134 PREDPP Reference
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1 ABSORPTION LAG PARAMETER
MEANING: Absorption lag (ALAG) parameter for PREDPP
CONTEXT: Additional PK Parameters
USAGE:
$PK
ALAG1= ....DISCUSSION:
Absorption lag parameters are used with PREDPP. They are optional additional PK parameters. With NM-TRAN, they are symbolized in the $PK block by reserved variables ALAGn, where n is the compartment number to which the parameter applies.
There is one absorption lag time (parameter) associated with every possible dose compartment of the kinetic model (the output compartment is not a possible dose compartment) and the absorption lag time used for a given dose is that one associated with the compartment into which the dose is given (the dose compartment).
The event time t on a dose record refers to the recorded time the dose was administered. In the case of a regular infusion, t is the time the infusion was initiated. An absorption lag time is an increment of time L such that the time that the dose is regarded (by PREDPP) as entering (or starting to enter) the system is t+L.
Absorption lag times are optional in the sense that absorption lag times associated with compartments never used as dose compartments may be ignored. The values of absorption lag times that are not computed in PK are always understood to be 0.
An absorption lag time for a dose is computed by the PK routine using, if needed, information in the dose record. When additional doses are specified on a dose event record, the absorption lag time applies to the dose and to all the additional doses. With a steady-state multi-ple dose the absorption lag time applies not only to this dose, but also to all the preceding implied doses. With a steady-state dose, the lag time should be less than the interdose interval.
(See cmt, pk, $pk, default_compartment).
REFERENCES: Guide IV, section V.C.5; Guide VI, section III.F.6 , V.F.1 , V.H
2 ADVAN (GENERAL)
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVANnSAMPLE:
$SUBROUTINE ADVAN1DISCUSSION:
PREDPP contains a library of routines, called ADVAN routines, which implement specific kinetic models. Exactly one ADVAN routine must be selected for each NONMEM/PREDPP run. Its function is to “advance” the kinetic system from one state time point to the next. The ADVAN routines are:
ADVAN1 One Compartment Linear Model ADVAN2 One Compartment Linear Model with First Order Absorption ADVAN3 Two Compartment Linear Model ADVAN4 Two Compartment Linear Model with First Order Absorption ADVAN5 General Linear Model ADVAN6 General Nonlinear Model ADVAN7 General Linear Model with Real Eigenvalues ADVAN8 General Nonlinear Model with Stiff Differential Equations ADVAN9 General Nonlinear Model with Equilibrium Compartments ADVAN10 One Compartment Model with Michaelis-Menten Elimination ADVAN11 Three Compartment Linear Model ADVAN12 Three Compartment Linear Model with First Order Absorption ADVAN13 General Nonlinear Model using LSODA ADVAN14 General Nonlinear Model using CVODA ADVAN15 General Nonlinear Model with Equilibrium Compartments using IDA ADVAN16 Delay Differential Equation Model using RADAR5 ADVAN17 Delay Differential Equation Model with Equilibrium Compartments using RADAR5 ADVAN18 Delay Differential Equation Model using DDE_SOLVER
With a general ADVAN (numbered 5 and above, except for 10, 11, 12), a $MODEL record (or user-supplied MODEL subroutine) must be provided to specify certain details of the model. With ADVAN 6, 8, 9, 13, 14, 15, 16, 17, 18, a $DES block (or DES subroutine) must be provided to evaluate the differential equations. With ADVAN9 and ADVAN15 and ADVAN17, $AES and $AESINITIAL blocks (or AES subroutine) may also be provided to evaluate the algebraic expressions. With any ADVAN for which $DES is required, and with ADVAN10 or SS6, TOL must be specified by means of the TOL option of the $SUBROUTINES record (or a $TOL block or TOL subroutine).
To use a given ADVAN routine, follow two steps:
1. Specify this ADVAN to NM-TRAN on the $SUBROUTINES record. This-
enables NM-TRAN to interpret other records such as
$PK. - 2. Include the specified
ADVANroutine when building the NONMEM exe- -
cutable. NM-TRAN itself places the name of the specified
ADVANroutine (and any other routines from the PREDPP library required by thatADVAN) in its output fileFREPORT.
The nmfe and nmfe.bat commands automatically include the correct ADVAN routine in the NONMEM executable.
REFERENCES: Guide VI, section I , III.A , VII.C; Guide IV, section V.C.3 , V.C.5
3 ADVAN1
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN1SAMPLE:
$SUBROUTINE ADVAN1DISCUSSION:
ADVAN1 is a routine in PREDPP’s library which implements the kinetic equations for the One Compartment Linear Model.
Compt. Function Initial On/Off Dose Default Default
No. Status Allowed Allowed for Dose for Obs.
1 Central On No Yes Yes Yes
2 Output Off Yes No No NoTRANS routines that may be used: TRANS1, TRANS2
Basic PK parameter with TRANS1:
K (rate constant of elimination)
Basic PK parameters with TRANS2: (See TRANS2).
Additional PK parameters:
S1 - Scale for central compartment (also called SC) S2 - Scale for output compartment (also called S0) F1 - Bioavailability for central compartment R1 - Rate for central compartment D1 - Duration for central compartment ALAG1 - Absorption lag for central compartment F0 - Output fraction (also called F2, FO) XSCALE - Time scale MTIME(i) - Model event times
REFERENCES: Guide VI, section VII.C.1
4 ADVAN10
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN10SAMPLE:
$SUBROUTINE ADVAN10DISCUSSION:
ADVAN10 is a routine in PREDPP’s library which implements the kinetic equations for the One Compartment Model with Michaelis-Menten Elimination.
Compt. Function Initial On/Off Dose Default Default
No. Status Allowed Allowed for Dose for Obs.
1 Central On No Yes Yes Yes
2 Output Off Yes No No NoTOL is required; (See $SUBROUTINES).
If steady-state doses are present, steady-state routine SS6 is used, and consequently a $DES block (or user-supplied DES routine) is required. Unless there are steady-state infusions, it may be a “dummy routine”. (See Guide VI, section VII.C.6)
TRANS routines that may be used: TRANS1
Basic PK parameter with TRANS1:
VM (maximum rate) KM (Michaelis constant)
Additional PK parameters:
S1 - Scale for central compartment (also called SC) S2 - Scale for output compartment (also called S0) F1 - Bioavailability for central compartment R1 - Rate for central compartment D1 - Duration for central compartment ALAG1 - Absorption lag for central compartment F0 - Output fraction (also called F2, FO) XSCALE - Time scale MTIME(i) - Model event times
Required PREDPP Library subroutines: ADVAN10 - MMPHI
REFERENCES: Guide VI, section VII.C.6 , VII.C.10
5 ADVAN11
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN11SAMPLE:
$SUBROUTINE ADVAN11DISCUSSION:
ADVAN11 is a routine in PREDPP’s library which implements the kinetic equations for the Three Compartment Linear Model.
Compt. Function Initial On/Off Dose Default Default
No. Status Allowed Allowed for Dose for Obs.
1 Central On No Yes Yes Yes
2 Peripheral 1 On No Yes No No
3 Peripheral 2 On No Yes No No
4 Output Off Yes No No NoTRANS routines that may be used: TRANS1, TRANS4, TRANS6
Basic PK parameters with TRANS1:
K (rate constant of elimination) K12 (rate constant from central to peripheral 1) K21 (rate constant from peripheral 1 to central) K13 (rate constant from central to peripheral 2) K31 (rate constant from peripheral 2 to central)
Basic PK parameters with TRANS4: (See TRANS4).
Basic PK parameters with TRANS6: (See TRANS6).
Additional PK parameters:
S1 - Scale for central compartment (also called SC) S2 - Scale for peripheral compartment 1 S3 - Scale for peripheral compartment 2 S4 - Scale for output compartment (also called S0) F1 - Bioavailability for central compartment F2 - Bioavailability for peripheral compartment 1 F3 - Bioavailability for peripheral compartment 2 R1 - Rate for central compartment R2 - Rate for peripheral compartment 1 R3 - Rate for peripheral compartment 2 D1 - Duration for central compartment D2 - Duration for peripheral compartment 1 D3 - Duration for peripheral compartment 2 ALAG1 - Absorption lag for central compartment ALAG2 - Absorption lag for peripheral compartment 1 ALAG3 - Absorption lag for peripheral compartment 2 F0 - Output fraction (also called F4, FO) XSCALE - Time scale MTIME(i) - Model event times
Steady-state subroutines: SS11, SS6
Other required user or library routines:
Library: EXP3
Notes:
- 1 Analytical second derivatives used with the Laplacian method are
-
not obtained with
ADVAN11. Numerical second derivatives must be used. - 2 Can be greatly speeded up if calls to PK can be limited. (Use
-
CALLFL=1in$PKto call once per IR, and use theCALLdata item to force additional calls if and when necessary; e.g., when covariates used in the PK model change.)
REFERENCES: None
6 ADVAN12
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN12SAMPLE:
$SUBROUTINE ADVAN12DISCUSSION:
ADVAN12 is a routine in PREDPP’s library which implements the kinetic equations for the Three Compartment Linear Model with First Order Absorption.
Compt. Function Initial On/Off Dose Default Default
No. Status Allowed Allowed for Dose for Obs.
1 Depot Off Yes Yes Yes No
2 Central On No Yes No Yes
3 Peripheral 1 On No Yes No No
4 Peripheral 2 On No Yes No No
5 Output Off Yes No No NoTRANS routines that may be used: TRANS1, TRANS4, TRANS6
Basic PK parameters with TRANS1:
K (rate constant of elimination) K23 (rate constant from central to peripheral 1) K32 (rate constant from peripheral 1 to central) K24 (rate constant from central to peripheral 2) K42 (rate constant from peripheral 2 to central) KA (rate constant of absorption)
Basic PK parameters with TRANS4: (See TRANS4).
Basic PK parameters with TRANS6: (See TRANS6).
Additional PK parameters:
S1 - Scale for depot compartment S2 - Scale for central compartment (also called SC) S3 - Scale for peripheral compartment 1 S4 - Scale for peripheral compartment 2 S5 - Scale for output compartment (also called S0) F1 - Bioavailability for depot compartment F2 - Bioavailability for central compartment F3 - Bioavailability for peripheral compartment 1 F4 - Bioavailability for peripheral compartment 2 R1 - Rate for depot compartment R2 - Rate for central compartment R3 - Rate for peripheral compartment 1 R4 - Rate for peripheral compartment 2 D1 - Duration for depot compartment D2 - Duration for central compartment D3 - Duration for peripheral compartment 1 D4 - Duration for peripheral compartment 2 ALAG1 - Absorption lag for depot compartment ALAG2 - Absorption lag for central compartment ALAG3 - Absorption lag for peripheral compartment 1 ALAG4 - Absorption lag for peripheral compartment 2 F0 - Output fraction (also called F5, FO) XSCALE - Time scale MTIME(i) - Model event times
Steady-state subroutines: SS12, SS6
Other required user or library routines:
Library: EXP3 EXP4
Notes:
- 1 Analytical second derivatives used with the Laplacian method are
-
not obtained with
ADVAN12. Numerical second derivatives must be used. - 2 Can be greatly speeded up if calls to PK can be limited. (Use
-
CALLFL=1in$PKto call once per IR, and use theCALLdata item to force additional calls if and when necessary; e.g., when covariates used in the PK model change.)
REFERENCES: None
7 ADVAN2
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN2SAMPLE:
$SUBROUTINE ADVAN2DISCUSSION:
ADVAN2 is a routine in PREDPP’s library which implements the kinetic equations for the One Compartment Linear Model with First Order Absorption.
Compt. Function Initial On/Off Dose Default Default
No. Status Allowed Allowed for Dose for Obs.
1 Depot Off Yes Yes Yes No
2 Central On No Yes No Yes
3 Output Off Yes No No NoTRANS routines that may be used: TRANS1, TRANS2
Basic PK parameters with TRANS1:
K (rate constant of elimination) KA (rate constant of absorption)
Basic PK parameters with TRANS2: (See TRANS2).
Additional PK parameters:
S1 - Scale for depot compartment S2 - Scale for central compartment (also called SC) S3 - Scale for output compartment (also called S0) F1 - Bioavailability for depot compartment F2 - Bioavailability for central compartment R1 - Rate for depot compartment R2 - Rate for central compartment D1 - Duration for depot compartment D2 - Duration for central compartment ALAG1 - Absorption lag for depot compartment ALAG2 - Absorption lag for central compartment F0 - Output fraction (also called F3, FO) XSCALE - Time scale MTIME(i) - Model event times
REFERENCES: Guide VI, section VII.C.2
8 ADVAN3
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN3SAMPLE:
$SUBROUTINE ADVAN3DISCUSSION:
ADVAN3 is a routine in PREDPP’s library which implements the kinetic equations for the Two Compartment Linear Model.
Compt. Function Initial On/Off Dose Default Default
No. Status Allowed Allowed for Dose for Obs.
1 Central On No Yes Yes Yes
2 Peripheral On No Yes No No
3 Output Off Yes No No NoTRANS routines that may be used: TRANS1, TRANS3, TRANS4, TRANS5, TRANS6 Basic PK parameters with TRANS1:
K (rate constant of elimination) K12 (rate constant from central to peripheral) K21 (rate constant from peripheral to central)
Basic PK parameters with TRANS3: (See TRANS3).
Basic PK parameters with TRANS4: (See TRANS4).
Basic PK parameters with TRANS5: (See TRANS5).
Basic PK parameters with TRANS6: (See TRANS6).
Additional PK parameters:
S1 - Scale for central compartment (also called SC) S2 - Scale for peripheral compartment S3 - Scale for output compartment (also called S0) F1 - Bioavailability for central compartment F2 - Bioavailability for peripheral compartment R1 - Rate for central compartment R2 - Rate for peripheral compartment D1 - Duration for central compartment D2 - Duration for peripheral compartment ALAG1 - Absorption lag for central compartment ALAG2 - Absorption lag for peripheral compartment F0 - Output fraction (also called F3, FO) XSCALE - Time scale MTIME(i) - Model event times
REFERENCES: Guide VI, section VII.C.3
9 ADVAN4
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN4SAMPLE:
$SUBROUTINE ADVAN4DISCUSSION:
ADVAN4 is a routine in PREDPP’s library which implements the kinetic equations for the Two Compartment Linear Model with First Order Absorption.
Compt. Function Initial On/Off Dose Default Default
No. Status Allowed Allowed for Dose for Obs.
1 Depot Off Yes Yes Yes No
2 Central On No Yes No Yes
3 Peripheral On No Yes No No
4 Output Off Yes No No NoTRANS routines that may be used: TRANS1, TRANS3, TRANS4, TRANS5, TRANS6
Basic PK parameters with TRANS1:
K (rate constant of elimination) K23 (rate constant from central to peripheral) K32 (rate constant from peripheral to central) KA (rate constant of absorption)
Basic PK parameters with TRANS3: (See TRANS3).
Basic PK parameters with TRANS4: (See TRANS4).
Basic PK parameters with TRANS5: (See TRANS5).
Basic PK parameters with TRANS6: (See TRANS6).
Additional PK parameters:
S1 - Scale for depot compartment S2 - Scale for central compartment (also called SC) S3 - Scale for peripheral compartment S4 - Scale for output compartment (also called S0) F1 - Bioavailability for depot compartment F2 - Bioavailability for central compartment F3 - Bioavailability for peripheral compartment R1 - Rate for depot compartment R2 - Rate for central compartment R3 - Rate for peripheral compartment D1 - Duration for depot compartment D2 - Duration for central compartment D3 - Duration for peripheral compartment ALAG1 - Absorption lag for depot compartment ALAG2 - Absorption lag for central compartment ALAG3 - Absorption lag for peripheral compartment F0 - Output fraction (also called F4, FO) XSCALE - Time scale MTIME(i) - Model event times
REFERENCES: Guide VI, section VII.C.4
10 ADVAN5 ADVAN7
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN5SAMPLE:
$SUBROUTINE ADVAN5DISCUSSION:
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 constant matrix are known to be real (which is true for many pharmacokinetic 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 symbolizes 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 - Time scale MTIME(i) - Model event times
Required PREDPP Library subroutines:
ADVAN5 - REXPON, RXSUBS
ADVAN7 - RRXPON, RXSUBSNotes:
- 1 Analytical second derivatives used with the Laplacian method are
-
not obtained with
ADVAN5andADVAN7. Numerical second derivatives must be used.
REFERENCES: Guide VI, section VII.C.5 , VII.C.7; Guide IV, section V.C.4
11 ADVAN6 ADVAN8 ADVAN13 ADVAN14 ADVAN16 ADVAN18
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN6SAMPLE:
$SUBROUTINE ADVAN6DISCUSSION:
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 distributed 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 integration, 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 ..`CVODEU.f90`. See .._guide.pdf and .._guide.pdf.
ADVAN16 uses the RADAR5 delay differential equation solver. See INTRODUCTION TO NONMEM 7, Using the Delay differential equation Solvers with the ddexpand program. See also ..-v2.pdf. See also .._dde.pdf
ADVAN18 uses the DDE_SOLVER delay differential equation solver. See INTRODUCTION TO NONMEM 7, Using the Delay differential equation Solvers with the ddexpand program. See also .._f90.pdf. See also .._dde.pdf
ADVAN8 may be used in preference to ADVAN6 when the differential equations 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 NONMEM 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, 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. 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, simulation, 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 specify larger NRD values than for other ADVANs (e.g., ADVAN6). Values 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 compartment’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 conditions 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 (Initial 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, JAC2REFERENCES: Guide VI, section VII.C.6 , VII.C.8; Guide IV, section V.C.4 , V.C.5
12 ADVAN9_15
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN9
$SUBROUTINES [ADVAN=]ADVAN15
$SUBROUTINES [ADVAN=]ADVAN17SAMPLE:
$SUBROUTINE ADVAN9
$SUBROUTINE ADVAN15
$SUBROUTINE ADVAN17DISCUSSION:
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 equilibrium 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 expressions, 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 compartment’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 conditions 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 (Initial 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, $pk, model, pk). (See Initial_Steady_State:_I_SS,ISSMOD).
ADVAN9 uses the Lawrence Livermore National Laboratory (LLNL) solver for differential-algebraic equations, implicit form (LSODI), using the backward differentiation formulas (BDF) for stiff problems.
ADVAN15 uses IDA from the LLNL SUNDIALS system for differential-algebraic equations and is a descendent of the LSODI1 (ADVAN9) system. ADVAN15 also has a root-finding algorithm. The user may choose to make modifications to parameters in ..`IDAU.f90. See ..\guides\idas_guide.pdf and ..\guides\ida_guide.pdf. SeeINTRODUCTIONTO NONMEM 7,$SUBROUTINES: Yet Another New Differential 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 ..-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
ADVAN9andADVAN15andADVAN17. Numerical second derivatives must be used.
REFERENCES: Guide VI, section VI.B , VII.C.9; Guide IV, section V.C.8
13 BIOAVAILABILITY FRACTION PARAMETER
MEANING: Bioavailability fraction (F) parameter for PREDPP
CONTEXT: Additional PK Parameters
USAGE:
$PK
F1= ....DISCUSSION:
Bioavailability fraction parameters are used with PREDPP. They are optional additional PK parameters. With each possible dose compartment of the kinetic model (the output compartment is not a possible dose compartment), there is associated one bioavailability fraction (parameter), symbolized in the $PK record by the reserved variable Fn, where n is the number of the compartment.
If the amount on a dose record is A, and the bioavailability fraction is F, only the fraction F of A actually appears in the dose compartment (either instantaneously at the time the dose enters the compartment - with a bolus dose, or over a period of time - with a regular infusion; the bioavailability fraction does not apply to a steadystate infusion).
Bioavailability fractions are optional in the sense that bioavailability fractions associated with compartments never used as dose compartments may be ignored. The values of bioavailability fractions that are not computed in PK are always understood to be 1.
When additional doses are specified on a dose event record, the bioavailability fraction applies to the dose and to all the additional doses. When a steady-state dose is specified on a dose event record, the bioavailability fraction applies to the dose and to all implied doses leading to the steady-state.
(See cmt, pk, $pk, default_compartment).
REFERENCES: Guide IV, section V.C.5; Guide V, section 6.8 , 7.4.4; Guide VI, section III.F.6 , V.F.1 , V.H
14 DURATION PARAMETER
MEANING: Duration (D) parameter for PREDPP
CONTEXT: Additional PK Parameters
USAGE:
$PK
D1= ....DISCUSSION:
Duration parameters are used with PREDPP. They are optional additional PK parameters. With NM-TRAN, they are symbolized in the $PK block by reserved variables Dn, where n is the compartment number to which the parameter applies.
There is one duration parameter associated with every possible dose compartment of the kinetic model (the output compartment is not a possible dose compartment) and the duration parameter used for a given dose is that one associated with the compartment into which the dose is given (the dose compartment).
A duration-modeled zero-order bolus dose is actually an infusion, but one whose duration is given by the rate parameter computed by the PK routine.
Duration parameters are optional in the sense that duration parameters associated with compartments never receiving duration-modeled zeroorder bolus doses may be ignored. However, if the RATE data item on some dose event record contains the value -2, then a duration parameter for the dose compartment must be computed in the PK routine.
A duration parameter is computed by the PK routine using, if needed, information in the dose record. Therefore, its value for the given dose is constant over time.
When additional doses are specified on a dose event record the duration parameter applies to the dose and to all the additional doses.
(See cmt, rate, pk, $pk, default_compartment). (See multi-ple dose example).
REFERENCES: Guide IV, section V.C.5; Guide V, section 12.2.3; Guide VI, section III.F.3
15 OUTPUT FRACTION PARAMETER
MEANING: Output fraction (F0) parameter for PREDPP
CONTEXT: Additional PK Parameters
USAGE:
$PK
F0= ....DISCUSSION:
The output fraction parameter is used with PREDPP. It is an optional additional PK parameter. With NM-TRAN, it are symbolized in the $PK block by any one of the reserved variables FO, F0, or Fn, where n is the compartment number of the output compartment.
With any of the kinetic models a (peripheral) output compartment is always present. Associated with this compartment is a PK parameter, the output fraction , denoted here by Fo. Of the entire amount, Ao, of drug introduced into the system by various dosage patterns and then eliminated from the system during a given time interval, a fraction Fo of Ao goes into this output compartment.
If the output compartment is never turned on, the output fraction can be ignored. If the value of the output fraction is not computed in PK, it is always understood to be 1
The use of Fo depends on the assumption that the rate of change of drug amount in the output compartment is linear in the other compartment amounts. Other than this linearity restriction, the system can be nonlinear.
Tyically, the output compartment is used for urine observations, and the central for plasma observations, with any ADVAN.
(See cmt, pk, $pk, default_compartment).
REFERENCES: Guide IV, section V.C.5; Guide V, section 6.9; Guide V, section 7.4.1; Guide V, section 7.4.5; Guide V, section 7.4.3.3; Guide VI, section III.F.7
16 RATE PARAMETER
MEANING: Rate (R) parameter for PREDPP
CONTEXT: Additional PK Parameters
USAGE:
$PK
R1= ....DISCUSSION:
Rate parameters are used with PREDPP. They are optional additional PK parameters. With NM-TRAN, they are symbolized in the $PK block by reserved variables Rn, where n is the compartment number to which the parameter applies.
There is one rate parameter associated with every possible dose compartment of the kinetic model (the output compartment is not a possible dose compartment) and the rate parameter used for a given dose is that one associated with the compartment into which the dose is given (the dose compartment).
A rate-modeled zero-order bolus dose is actually an infusion, but one whose rate is given by the rate parameter computed by the PK routine.
Rate parameters are optional in the sense that rate parameters associated with compartments never receiving rate-modeled zero-order bolus doses or rate-modeled steady-state infusions may be ignored. However, if the RATE data item on some dose event record contains the value -1, then a rate parameter for the dose compartment must be computed in the PK routine.
Rate parameters act continuously. PREDPP obtains the value of a rate parameter, holding over the state-interval ( t1 , t2 ), from a call to PK with the record associated with t2, even if the dose event time occurs before t2. Therefore, if there are state times (e.g. t2) falling within the time interval over which a zero-order bolus dose appears in the system, there exists the possibility that the rate of drug input can change during the interval. For this to occur, the rate parameter would need to be modeled in terms of time varying covariates. As a result, a zero-order bolus dose where the rate is modeled might be better described as a piecewise zero-order process.
When additional doses are specified on a dose event record the rate parameter applies to the dose and to all the additional doses.
(See cmt, rate, pk, $pk, default_compartment). (See exogenous supplementation example).
REFERENCES: Guide IV, section V.C.5; Guide V, section 12.2.3; Guide VI, section III.F.4-5
17 SCALING PARAMETER
MEANING: Scaling (S) parameter for PREDPP
CONTEXT: Additional PK Parameters
USAGE:
$PK
S2= ....DISCUSSION:
Scaling parameters are used with PREDPP. They are optional additional PK parameters. With NM-TRAN, they are symbolized in the $PK block by reserved variables Sn, where n is the compartment number to which the parameter applies.
For each observation (or at any time other than an observation time for which a prediction is needed), PREDPP computes a prediction available to the ERROR routine. Associated with each observation is an observation compartment. The amount A in the observation compartment at the time of observation, divided by the value of a parameter S, is used as the prediction. The parameter S is called a scaling parameter. There is one such parameter associated with every compartment of the kinetic model (including the output compartment).
Scaling parameters are optional in the sense that scaling parameters associated with compartments with which predictions are not needed may be ignored. The values of scaling parameters that are not computed in PK are always understood to be 1.
A scaling parameter is computed by the PK routine using, if needed, information in the event record.
(See cmt, pcmt, pk, $pk, default_compartment).
With all versions of PREDPP and all ADVAN routines, observations of urine concentration Cu, as well as plasma concentrations Cp, may be included in the data. The default output compartment of all ADVANs may be used to accumulate urine data. This is discussed in Guide V, the Introductory Guide. See
Chapter 6, Section 9, The Output Compartment: Urine Collections and Observations Chapter 7, Secton 4.3.3. Scaling by a Data Item
REFERENCES: Guide IV, section V.C.5; Guide V, section 3.2.2 , 7.4.3; Guide V, section 6.9; Guide V, section 7.4.1; Guide VI, section III.F.1 , V.H
18 SS6 SS9
MEANING: Choice of Steady-State Routine for General Nonlinear Kinetics in PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [SS=]SS6SAMPLE:
$SUBROUTINE SS6DISCUSSION:
The SS6 subroutine computes steady-state kinetics in a very general way and may be used with any choice of ADVAN (other than ADVAN9, ADVAN15, or ADVAN17, with which only SS9 can be used). With NONMEM 7.4, SS6 is the only steady-state routine that can be used with ADVAN6, ADVAN8, ADVAN10, ADVAN13, ADVAN14, ADVAN16, ADVAN18 (With earlier versions of NONMEM 7, SS13 was used with ADVAN13.)
When SS6 or SS9 is used, a DES subroutine (or $DES block) is required to evaluate differential equations.
TOL is required; (See $subroutines).
With NONMEM 7.4, values of TOL and ATOL may be specified for evaluations of Steady State amounts. See options SSATOL and SSATOLC of the $SUBROUTINE and $TOL records, and the TOL routine.
Required PREDPP Library subroutines:
With SS6: ZSPOW1, FCN1, FCN2
With SS9: ZSPOW1, FCN2, FCN4REFERENCES: Guide VI, section VI.C , VII.B , VII.C.6 , VI.C.9; Guide IV, section V.C.3 , V.C.10
19 SS OPTION
MEANING: Choice of Steady-State Routine for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES … [SS=]name
SAMPLE:
$SUBROUTINE ADVAN=ADVAN6 SS=SS6DISCUSSION:
The SS option tells NM-TRAN that a SS routine should be included in the NONMEM/PREDPP executable. It is optional.
PREDPP contains a library of routines, including SS routines to compute steady-state kinetics. The SS routines all have the same entry name, SS. Most analytic ADVAN routines have a corresponding specific SS routine except for ADVAN8 and ADVAN10, for which SS6 is used.
If the SS data item is present in the $INPUT record, then an SS routine is required in the NONMEM/PREDPP executable. NM-TRAN will supply the SS option of the $SUBROUTINES record if it is not present. The default pairing of ADVAN and SS routines is:
ADVAN1-SS1 ; ADVAN2-SS2 ; ADVAN3-SS3 ; ADVAN4-SS4
ADVAN5-SS5 ; ADVAN6-SS6 ; ADVAN7-SS7 ; ADVAN8-SS6
ADVAN9-SS9 ; ADVAN10-SS6 ADVAN11-SS11 ; ADVAN12-SS12
ADVAN13-SS6; ADVAN14-SS6; ADVAN15-SS9; ADVAN16-SS6
ADVAN17-SS9; ADVAN18-SS6(With versions prior to NONMEM 7.4, SS13 was used with ADVAN13. See ADVAN13 help entry for other changes to ADVAN13.)
The SS option can be used to request creation of a NONMEM/PREDPP executable which contains an SS routine even though the current data set does not contain the SS data item.
The only real effect of the SS option is to list the name of the desired SS routine in NM-TRAN’s FREPORT file. The actual construction of the executable is the users responsibility.
When the SS option is not included on the $SUBROUTINES record, and the SS data item does not appear on the $DATA record, then NM-TRAN lists the null SSS routine (SSS0) in FREPORT and no SS routine is listed. Otherwise, NM-TRAN lists the (non-null) SSS routine (“Supervisor of Steady-State”) and the appropriate SS routine.
The nmfe and nmfe.bat commands automatically include the listed SSS and SS routines in the NONMEM executable.
REFERENCES: Guide VI, section VII
20 SUBROUTINE
MEANING: Kind of subroutines in NONMEM/PREDPP Executable
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [SUBROUTINES=]kind
SAMPLE:
$SUBROUTINE SUBROUTINES=DPDISCUSSION:
The SUBROUTINES option tells NM-TRAN how to implement the abbreviated code. If there is no abbreviated code, the SUBROUTINES option is ignored. Possible values for kind are:
- DP This is the default. NM-TRAN generates FORTRAN subroutines from
-
abbreviated code which compute with double-precision arithmetic. These subroutines are written into NM-TRAN output file
FSUBS. DP may also be codedDOUBLEor D. Double-precision versions of NONMEM routines (and of PREDPP, if used) should be included when the NONMEM executable is constructed. NM-TRAN also places into fileFREPORTa line describing what kind of subroutines were specified.
GENERATED DP SUBROUTINES:
REFERENCES: Guide IV, section III.B.6; Guide III, section V.5.0, V.7.0, V.8.0
21 TIME SCALE PARAMETER
MEANING: Time scale (TSCALE) parameter for PREDPP
CONTEXT: Additional PK Parameters
USAGE:
$PK
TSCALE= ....DISCUSSION:
The time scale parameter is used with PREDPP. It is an optional additional PK parameter. With NM-TRAN, it is symbolized in the $PK block by either of the reserved variables TSCALE or XSCALE.
If a time scale parameter is modeled by PK, then time itself may be scaled differently between individuals. There is a single time scale parameter that multiplies all rate constants. The parameter acts continuously (and could therefore theoretically itself vary with time measured on an external clock). It can only be used with linear kinetic models. If it is not used, it can be ignored. If the value of the time scale parameter is not computed in PK, it is always understood to be 1.
The time scale parameter does not scale the duration parameter D of a duration-modeled zero-order bolus dose.
PREDPP ignores the time scale parameter with general non-linear models (ADVAN6, 8, 9, 13,14,15,16,17,18).
(See pk, $pk).
REFERENCES: Guide IV, section V.C.5; Guide VI, section III.F.8
22 TRANS (OPTION)
MEANING: Choice of Translator Routine for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [TRANS=]TRANSnSAMPLE:
$SUBROUTINE ADVAN1 TRANS1DISCUSSION:
PREDPP contains a library of routines, called translator routines, which perform re-parameterization of the basic PK parameters computed by the PK routine. Exactly one TRANS routine must be selected for
- each NONMEM/PREDPP run. They are:
-
TRANS1Dummy, or null, translator; may be used with allADVANroutines. It is the default.TRANS2Used withADVAN1andADVAN2.TRANS3Used withADVAN3andADVAN4.TRANS4Used withADVAN3,ADVAN4,ADVAN11,ADVAN12TRANS5Used withADVAN3andADVAN4.TRANS6Used withADVAN3,ADVAN4,ADVAN11,ADVAN12
Each has its own entry.
REFERENCES: Guide VI, section III.A , III.M
23 TRANS1
MEANING: Choice of Translator Routine for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [TRANS=]TRANS1SAMPLE:
$SUBROUTINE ADVAN1 TRANS1DISCUSSION:
TRANS1 is a translator routine in PREDPP’s library which can be used with any ADVAN routine. It is a “dummy” translator that does not perform any reparameterization of the basic PK parameters. It is the default translator when none is specified on the $SUBROUTINES record.
REFERENCES: Guide VI, section III.A , III.M
24 TRANS2
MEANING: Choice of Translator Routine for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [TRANS=]TRANS2SAMPLE:
$SUBROUTINE ADVAN1 TRANS2DISCUSSION:
TRANS2 is a routine in PREDPP’s library which can be used with ADVAN1 or ADVAN2. It performs a reparameterization of the basic PK parameters to the internal parameters K and KA.
Basic PK parameters for ADVAN1, TRANS2:
CL clearance V volume of distribution
Relationship: K=CL/V
Basic PK parameters for ADVAN2, TRANS2:
CL clearance V volume of distribution KA rate constant of absorption
Relationship: K=CL/V KA=KA
REFERENCES: Guide VI, section III.A , VII.C.1
25 TRANS3
MEANING: Choice of Translator Routine for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [TRANS=]TRANS3SAMPLE:
$SUBROUTINE ADVAN3 TRANS3DISCUSSION:
TRANS3 is a routine in PREDPP’s library which can be used with ADVAN3 or ADVAN4. It performs a reparameterization of the basic PK parameters to the internal parameters K, K12, K21, and KA.
Basic PK parameters for ADVAN3, TRANS3:
CL clearance V central volume Q intercompartmental clearance VSS volume of distribution at steady-state
Relationship:
K=CL/V
K12=Q/V
K21=Q/(VSS-V)Basic PK parameters for ADVAN4, TRANS3:
CL clearance V central volume Q intercompartmental clearance VSS volume of distribution at steady-state KA absorption rate constant
Relationship:
K=CL/V
K23=Q/V
K32=Q/(VSS-V)
KA=KAREFERENCES: Guide VI, section III.A , VII.C.3
26 TRANS4
MEANING: Choice of Translator Routine for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [TRANS=]TRANS4SAMPLE:
$SUBROUTINE ADVAN3 TRANS4DISCUSSION:
TRANS4 is a routine in PREDPP’s library which can be used with ADVAN3, ADVAN4, ADVAN11, or ADVAN12. It performs a reparameterization of the basic PK parameters to the internal parameters K, K12, K21, and KA.
Basic PK parameters for ADVAN3, TRANS4:
CL clearance V1 central volume Q intercompartmental clearance V2 peripheral volume
Relationship:
K=CL/V1
K12=Q/V1
K21=Q/V2Basic PK parameters for ADVAN4, TRANS4:
CL clearance V2 central volume Q intercompartmental clearance V3 peripheral volume KA absorption rate constant
Relationship:
K=CL/V2
K23=Q/V2
K32=Q/V3
KA is unchangedBasic PK parameters for ADVAN11, TRANS4:
CL clearance V1 central volume Q2 intercompartmental clearance (central and periph. 1) V2 peripheral 1 volume Q3 intercompartmental clearance (central and periph. 2) V3 peripheral 2 volume
Relationship:
K=CL/V1
K12=Q2/V1
K21=Q2/V2
K13=Q3/V1
K31=Q3/V3Basic PK parameters for ADVAN12, TRANS4:
CL clearance V2 central volume Q3 intercompartmental clearance (central and periph 1) V3 peripheral 1 volume Q4 intercompartmental clearance (central and periph 2) V4 peripheral 2 volume KA absorption rate constant
Relationship:
K=CL/V2
K23=Q3/V2
K32=Q3/V3
K24=Q4/V2
K42=Q4/V4
KA=KAREFERENCES: Guide VI, section VII.C.3 , VII.C.4
27 TRANS5
MEANING: Choice of Translator Routine for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [TRANS=]TRANS5SAMPLE:
$SUBROUTINE ADVAN3 TRANS5DISCUSSION:
TRANS5 is a routine in PREDPP’s library which can be used with ADVAN3 or ADVAN4. It performs a reparameterization of the basic PK parameters to the internal parameters K, K12, K21, and KA.
Basic PK parameters for ADVAN3, TRANS5:
AOB A/BALPHA alpha BETA beta
Relationship:
K21=(AOB*BETA+ALPHA)/(AOB+1)
K=(ALPHA*BETA)/K21
K12=ALPHA+BETA-K21-KBasic PK parameters for ADVAN4, TRANS5:
AOB A/BALPHA alpha BETA beta KA absorption rate constant
Relationship:
K32=(AOB*BETA+ALPHA)/(AOB+1)
K=(ALPHA*BETA)/K32
K23=ALPHA+BETA-K32-K
KA=KAREFERENCES: Guide VI, section VII.C.3 , VII.C.4
28 TRANS6
MEANING: Choice of Translator Routine for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [TRANS=]TRANS6SAMPLE:
$SUBROUTINE ADVAN3 TRANS6DISCUSSION:
TRANS6 is a routine in PREDPP’s library which can be used with ADVAN3, ADVAN4, ADVAN11, and ADVAN12. It performs a reparameterization of the basic PK parameters.
Basic PK parameters for ADVAN3, TRANS6:
ALPHA alpha BETA beta K21 rate constant (peripheral to central)
Relationship:
K=ALPHA*BETA/K21
K12=ALPHA+BETA-K21-KConstraint:
Assuming that ALPHA < BETA, then ALPHA < K21 < BETA. The roles of ALPHA and BETA are exchangeable.
Basic PK parameters for ADVAN4, TRANS6:
ALPHA alpha BETA beta K32 rate constant (peripheral to central) KA absorption rate constant
Relationship: K=ALPHA*BETA/K32 K23=ALPHA+BETA-K32-K KA is unchanged
Constraint:
Assuming that ALPHA < BETA, then ALPHA < K32 < BETA. The roles of ALPHA and BETA are exchangeable.
Basic PK parameters for ADVAN11, TRANS6:
ALPHA alpha BETA beta GAMMA gamma K21 rate constant (peripheral 1 to central) K31 rate constant (peripheral 2 to central)
Relationship:
K=ALPHA*BETA*GAMMA/(K21*K31)
K13=(P+K31*K31-K31*S-K*K21)/(K21-K31)
K12=S-K-K13-K21-K31
where
S=ALPHA+BETA+GAMMA
P=ALPHA*BETA+ALPHA*GAMMA+BETA*GAMMAConstraint:
Assuming that ALPHA<BETA<GAMMA, then ALPHA<K21<BETA<K31<GAMMA or ALPHA<K31<BETA<K21<GAMMA. The roles of ALPHA, BETA, GAMMA, K21, K31, K12, and K13 are symmetric and are exchangeable.
Basic PK parameters for ADVAN12, TRANS6:
ALPHA alpha BETA beta GAMMA gamma K32 rate constant (peripheral 1 to central) K42 rate constant (peripheral 2 to central) KA absorption rate constant
Relationship:
K=ALPHA*BETA*GAMMA/(K32*K42)
K24=(P+K42*K42-K42*S-K*K32)/(K32-K42)
K23=S-K-K24-K32-K42
where
S=ALPHA+BETA+GAMMA
P=ALPHA*BETA+ALPHA*GAMMA+BETA*GAMMA
KA is unchangedConstraint:
Assuming that ALPHA<BETA<GAMMA, then ALPHA<K32<BETA<K42<GAMMA or ALPHA<K42<BETA<K32<GAMMA. The roles of ALPHA, BETA, GAMMA, K32, K42, K23, and K24 are symmetric and are exchangeable.
REFERENCES: None