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| ADVAN9_15 |
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MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN9
$SUBROUTINES [ADVAN=]ADVAN15
$SUBROUTINES [ADVAN=]ADVAN17
SAMPLE:
$SUBROUTINE ADVAN9
$SUBROUTINE ADVAN15
$SUBROUTINE ADVAN17
DISCUSSION:
ADVAN9 and ADVAN15 and ADVAN17 are routines in PREDPP's library which
implement the general non-linear model with equilibrium compartments.
This general non-linear model is used for systems in which a drug is
distributed between compartments according to a system of first-order
differential-algebraic processes. It may be useful when the system
consists of only stiff differential equations, and there are no equi-
librium compartments (i.e., no algebraic equations). It may also be
used when the system consists of only algebraic equations (i.e., no
differential equations).
A $MODEL record is required to describe the compartments and their
attributes. The $DES record describes the differential equations, if
any. The $AES and $AESINITIAL records describe the algebraic expres-
sions, if any.
TOL is required; (See $SUBROUTINES).
TRANS routines that may be used: TRANS1
Explicit Basic PK parameters:
P(n) (nth basic PK parameter)
Implicit basic PK parameters:
PK-defined variables used also in $AES or $DES blocks
Additional PK parameters:
Suppose there are m compartments in the system, including the output
compartment. 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 - Time scale
MTIME(i) - Model event times
With NONMEM 7.4, ATOL may be specified for ADVAN9 and ADVAN15.
(ADVAN17 is new with NONMEM 7.5. The following applies to ADVAN17 as
well.) TOL (relative tolerance) and ATOL (Absolute tolerance) may be
specified on the $SUBROUTINE record, the $TOL record, or by a user-
supplied TOL subroutine. See also the ATOL option of the $ESTIMATION
and $COVARIANCE records.
ATOL is not required. The default is 12 (that is, accuracy is
10**(-12)). Usually the problem runs quickly when using this setting.
On occasion, however, you may want to reduce ATOL (usually set it
equal to that of TOL), and improve speeds of up to 3 to 4 fold.
With ADVAN9, the user may find that the TOL option should specify
larger NRD values than for other ADVANs (e.g., ADVAN6). Values of 7
or 8 may not be unreasonable.
Reserved variable MXSTEP (the maximum number of integration steps)
can be specified for ADVAN9 and ADVAN15 and ADVAN17, as well as for
ADVAN13 and ADVAN14 and ADVAN16.
(See mxstep).
With ADVAN9, if there is a period of time during which some compart-
ment's amount should be zero, that compartment should be turned off.
Otherwise, very small amounts can appear in the compartment, which can
cause difficulties during subsequent time periods.
By default, the initial conditions (i.e., compartment amounts) are
zero at the start of each individual record. Different initial condi-
tions may be specified using a compartment initialization block in PK.
When endogenous drug is provided in the differential equations, non-
zero initial conditions can be computed using a steady-state dose
event record with SS>0 and AMT=0 and RATE=0, or using the I_SS (Ini-
tial Steady State) feature of MODEL and/or PK. Note that with either
method, steady-state is computed only for compartments specified by
differential equations. The equilibrium compartments are not computed
(i.e., the algebraic equations are not evaluated) until the system is
advanced beyond the initial value of TIME.
The CALL data item may be used to force a call to ADVAN, which will
then evaluate the algebraic equations.
(See Compartment_Initialization_Block, SS_dose).
(See $model, $pk, model, pk).
(See Initial_Steady_State:_I_SS,ISSMOD).
ADVAN9 uses the Lawrence Livermore National Laboratory (LLNL) solver
for differential-algebraic equations, implicit form (LSODI), using the
backward differentiation formulas (BDF) for stiff problems.
ADVAN15 uses IDA from the LLNL SUNDIALS system for differential-alge-
braic equations and is a descendent of the LSODI1 (ADVAN9) system.
ADVAN15 also has a root-finding algorithm. The user may choose to
make modifications to parameters in ..\pr\IDAU.f90.
See ..\guides\idas_guide.pdf and ..\guides\ida_guide.pdf.
See INTRODUCTION TO NONMEM 7, $SUBROUTINES: Yet Another New Differen-
tial Equation Solving Method: IDAS (ADVAN15)
ADVAN16 and ADVAN17 use the RADAR5 Delay Differential Equation Solver.
ADVAN17 may be used when there are equilibrium compartments.
See INTRODUCTION TO NONMEM 7, Using the RADAR5 Delay differential
equation Solver with the ddexpand program.
See also ..\guides\manrad5-v2.pdf.
Required PREDPP Library subroutines:
ADVAN9 - ADDA, FCN5, JAC, LEQT22, LSODI1, RES, ZSPOW2
ADVAN15 - ADDA, FCN5, JAC, LEQT22, IDA, RES, ZSPOW2
ADVAN17 - JAC, LEQT22, RADAR5NM, RADAR5U, RES, ZSPOW2, FCN2, FCN4,
FCN5
1 Analytical second derivatives used with the Laplacian method are
not obtained with ADVAN9 and ADVAN15 and ADVAN17. Numerical sec-
ond derivatives must be used.
REFERENCES: Guide VI Section VI.B, VII.C.9
REFERENCES: Guide IV Section V.C.8
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