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RE: [NMusers] Simultaneous pk model of 2 drugs

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

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