5.

A $MODEL record is required to describe the compartments and their

attributes. The $PK record (or, if a user-supplied PK routine is

used, the $MODEL record) describes how the compartments are linked.

TRANS routines that may be used: TRANS1

Suppose there are m compartments in the system, including the output

compartment.

Basic PK parameters with TRANS1:

Kij (rate constant from compartment i to compartment j)

Ki0 (alternate name for Kim)

The letter T may be used as a separator between the two compartment

numbers, e.g., KiTj. The letter T is optional when there is no

ambiguity, but required when there are two possible interpretations

of the numbers that follow K. E.g., with 12 compartments, K111 is

ambiguous. It should be coded K1T11 or K11T1, depending if it sym-

bolizes the rate constant from compartment 1 to compartment 11 or

from compartment 11 to compartment 1.

Additional PK parameters:

For each compartment n in the system (n=1, ..., m):

Sn - Scale for nth compartment

S0 - Alternate name for scale for output compartment

For each dosable compartment n in the system:

Fn - Bioavailability for nth compartment

Rn - Rate for nth compartment

Dn - Duration for nth compartment

ALAGn - Absorption lag for nth compartment

Other additional PK parameters:

F0 - Output fraction (also called Fm, FO)

XSCALE - X parameter

Received on Wed Sep 07 2016 - 05:08:19 EDT