56 PREDPP

PREDPP — ADVAN/TRANS family and PK parameters.

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 multiple 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, Section 53.77, Section 53.77, Section 51.11).

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 =]ADVANn

SAMPLE:

$SUBROUTINE ADVAN1

DISCUSSION:

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:

Routine	Description
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:

Specify this ADVAN to NM-TRAN on the $SUBROUTINES record. This enables NM-TRAN to interpret other records such as $PK.
Include the specified ADVAN routine when building the NONMEM executable. NM-TRAN itself places the name of the specified ADVAN routine (and any other routines from the PREDPP library required by that ADVAN) in its output file FREPORT.

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 =]ADVAN1

SAMPLE:

$SUBROUTINE ADVAN1

DISCUSSION:

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        No

TRANS routines that may be used: TRANS1, TRANS2.

Basic PK parameter with TRANS1:

K (rate constant of elimination)

Basic PK parameters with TRANS2: (See Section 56.27).

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 =]ADVAN10

SAMPLE:

$SUBROUTINE ADVAN10

DISCUSSION:

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        No

TOL is required; (See Section 50.43).

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 =]ADVAN11

SAMPLE:

$SUBROUTINE ADVAN11

DISCUSSION:

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        No

TRANS 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 Section 56.29). Basic PK parameters with TRANS6: (See Section 56.31).

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.

NOTE:

Analytical second derivatives used with the Laplacian method are not obtained with ADVAN11. Numerical second derivatives must be used.
Can be greatly speeded up if calls to PK can be limited. (Use CALLFL=1 in $PK to call once per IR, and use the CALL data 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 =]ADVAN12

SAMPLE:

$SUBROUTINE ADVAN12

DISCUSSION:

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        No

TRANS 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 Section 56.29). Basic PK parameters with TRANS6: (See Section 56.31).

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.

NOTE:

Analytical second derivatives used with the Laplacian method are not obtained with ADVAN12. Numerical second derivatives must be used.
Can be greatly speeded up if calls to PK can be limited. (Use CALLFL=1 in $PK to call once per IR, and use the CALL data 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 =]ADVAN2

SAMPLE:

$SUBROUTINE ADVAN2

DISCUSSION:

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        No

TRANS 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 Section 56.27).

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 =]ADVAN3

SAMPLE:

$SUBROUTINE ADVAN3

DISCUSSION:

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        No

TRANS 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 Section 56.28). Basic PK parameters with TRANS4: (See Section 56.29). Basic PK parameters with TRANS5: (See Section 56.30). Basic PK parameters with TRANS6: (See Section 56.31).

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 =]ADVAN4

SAMPLE:

$SUBROUTINE ADVAN4

DISCUSSION:

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        No

TRANS 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)

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 =]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 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, RXSUBS

NOTE:

Analytical second derivatives used with the Laplacian method are not obtained with ADVAN5 and ADVAN7. 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 =]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 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 ..\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 equation 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 equation 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 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 Section 50.43). (See Section 53.109).

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. It may also supply specific values for each compartment, and for Steady State amounts. (See Section 53.109).

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 Section 53.61).

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.

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; 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 =]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 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 Section 50.43).

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 Section 53.61).

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 Section 53.14, SS_dose). (See Section 53.55, Section 53.77, Section 53.55, Section 53.77). (See Initial_Steady_State:_I_SS, Section 53.45).

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 ..\pr\IDAU.f90. See ..\guides\idas_guide.pdf and ..\guides\ida_guide.pdf. See INTRODUCTION TO 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 ..\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

NOTE:

Analytical second derivatives used with the Laplacian method are not obtained with ADVAN9 and ADVAN15 and ADVAN17. 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 steady-state 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, Section 53.77, Section 53.77, Section 51.11).

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 zero-order 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, Section 53.77, Section 53.77, Section 51.11). (See Section 60.41).

REFERENCES: Guide IV, section V.C.5; Guide V, section 12.2.3; Guide VI, section III.F.3

15 HINIT_, HMIN_, HMAX_ (NM760)

MEANING: PREDPP-PK global variables

CONTEXT: User-supplied routines

USAGE:

USE PRLS01_REAL, ONLY: HINIT_,HMIN_,HMAX_

GLOBAL DECLARATION:

USE SIZES, ONLY: DPSIZE
REAL (KIND=DPSIZE) HINIT_,HMIN_,HMAX_

DISCUSSION:

These reserved variables are used to modify the integration step size behavior in ADVAN9, ADVAN13, ADVAN14, and ADVAN15. When a modeled short, large rate input occurs at some time during the simulation, that is not a scheduled bolus event or is not easily specified with MTIME(), the LSODA type ODE solvers can miss this event. For example, a gamma function shaped input with a large N>20 parameter, can create a stiff, pseudo-bolus input that may be missed by one of these ADVANs. One way to avoid missing this input is to set the integration step size to an upper limit:

$PK HMAX_ = 0.01

One may also set the initial step size (HINIT_), or minimal step size (HMIN_) within the $PK block in a similar manner.

The usual technique for handling short-term rate inputs is to set the RTOL and ATOL to very high levels, such as between 13 and 15, but this may not work for every problem, and one may need to resort to explicitly limiting the HMAX_ or HINIT_ in the manner shown above.

For a discussion of these variables, See INTRODUCTION TO NONMEM 7, “HMIN_, HINIT_,HMAX_: Avoiding missed short events in ADVAN9, ADVAN13, ADVAN14, and ADVAN15 (nm760)”

REFERENCES: Guide Introduction_7

16 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 is 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 $F_o$. Of the entire amount, $A_o$, of drug introduced into the system by various dosage patterns and then eliminated from the system during a given time interval, a fraction $F_o$ of $A_o$ 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 $F_o$ 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.

Typically, the output compartment is used for urine observations, and the central for plasma observations, with any ADVAN.

(See cmt, Section 53.77, Section 53.77, Section 51.11).

REFERENCES: Guide IV, section V.C.5; Guide V, sections 6.9, 7.4.1, 7.4.5, 7.4.3.3; Guide VI, section III.F.7

17 PASTZERO (NM75)

MEANING: PREDPP-PK global variables

CONTEXT: User-supplied routines

USAGE:

USE PRDDESLVU, ONLY: PASTZERO

GLOBAL DECLARATION:

USE SIZES, ONLY: DPSIZE
REAL (KIND=DPSIZE) PASTZERO

DISCUSSION:

This variable is reserved with ADVAN18, for use with Delay Differential Equations. Sometimes you may wish to have the equations transition from the past to the present other than at time T=0. In this case, set PASTZERO to a non-zero (including negative) value. For example,

$DES PASTZERO = -10.0

REFERENCES: Guide Introduction_7

18 PASTZERO (NM75) — ADVAN16, ADVAN17

MEANING: PREDPP-PK global variables

CONTEXT: User-supplied routines

USAGE:

USE PRRADAR5U, ONLY: PASTZERO

GLOBAL DECLARATION:

USE SIZES, ONLY: DPSIZE
REAL (KIND=DPSIZE) PASTZERO

DISCUSSION:

This variable is reserved with ADVAN16 and ADVAN17, for use with Delay Differential Equations. Sometimes you may wish to have the equations transition from the past to the present other than at time T=0. In this case, set PASTZERO to a non-zero (including negative) value. For example,

$DES PASTZERO = -10.0

REFERENCES: Guide Introduction_7

19 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, Section 53.77, Section 53.77, Section 51.11). (See Section 60.26).

REFERENCES: Guide IV, section V.C.5 REFERENCES: Guide V, section 12.2.3 REFERENCES: Guide VI, section III.F.4-5

20 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, Section 53.77, Section 53.77, Section 51.11).

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 REFERENCES: Guide V, section 3.2.2, 7.4.3 REFERENCES: Guide V, section 6.9 REFERENCES: Guide V, section 7.4.1 REFERENCES: Guide VI, section III.F.1, V.H

21 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 = SS6

DISCUSSION:

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

22 SS6 SS9

MEANING: Choice of Steady-State Routine for General Nonlinear Kinetics in PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [SS =]SS6

SAMPLE:

$SUBROUTINE SS6

DISCUSSION:

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 Section 50.43). 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, FCN4

REFERENCES: Guide VI, section VI.C, VII.B, VII.C.6, VI.C.9 REFERENCES: Guide IV, section V.C.3, V.C.10

23 SUBROUTINE

MEANING: Kind of subroutines in NONMEM/PREDPP Executable

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

`$SUBROUTINES` [SUBROUTINES =]kind

SAMPLE:

`$SUBROUTINE` SUBROUTINES = DP

DISCUSSION:

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 coded DOUBLE or 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 file FREPORT a line describing what kind of subroutines were specified.

GENERATED DP SUBROUTINES:

REFERENCES: Guide IV, section III.B.6 REFERENCES: Guide III, section V.5.0, V.7.0, V.8.0

24 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 Section 53.77, Section 53.77).

REFERENCES: Guide IV, section V.C.5

REFERENCES: Guide VI, section III.F.8

25 TRANS (OPTION)

MEANING: Choice of Translator Routine for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [TRANS =]TRANSn

SAMPLE:

$SUBROUTINE ADVAN1 TRANS1

DISCUSSION:

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:

TRANS1 Dummy, or null, translator; may be used with all ADVAN routines. It is the default.
TRANS2 Used with ADVAN1 and ADVAN2.
TRANS3 Used with ADVAN3 and ADVAN4.
TRANS4 Used with ADVAN3, ADVAN4, ADVAN11, ADVAN12.
TRANS5 Used with ADVAN3 and ADVAN4.
TRANS6 Used with ADVAN3, ADVAN4, ADVAN11, ADVAN12.

Each has its own entry.

REFERENCES: Guide VI, section III.A, III.M

26 TRANS1

MEANING: Choice of Translator Routine for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [TRANS =]TRANS1

SAMPLE:

$SUBROUTINE ADVAN1 TRANS1

DISCUSSION:

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

27 TRANS2

MEANING: Choice of Translator Routine for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [TRANS =]TRANS2

SAMPLE:

$SUBROUTINE ADVAN1 TRANS2

DISCUSSION:

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

28 TRANS3

MEANING: Choice of Translator Routine for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [TRANS =]TRANS3

SAMPLE:

$SUBROUTINE ADVAN3 TRANS3

DISCUSSION:

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=KA

REFERENCES: Guide VI, section III.A, VII.C.3

29 TRANS4

MEANING: Choice of Translator Routine for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [TRANS =]TRANS4

SAMPLE:

$SUBROUTINE ADVAN3 TRANS4

DISCUSSION:

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/V2

Basic 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 unchanged

Basic 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/V3

Basic 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=KA

REFERENCES: Guide VI, section VII.C.3, VII.C.4

30 TRANS5

MEANING: Choice of Translator Routine for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [TRANS =]TRANS5

SAMPLE:

$SUBROUTINE ADVAN3 TRANS5

DISCUSSION:

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/B
ALPHA alpha
BETA beta

Relationship:

K21=(AOB*BETA+ALPHA)/(AOB+1)
K=(ALPHA*BETA)/K21
K12=ALPHA+BETA-K21-K

Basic PK parameters for ADVAN4, TRANS5:

AOB A/B
ALPHA alpha
BETA beta
KA absorption rate constant

Relationship:

K32=(AOB*BETA+ALPHA)/(AOB+1)
K=(ALPHA*BETA)/K32
K23=ALPHA+BETA-K32-K
KA=KA

REFERENCES: Guide VI, section VII.C.3, VII.C.4

31 TRANS6

MEANING: Choice of Translator Routine for PREDPP

CONTEXT: Option of NM-TRAN $SUBROUTINES record

USAGE:

$SUBROUTINES [TRANS =]TRANS6

SAMPLE:

$SUBROUTINE ADVAN3 TRANS6

DISCUSSION:

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-K

Constraint:

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*GAMMA

Constraint:

Assuming that ALPHA<BETA<GAMMA, then

ALPHA<K21<BETA<K31<GAMMA

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 unchanged

Constraint:

Assuming that ALPHA<BETA<GAMMA, then

ALPHA<K32<BETA<K42<GAMMA

ALPHA<K42<BETA<K32<GAMMA.

The roles of ALPHA, BETA, GAMMA, K32, K42, K23, and K24 are symmetric and are exchangeable.

REFERENCES: None.