Modeling Language

System parameters <P>

Each system parameter is specified with a name, value, lower bound, upper bound, units, whether it should be editable in the ShinyApp and the ‘type’ of parameter (grouping in the ShinyApp). The values of eps (machine precision, smallest value that is not zero) and inf (infinity) can be used. For example to specify a parameter koffR with a value of .1 that is positive and a parameter KDR with a value of .04 that is also positive the following would be used:

#   name  value    lb     ub   units  editable type
<P> koffR 0.1      eps    inf   1/hr  yes      Target
<P> KDR   0.04     eps    inf   nM    yes      Target

Parameter sets

Often a model will be developed to incorporate different situations or scenarios. For example, a model may be used to describe both healthy and diseased individuals. When these differences are simply parametric in nature, it can be cumbersome to code a model multiple times (once for each parameterization). This framework provides a mechanism for including multiple parameterizations withing the same system file. Consider the system below where we want to describe antibody disposition. For humans this is described by a two compartment model, but for mice a single compartment is needed.

Model parameterizations

First we create a set of parameters describing the human scenario. These are the mean parameters taken from the literature [DM]:

<P> Weight   70.0    eps inf kg   yes   System # Organism weight
<P> CL        0.0129 eps inf L/hr yes   System # Systemic Clearance
<P> Q         0.0329 eps inf L/hr yes   System # Inter-compartmental clearance
<P> Vp        3.1    eps inf L    yes   System # Vol. central compartment
<P> Vt        2.8    eps inf L    yes   System # Vol. peripheral compartment

When a parameter is created using the <P> descriptor it is part of the default parameter set. This is the short name¹ for a parameter set. A longer more verbose name can be given as well, and this is what will be seen in the ShinyApp. The human parameter set can be labeled using the PSET descriptor in the following way:

<PSET:default> mAb in Human

Where default is the parameter set short name name, and “mAb in Human” is the value shown to the user in the ShinyApp.

Next, to add the parameterization for mice we simply create a new set in the following way:

<PSET:mouse> mAb in Mouse

This alone would create a new parameter set with a short name mouse, and is an exact copy of the default parameter set. To identify the parametric differences between the mouse and human we use PSET in the following way:

<PSET:mouse:Weight > 0.020 # 20 gram mouse
<PSET:mouse:CL >     7.71e-6
<PSET:mouse:Q>       0.0
<PSET:mouse:Vp >     1.6e-3
<PSET:mouse:Vt >     1   # arbitrary

Consider the clearance parameter entry where we want the murine half-life of an antibody [VR]:

<PSET:mouse:CL> 7.71e-6

We use the set name (mouse) and the parameter name (CL) and then we overwrite the default with the specified value 7.71e-6. The other aspects of the parameter (bounds, edit flag, etc.) will be the same as the default value.

Secondary parameters <As> and <Ad>

A static secondary parameter refers to parameter does not change during a simulation. These are specified using the <As> descriptor and can be written in terms of system parameters or previously defined static secondary parameters. These can be used in differential equations, defining initial conditions, input scaling and model outputs. This is similar to secondary parameters defined in the $PK block in NONMEM. For example, if you wanted to define the rate of elimination in terms of the system parameters for clearance CL and volume of distribution Vp the following would be used:

<As> kel = CL/Vp

A dynamic secondary parameters refers to a parameter that can change during a simulation. This typically means it is defined, using the <Ad> descriptor, in terms of a state or another dynamic secondary parameter. These can be used in differential equations and model outputs. These are similar to the parameters defined in the $DES block in NONMEM. For example if you wanted to use the concentration in the central compartment Cp but it was dependent on the amount in that compartment Ap and the volume of that compartment Vp the following would be used:

<Ad> Cp = Ap/Vp

Variance parameters <VP>

Variance parameters are specified using the same format as system parameters (<P>) :

#    name    value lower_bound upper_bound units editable grouping
<VP > SLOPE  0.01  eps         inf         1/hr   yes     Variance

The difference being that the <VP> descriptor is used and that the grouping is set to Variance. These are used when performing parameter estimation and when simulating with residual variability.

Parameter estimation information <EST:?>?

Currently applies only to nlmixr2/rxode . Essentially all the parameters not listed here will be fixed.

This descriptor specifies information about parameters for estimation. Sometimes it is necessary to estimate parameters in the log space. Here you can specify the parmaeters to log transform (LT). If you wanted to log transform parameters P1, P2, and P3 you would do the following:

<EST:LT> P1; P2; P3

NOTE That for the Monolix outputs to work correctly you will need to logtransform any parameters that have log-normal IIV assigned.

By default all parameters will be specified for estimation. If you want to estimate a subset of parameters (P), say P1 and P2, you can use the following:

<EST:P> P1; P2

Variability: defining the variance/covariance Matrix <IIV:?>? & <IIVCOR:?>?

Any variable name assigned to inter-individual variability (IIV) or correlation/covariance (IIVCOR) term that makes sense to the user may be used. The following sample codes have variable names (eg: ETACL) that most likely make sense to a population modeler or NONMEM user. To define an IIV term named ETACL with a variance of 0.15 use the following:

<IIV:ETACL> 0.15

The next we need to associate this IIV term with a system parameter. To associate this IIV term with the clearance (system parameter CL) and specify that it has a log normal distribution (LN) we would simply write:

<IIV:ETACL:LN> CL

Alternatively a normal (N) distribution can be used.

Next we specify the IIV term ETAV with a variance of 0.1. This IIV term also has a log normal distribution and is applied to the parameter V:

<IIV:ETAV> 0.10
<IIV:ETAV:LN> V

Now we can define the covariance (off-diagonal elements) between CL and V to be 0.01 by using:

<IIVCOR:ETAV:ETACL> 0.01

The order isn’t important and the IIV terms can be reversed

IIV and parameter sets <IIVSET:?>? & <IIVCORSET:?>?

By default all parameter sets will have inter individual variability specified using the <IIV> and <IIVCOR> descriptors. To associate a specific set of IIVs to a parameter set use the <IIVSET> and <IIVCORSET> descriptors. These set descriptors operate differently than the parameter set descriptors (<PSET>). The <PSET> just overwrites the default values and inherits the default variance/covariance information. If you alter the IIV information for a parameter set it will reset the IIV information for that parameter set. The entire variance covariance matrix will need to be specified for that parameter set.

If the parameter set MYPSET has been defined then the following could be used to define the IIV for the parameters Q and CL:

<IIVSET:MYPSET:ETAQ>           0.05
<IIVSET:MYPSET:ETAQ:LN>        Q

<IIVSET:MYPSET:ETACL>          0.25
<IIVSET:MYPSET:ETACL:LN>       CL

<IIVCORSET:MYPSET:ETAQ:ETACL>  0.01

All the other system parameters will have no IIV information for this parameter set.

Writing ODEs <ODE:?>

Portions of differential equations can be specified here where ? is the state or compartment. To define dA/dT as koffR*C - konR*A*B we would write:

<ODE:A> koffR*C - konR*A*B 

It might be more convenient to specify an ODE across several lines, making things more readable. Just use multiple statements and they will be appended together. This would give the same result as the example above:

<ODE:A>    koffR*C
<ODE:A>  - konR*A*B 

Rate equations =?=>

It may be more convenient to write out chemical reactions rather than differential equations. This can be done using the general form:

[CR1]Reactant1 + [CR2]Reactant2 + ... =kf=> [CP1]Product1 + [CP2]Product2 + ...

Where the stoichiometric coefficients, beginning with CR and CP above, in brackets only need to be specified if they are not one. The reaction order will be assumed to be equal to the stoichiometric coefficient of the reactant. For a more specific example Consider decomposition of hydrogen peroxide into water and oxygen:

$$ H_2O_2 \xrightarrow{k_{deg}} H_2O + \frac{1}{2}O_2 $$

In the system format this would be written in the following manner:

H2O2 =kdeg=> H2O + [0.5]O2

And this will be translated in to the following differential equations:

$$ \frac{dH_2O_2}{dt}=-k_{deg}H_2O_2 \\ \frac{dH_2O}{dt}= k_{deg}H_2O_2 \\ \frac{dO_2}{dt}= 0.5k_{deg}H_2O_2 $$

Which could also be defined as differential equations using the <ODE:?>?. This is the equivalent:

<ODE:H2O2>   - kdeg*H2O2 
<ODE:H2O>      kdeg*H2O2 
<ODE:O2>   0.5*kdeg*H2O2 

The rates (e.g. kdeg) need to be defined as either a system or secondary parameter. This is where you can put saturable terms, such as Michaelis-Menten kinetics.

Equilibrium relationships <=kforward:kreverse=>

Forward and reverse reaction rates can be written separately:

A + B =konR=>   C       
C     =koffR=>  A + B

Or these can be written as equilibrium equations with the forward (konR) and reverse (koffR) rates specified as:

A + B  <=konR:koffR=>  C       

To specify this reaction as differential equations, the following could have also been used:

<ODE:A>  koffR*C - konR*A*B
<ODE:B>  koffR*C - konR*A*B
<ODE:C> -koffR*C + konR*A*B

The stoichiometric coefficients also define the reaction order here. For example, to create the following equilibrium reaction:

2A + 3B⇄_kr^k_f4C

This rate notation could be used in the system file:

[2]A + [3]B  <=kf:kr=>  [4]C       

Which will produce the following in terms of differential equations:

$$ \frac{dA}{dt} = 2k_rC^4 - 2k_fA^2B^3 \\ \frac{dB}{dt} = 3k_rC^4 - 3k_fA^2B^3 \\ \frac{dC}{dt} =-4k_rC^4 + 4k_fA^2B^3 $$ To write this equilibrium reaction as differential equations the following would be used:

<ODE:A>   =  2*kr*SIMINT_POWER[C][4] - 2*kf*SIMINT_POWER[A][2]*SIMINT_POWER[B][3]
<ODE:B>   =  3*kr*SIMINT_POWER[C][4] - 3*kf*SIMINT_POWER[A][2]*SIMINT_POWER[B][3]
<ODE:C>   = -4*kr*SIMINT_POWER[C][4] + 4*kf*SIMINT_POWER[A][2]*SIMINT_POWER[B][3]

See below about generic functions such as SIMINT_POWER[][].

Sources and sinks <S:?>

This method allows turnover to be described in terms of synthesis and degradation terms. If A is produced at a rate of ksynA (mass quantities), degraded at a rate of kdegA, and modeled in concentration units then the sources are specified on the left hand side of <S:?> and the sinks (elimination) are specified on the left hand side of <S:?>. Multiple sources and sinks can be separated by semicolons. In this example with a compartment volume V

ksynA/V <S:A> kdeg*A

Which is the same as writing out the differential equation:

<ODE:A> koffR*C - konR*A*B + ksynA/V - kdeg*A

Movement between compartments <C>

When mass moves between two physical spaces with different volumes we need to specify, for each compartment, the species, volume and rate of transport. The <C> descriptor allows us to just identify the compartment information separated by semicolons (order is important)

Species; Volume; Rate <C> Species; Volume; Rate

For movement between a central compartment A with a volume V to the tissue space At with a volume Vt at rates kps and ksp respectively this is specified in the following manner:

A; V; kps <C> At; Vt; ksp

Which is the equivalent of the following differential equation:

<ODE:A>   -kps*A + ksp*At*Vt/V
<ODE:At>  +kps*A*V/Vt - ksp*At

Initial conditions <I>

By default all initial conditions are zero. You can specify a non-zero initial condition using the <I> string to set a ‘state’ to a ‘value’

<I> state = value

Value can be any combination of numbers, system parameters <P> or static secondary parameters <As. Consider a turnover system where the value of ksyn and kdeg are specified as parameters:

<P> ksyn  0.1      eps    inf   1/hr  yes      Target
<P> kdeg  0.04     eps    inf   nM    yes      Target

We can calculate the initial value for a target as:

<As> T_IC = ksyn/kdeg

Then we can specify the initial value of the target as:

<I> T = T_IC

Bolus dosing <B:times>, <B:events>

The <B:?> descriptor is used to define bolus dosing. Dosing information is broken down into a list of times when bolus injections occur and a list of events containing the amount the specified compartment will receive.

Each of these has a scale that is used to convert the bolus dosing information from proscribed units (mg daily) into the units in which the system is coded (mg/mL and hours). So if dosing is done on days 0, 1, 2… but the simulation time is hours, then the scale for the dosing times is 24.The events contain the magnitude of the bolus at a given time. If you want to dose into a central compartment Cp in mg/kg and your central compartment is mg/mL then you need to scale by the body weight (e.g. 70 kg) and the volume of your central compartment (system or static secondary parameter Vp) then the scale is 70/Vp.

If you just want to create a palceholder you can do the following:

#  type       state   values    scale  units   
<B:times>;            [0];        24;  days   
<B:events>;     Cp;   [0];     70/Vc;  mpk   

If you want to setup default dosing for the shiny app or scripts, you can do somethign more complicated. If you have multiple compartments receiving a bolus, the times must include all times in which a bolus may be applied to the system. If a state does not receive a bolus on a particular time, its magnitude at that time is 0.

To illustrate this consider the following dosing schedule:

Dosing into two different states/compartments

In this example we want to dose two different drugs into two different states/compartments. Drug 1 (D1) will be dosed into Cp1 and drug 2 (D2) into Cp2. Dosing will be in mg/kg but concentrations are in mg/ml. The dosing time is in days, but the simulation time units are hours. We will be dosing D1 at 8 & 2 mpk on days 0 & 6. D2 will be dosed at 5 mpk on day 9.

#  type       state     values     scale  units   
<B:times>;            [0 6 9];       24;  days   
<B:events>;    Cp1;   [8 2 0];    70/V1;  mpk   
<B:events>;    Cp2;   [0 0 5];    70/V2;  mpk   

Assume V1 and V2 are the compartmental volumes for D1 and D2 in ml, and the subject body weight is 70 kg. This would convert those doses in mpk into mg/ml. Again these are the default doses that can be overwritten both in the ShinyApp and within scripts.

Continuous infusions <R:?>

Rates of infusion are defined using the <R:?> descriptor. Like bolus values, infusion rates have two components. There is a component that specifies switching times (e.g. switching from 10 mg/hr to 0). And each switching time has a corresponding rate of infusion. This infusion rate will be held constant until the next time. Also like the bolus specification there is a scale associated with both infusion times and the levels that converts the proscriptive units into the units of the simulation. Consider the following example:

# name      time/levels values    scale  units
<R:myrate>; times;      [0 30];   1/60;    min
<R:myrate>; levels;     [1 0];    60;   mg/min

These two entries create the infusion rate called myrate. This can be used in any of your system specifications (e.g., <ODE:Cp> myrate/Vp). The first row specifies the times when the rate is changed (0 and 30 minutes). If the system is coded in terms of hours, then the scale of 1/60 must be used. The levels indicate a rate of 1 mg/min that is switched off at 30 minutes. This has to be converted to mg/hr using the scale of 60. You can add as many paired rate entries as you need to describe as many infusion interventions as necessary.

Note: If you just want a placeholder you can just set both of the values to [0].

Covariates <CV:?>, <CVSET:?:?>

Simple covariates

For simulation purposes covariates (normally found in a dataset) need to be defined. Covariates can be either constant or change with time. The times values must be the same scale as the system. The following defines the value for the covariate RACE:

<CV:RACE>; times;  [0];     hours
<CV:RACE>; values; [1];     ethnicity

Covariates can also change with time. In this case consider the subject weight (WGT). It begins at 70 and measurements are made at several time points.

<CV:WGT>; times;  [ 0 1680 3360 5040 10080];     hours 
<CV:WGT>; values; [70   65   60   58    56];     kg     

Next we can alter how the simulations will interpret these values by setting the type of covariate. By default the weight will be linearly interpolated (type = linear), however we can hold the weight constant until the next measurement is encountered (last value carried forward) by declaring the type as step

<CVTYPE:WGT> step

Now if the model was parameterized for male and female subjects we can define two parameter sets (as described above) to account for this:

<PSET:default>  Male   
<PSET:female>   Female          

And the values for the covariate can be changed for the set ‘female’:

<CVSET:female:WGT>; times;   [ 0 1680 3360 10080]
<CVSET:female:WGT>; values;  [60   55   52    50]

Complicated covariates

Detailed time course profiles can be created as well. For example, to create a covariate profile that is zero from time 0-1 and at time 1 it jumps to 8 and decreases at a rate of 1 per unit time until time 5 where it stays at the value 4 until time 12. It might have a profile like the following:

Time-varying covariate input profile

# name        time/values  values                         units
<CV:mycov>  ; times;       [0 .999 1 5 12];  hours
<CV:mycov>  ; values;      [0 0    8 4 4 ];  --   
<CVTYPE:mycov> linear

Output error model <OE:?> ?

This links parameters defined using <VP:?> to specific outputs defined using . You can define either add for additive and/or prop for proportional error:

`<OE:OUTPUT> expression`

The OUTPUT can be the name of any output defined with <O>. The expression is a model type (add for additive, and prop for proportional) with an equal sign and the name of the variance paramter (<VP>) to use. To use more than one error model type you separate the statments with ; For example if you define the variance parameters add_err and prop_err and want to use a proportional error model to the output Cp you would use:

<OE:Cp> prop=prop_err

To use both additive and proportional error the following would work:

<OE:Cp> add=add_err; prop=prop_err

There are certain target-specific considerations. For example if you are using Matlab or R and you just wanted to do a weighted least squares estimation proportional to the prediction squared you would use the following but fix prop_err as 1.

<OE:Cp> prop=prop_err

To do least squares estimation you could do the following and fix add_err as 1.

<OE:Cp> add=add_err

These represent the default values though it’s possible to overwrite them. In the Matlab and R workflows if you define the variance at the cohort level, the error models in the system file will be overwritten. ## Functions and operators

Most of the standard operators behave as expected (+, -, *, & /) because most languages use these consistently. There are however certain operators and functions that differ between languages. For example, consider the power function (a^b). In FORTRAN this would be a**b, in Matlab it is a^b, and in C it is pow(a,b). Given the objectives here (write once and create multiple formats), this can be quite challenging. The solution used here is to convert language specific functions and operators into generic functions. So the power operator would be:

SIMINT_POWER[a][b]

This would then be converted to the appropriate output format depending on the output target. The following generic functions can be used:

Current simulation time

For some systems you will want to access the simulation time. To do this you can use the internal variable SIMINT_TIME.

Modeling quasi-equilibrium of target-mediated drugs

The free amount of a drug Cfree which is binding to a receptor with an affinity of KD given total values Ctot and Rtot the following can be calculated using the following equation:

$$ C_{free}=\frac{1}{2} \left[ (C_{tot}-R_{tot}-K_D) + \sqrt{(C_{tot}-R_{tot}-K_D)^2 + 4K_DC_{tot}} \right] $$

This can be tedious, especially using the generic functions above. To make this easier you can use the following generic function:

<Ad> Cfree = SIMINT_QEQ[Ctot][Rtot][KD]

To get Rfree, just switch the first two arguments:

<Ad> Rfree = SIMINT_QEQ[Rtot][Ctot][KD]

Set notation <SET:?>?

Consider the interactions occurring in an assay designed to detect drug (D) present in serum. In this assay a biotinylated target (TB) is used to pull down the drug and a labeled target (TL) is the signaling molecule used. The assay will provide a signal when a complex containing both TB and TL are present (TB:D:TL or TL:D:TB). Samples can contain soluble target as well (TS) which can interfere with the assay. To model this assay, the following interactions should be considered:

Mathematical sets

Several options are available to construct this system. The ODEs could simply be typed out for every possible combination. It’s also possible to use the equilibrium <=kon:koff=> for all the interactions as well. However, there is another option that will handle the enumeration more easily. First we define the two mathematical sets TSi and TSk:

<SET:TSi> TL; TB; TS
<SET:TSk> TL; TB; TS

With these defined we can then use the curly brace notation ({ }) with any of the descriptors used to construct a system. For example, the initial conditions for each of the target states are defined as parameters (T0_TL, T0_TS, T0_TB) in the model. These have to be identified as initial conditions using the <I> notation, and can be done with a single statement. This line:

<I> {TSi} = T0_{TSi} 

Expands to:

<I> TL = T0_TL
<I> TB = T0_TB
<I> TS = T0_TS

Similar to the initial condition, the equilibrium between the monomeric drug and the different targets can be defined using a single statement:

D + {TSi} <=kon:koff=> D_{TSi}

That uses only one of the sets (TSi) and will be expanded for each element in that set. To account for the formation of complexes that contain a drug molecule and two different target molecules, the following statement is used:

D_{TSi} + {TSk} <=kon:koff=> {TSk}_D_{TSi}

This statement contains two different sets (TSi and TSk). When multiple sets are encountered, every possible combination is evaluated

<SET:TRIN>    K; K1; K2; K3
<SET:TROUT>  K1; K2; K3; K4 

SIMINT_SET_ALIGN[TRIN;TROUT][<ODE:{TROUT}> 1.0/tau*({TRIN}-{TROUT})]

<ODE:K1> 1.0/tau*(K-K1)
<ODE:K2> 1.0/tau*(K1-K2)
<ODE:K3> 1.0/tau*(K2-K3)
<ODE:K4> 1.0/tau*(K3-K4)

<SET:SP> Mouse; Rat; Monkey; Human

<As> BW = SIMINT_SET_SUM[SP][EN_{SP}*BW_{SP}]

Constructing a piece-wise continuous function/parameter

To see an example use the following command (use ?system_new to see a list of the available system file examples):

system_new(system_file="pwc", file_name="system-pwc.txt")

In this example we specify fast (kelf) and slow (kels) rates of elimination. We want to have the fast rate be active when the drug concentration is above Cth and the time is below Tf. The system parameters would look like:

<P> kelf   1.0  eps inf   1/time   yes System
<P> kels   0.01 eps inf   1/time   yes System
<P> Cth   10    eps inf   conc     yes System
<P> Tf    10    eps inf   time     yes System

Now we need to define the rate of elimination such that the constraints above are followed. First we define kel as a dynamic secondary parameter with a value of 0.0. Then we define the different conditions and relevant values:

<Ad > kel = 0.0
<IF:kel:COND> SIMINT_AND[SIMINT_LT[SIMINT_TIME][Tf]][ SIMINT_GT[Cp][Cth]]; kelf
<IF:kel:ELSE> kels

R workflow

• auto_simulation_driver.R: R-Script with named with placeholders used to run simulations.
• auto_analysis_estimation.R: R-Script with named with placeholders used to perform naive-pooled parameter estimation.

Matlab workflow

• auto_simulation_driver.m: M-file with named with placeholders used to run simulations.
• auto_analysis_estimation.m: M-file with named with placeholders used to perform naive-pooled parameter estimation.

Other Software Targets

• target_adapt_5.for and target_adapt_5-PSET.prm: The system defined for Adapt Fortran and a parameter (prm) file for each parameter set PSET.

• target_berkely_madonna-PSET.txt: This is a text file containing the system for the parameter set PSET to run in Berkeley Madonna.

• target_mrgsolve-PSET.cpp: This is a C++ file containing the system for the parameter set PSET to run using the in mrgsolve package in R.

• target_nlmixr-PSET.R: This R script defines the system for analysis in nlmixr2 for the parameter set PSET. Note: The nlmixr2 target can be used to create input model files for both NONMEM and Monolix