+--------------------------------------------------------------------+
| |
| ADVAN6 ADVAN8 ADVAN13 ADVAN14 ADVAN16 ADVAN18 |
| |
+--------------------------------------------------------------------+
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN6
SAMPLE:
$SUBROUTINE ADVAN6
DISCUSSION:
ADVAN6, ADVAN8 ADVAN13, ADVAN14, ADVAN16, ADVAN18 are routines in
PREDPP's library which implement the general non-linear model. The
general non-linear model is used for systems in which a drug is dis-
tributed between compartments according to first-order processes. The
differences are in the package of code that performs the integration
of the differential equations.
ADVAN6 uses IMSL's DVERK, a Runge-Kutta-Verner fifth and sixth
order method of integration, for nonstiff problems.
ADVAN8 uses IMSL's DGEAR, the Gear method of numerical integra-
tion, for stiff problems.
ADVAN13 uses the LLNL solver for ordinary differential equations
(LSODA), with automatic method switching for stiff (BDF) and non-
stiff (Adams method) problems. It is a decendent of ADVAN8.
ADVAN14 uses CVODES from the LLNL SUNDIALS system for ordinary
differential equations and is a descendent of LSODA (ADVAN13).
ADVAN14 also has a root-finding algorithm.
The user may choose to make modifications to ..\pr\CVODEU.f90.
See ..\guides\cvs_guide.pdf and ..\guides\cv_guide.pdf.
ADVAN16 uses the RADAR5 delay differential equation solver.
See INTRODUCTION TO NONMEM 7, Using the Delay differential equa-
tion Solvers with the ddexpand program.
See also ..\guides\manrad5-v2.pdf.
See also ..\examples\dde\advan16_dde.pdf
ADVAN18 uses the DDE_SOLVER delay differential equation solver.
See INTRODUCTION TO NONMEM 7, Using the Delay differential equa-
tion Solvers with the ddexpand program.
See also ..\guides\ddes_f90.pdf.
See also ..\examples\dde\advan16_dde.pdf
ADVAN8 may be used in preference to ADVAN6 when the differential equa-
tions describing the processes are stiff. ADVAN13 may be preferable
with a mixed system (both stiff and non-stiff). For discussion of
ADVAN14 as well as changes to ADVAN13, see Guide INTRODUCTION TO NON-
MEM 7.
A $MODEL record is required to describe the compartments and their
attributes. The $DES record is required to describe the differential
equations.
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 $DES block
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
TOLERANCE values
TOL (Relative Tolerance) is required; this can be supplied with
the $SUBROUTINE or $TOL record, or a user-supplied TOL routine,
which sets NRD=TOL.
(See $SUBROUTINES).
(See $TOL).
With NONMEM 7.4, ATOL (Absolute tolerance) may be specified for
ADVAN9, ADVAN13, ADVAN14, ADVAN16, ADVAN18.
For example, $SUBROUTINE ... ATOL=n.
The default is 12 (that is, accuracy is 10**(-12)). Usually the
problem runs quickly when using this setting. On occasion, how-
ever, you may want to reduce ATOL (usually set it equal to that
of TOL), and improve speeds of up to 3 to 4 fold. Values of TOL
and ATOL may also be specified for evaluations of Steady State
amounts, and also for the Covariance Step.
See options ATOL, TOLC, ATOLC, SSATOL, SSATOLC of the $SUBROUTINE
and $TOL records.
A user-supplied TOL routine may assign values of NRD and ANRD
specifically for the initial (base) setting and each NONMEM step
(estimation, covariance, simulation, table/scatter step, simu-
lation, initial parameters estimate, nonparametric). It may also
supply specific values for each compartment, and for Steady State
amounts.
(See TOL).
With ADVAN13, the user may find that the TOL option should spec-
ify larger NRD values than for other ADVANs (e.g., ADVAN6). Val-
ues of 7 or 8 may not be unreasonable with double precision.
See INTRODUCTION TO NONMEM 7, Controlling the Accuracy of the
Gradient Evaluation and Individual Objective Function Evaluation
Reserved variable MXSTEP (the maximum number of integration steps)
can be specified for ADVAN13 and ADVAN14 and ADVAN16.
(See mxstep).
With ADVAN13, 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 specified in the differential equations, non-
zero initial conditions may also 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.
(See Compartment_Initialization_Block, SS_dose).
(See $model, $pk).
(See model, pk).
(See Initial_Steady_State:_I_SS,ISSMOD).
Required PREDPP Library subroutines:
ADVAN6 - DVERK1, FCN1
ADVAN8 - DGEAR1, FCN1, FCN3
ADVAN13 - LSODA, FCN1, JAC2
ADVAN14 - CVODE, FCN1, JAC2
ADVAN16 - RADAR5NM, FCN1, JAC2
ADVAN18 - ADDELSV, FCN1, JAC2
REFERENCES: Guide VI Section VII.C.6, VII.C.8
REFERENCES: Guide IV Section V.C.4, V.C.5
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