nlmixrdevelopment/RxODE.doc
Facilities for Simulating from ODE-Based Models

Package index
Search the nlmixrdevelopment/RxODE.doc package
Vignettes
Functions
2
Source code
1
Man pages
1
Home
/
GitHub
/
nlmixrdevelopment/RxODE.doc
/

In nlmixrdevelopment/RxODE.doc: Facilities for Simulating from ODE-Based Models 

options(cli.unicode=FALSE, crayon.enabled=FALSE);
options(knitr.table.format = "html")
knitr::opts_chunk$set( comment = "#>")
htmltools::img(src = knitr::image_uri("logo.png"), 
               alt = 'RxODE', 
               style = 'position:absolute; top:0; right:0; padding:10px; border: 0;')
options(width=80)
Sys.setenv(RSTUDIO_CONSOLE_WIDTH=80)

RxODE event tables

In general, RxODE event tables follow NONMEM convention with the exceptions:

Here are the legal entries to a data table:

| Data Item | Meaning | Notes | |-----------|-----------------------|------------------------------------------------------------------------------| | id | Individual identifier | Must be an integer > 0, sorted | | time | Individual time | For each ID must be ascending and non-negative | | amt | dose amount | Positive for doses zero/NA for observations | | rate | infusion rate | When specified the infusion duration will be dur=amt/rate | | | | rate = -1, rate modeled; rate = -2, duration modeled | | dur | infusion duration | When specified the infusion rate will be rate = amt/dur | | evid | event ID | 0=Observation; 1=Dose; 2=Other; 3=Reset; 4=Reset+Dose; 5=Replace; 6=Multiply | | cmt | Compartment | Represents compartment #/name for dose/observation | | ss | Steady State Flag | 0 = non-steady-state; 1=steady state; 2=steady state +prior states | | ii | Inter-dose Interval | Time between doses. | | addl | # of additional doses | Number of doses like the current dose. |

Other notes:

When returning the RxODE solved data-set there are a few additional event ids (EVID):

These can only be accessed when solving with the option combination addDosing=TRUE and subsetNonmem=FALSE. If you want to see the classic EVID equivalents you can use addDosing=NA.

Creating RxODE's event tables

An event table in RxODE is a specialized data frame that acts as a container for all of RxODE's events and observation times.

To create an RxODE event table you may use the code eventTable(), et(), or even create your own data frame with the right event information contained in it.

library(RxODE)
(ev <- eventTable());

or

(ev <- et());

For these models, we can illustrate by using the model shared in the RxODE tutorial:

## Model from RxODE tutorial
m1 <-RxODE({
    KA=2.94E-01;
    CL=1.86E+01;
    V2=4.02E+01;
    Q=1.05E+01;
    V3=2.97E+02;
    Kin=1;
    Kout=1;
    EC50=200;
    ## Added modeled bioavaiblity, duration and rate
    fdepot = 1;
    durDepot = 8;
    rateDepot = 1250;
    C2 = centr/V2;
    C3 = peri/V3;
    d/dt(depot) =-KA*depot;
    f(depot) = fdepot
    dur(depot) = durDepot
    rate(depot) = rateDepot
    d/dt(centr) = KA*depot - CL*C2 - Q*C2 + Q*C3;
    d/dt(peri)  =                    Q*C2 - Q*C3;
    d/dt(eff)  = Kin - Kout*(1-C2/(EC50+C2))*eff;
    eff(0) = 1
});

Adding doses to the event table

Once created you can add dosing to the event table by the add.dosing, and et functions.

Using the add.dosing function you have:

| argument | meaning | |-----------------|-----------------------------------------| | dose | dose amount | | nbr.doses | Number of doses; Should be at least 1. | | dosing.interval | Dosing interval; By default this is 24. | | dosing.to | Compartment where dose is administered. | | rate | Infusion rate | | start.time | The start time of the dose |

ev <- eventTable(amount.units="mg", time.units="hr")

## The methods ar attached to the event table, so you can use them
## directly
ev$add.dosing(dose=10000, nbr.doses = 3)# loading doses
## Starts at time 0; Default dosing interval is 24

## You can also pipe the event tables to these methods.
ev <- ev %>%
    add.dosing(dose=5000, nbr.doses=14, dosing.interval=12)# maintenance

ev

Notice that the units were specified in the table. When specified, the units use the units package to keep track of the units and convert them if needed. Additionally, ggforce uses them to label the ggplot axes. The set_units and drop_units are useful to set and drop the RxODE event table units.

In this example, you can see the time axes is labeled:

rxSolve(m1, ev) %>% plot(C2)

If you are more familiar with the NONMEM/RxODE event records, you can also specify dosing using et with the dose elements directly:

ev <- et(timeUnits="hr") %>%
    et(amt=10000, until = set_units(3, days), ii=12) # loading doses

ev

Which gives:

rxSolve(m1, ev) %>% plot(C2)

This shows how easy creating event tables can be.

Adding sampling to an event table

If you notice in the above examples, RxODE generated some default sampling times since there was not any sampling times. If you wish more control over the sampling time, you should add the samples to the RxODE event table by add.sampling or et

ev <- eventTable(amount.units="mg", time.units="hr")

## The methods ar attached to the event table, so you can use them
## directly
ev$add.dosing(dose=10000, nbr.doses = 3)# loading doses

ev$add.sampling(seq(0,24,by=4))

ev

Which gives:

solve(m1, ev) %>% plot(C2)

Or if you use et you can simply add them in a similar way to add.sampling:

ev <- et(timeUnits="hr") %>%
    et(amt=10000, until = set_units(3, days), ii=12) %>% # loading doses
    et(seq(0,24,by=4))

ev

which gives the following RxODE solve:

solve(m1, ev) %>% plot(C2)

Note the jagged nature of these plots since there was only a few sample times.

Expand the event table to a multi-subject event table.

The only thing that is needed to expand an event table is a list of IDs that you want to expand;

ev <- et(timeUnits="hr") %>%
    et(amt=10000, until = set_units(3, days), ii=12) %>% # loading doses
    et(seq(0,48,length.out=200)) %>%
    et(id=1:4)

ev

You can see in the following simulation there are 4 individuals that are solved for:

set.seed(42)
solve(m1, ev,
      params=data.frame(KA=0.294*exp(rnorm(4)), 18.6*exp(rnorm(4)))) %>%
    plot(C2)

Add doses and samples within a sampling window

In addition to adding fixed doses and fixed sampling times, you can have windows where you sample and draw doses from. For dosing windows you specify the time as an ordered numerical vector with the lowest dosing time and the highest dosing time inside a list.

In this example, you start with a dosing time with a 6 hour dosing window:

set.seed(42)
ev <- et(timeUnits="hr") %>%
    et(time=list(c(0,6)), amt=10000, until = set_units(2, days), ii=12) %>% # loading doses
    et(id=1:4)

ev

You can clearly see different dosing times in the following simulation:

ev <- ev %>% et(seq(0,48,length.out=200))

solve(m1, ev, params=data.frame(KA=0.294*exp(rnorm(4)), 18.6*exp(rnorm(4)))) %>% plot(C2)

Of course in reality the dosing interval may only be 2 hours:

set.seed(42)
ev <- et(timeUnits="hr") %>%
    et(time=list(c(0,2)), amt=10000, until = set_units(2, days), ii=12) %>% # loading doses
    et(id=1:4) %>%
    et(seq(0,48,length.out=200))

solve(m1, ev, params=data.frame(KA=0.294*exp(rnorm(4)), 18.6*exp(rnorm(4)))) %>% plot(C2)

The same sort of thing can be specified with sampling times. To specify the sampling times in terms of a sampling window, you can create a list of the sampling times. Each sampling time will be a two element ordered numeric vector.

set.seed(42)
ev <- et(timeUnits="hr") %>%
    et(time=list(c(0,2)), amt=10000, until = set_units(2, days), ii=12) %>% # loading doses
    et(id=1:4)

## Create 20 samples in the first 24 hours and 20 samples in the second 24 hours
samples <- c(lapply(1:20, function(...){c(0,24)}),
             lapply(1:20, function(...){c(20,48)}))

## Add the random collection to the event table
ev <- ev %>% et(samples)

library(ggplot2)
solve(m1, ev, params=data.frame(KA=0.294*exp(rnorm(4)), 18.6*exp(rnorm(4)))) %>% plot(C2) + geom_point()

This shows the flexibility in dosing and sampling that the RxODE event tables allow.

Combining event tables

Since you can create dosing records and sampling records, you can create any complex dosing regimen you wish. In addition, RxODE allows you to combine event tables by c, seq, rep, and rbind.

Sequencing event tables

One way to combine event table is to sequence them by c, seq or etSeq. This takes the two dosing groups and adds at least one inter-dose interval between them:

## bid for 5 days
bid <- et(timeUnits="hr") %>%
       et(amt=10000,ii=12,until=set_units(5, "days"))

## qd for 5 days
qd <- et(timeUnits="hr") %>%
      et(amt=20000,ii=24,until=set_units(5, "days"))

## bid for 5 days followed by qd for 5 days
et <- seq(bid,qd) %>% et(seq(0,11*24,length.out=100));

rxSolve(m1, et) %>% plot(C2)

When sequencing events, you can also separate this sequence by a period of time; For example if you wanted to separate this by a week, you could easily do that with the following sequence of event tables:

## bid for 5 days followed by qd for 5 days
et <- seq(bid,set_units(1, "week"), qd) %>%
    et(seq(0,18*24,length.out=100));

rxSolve(m1, et) %>% plot(C2)

Note that in this example the time between the bid and the qd event tables is exactly one week, not 1 week plus 24 hours because of the inter-dose interval. If you want that behavior, you can sequence it using the wait="+ii".

## bid for 5 days followed by qd for 5 days
et <- seq(bid,set_units(1, "week"), qd,wait="+ii") %>%
    et(seq(0,18*24,length.out=100));

rxSolve(m1, et) %>% plot(C2)

Also note, that RxODE assumes that the dosing is what you want to space the event tables by, and clears out any sampling records when you combine the event tables. If that is not true, you can also use the option samples="use"

Repeating event tables

You can have an event table that you can repeat with etRep or rep. For example 4 rounds of 2 weeks on QD therapy and 1 week off of therapy can be simply specified:

qd <-et(timeUnits = "hr") %>% et(amt=10000, ii=24, until=set_units(2, "weeks"), cmt="depot")

et <- rep(qd, times=4, wait=set_units(1,"weeks")) %>%
      add.sampling(set_units(seq(0, 12.5,by=0.005),weeks))

rxSolve(m1, et)  %>% plot(C2)

This is a simplified way to use a sequence of event tables. Therefore, many of the same options still apply; That is samples are cleared unless you use samples="use", and the time between event tables is at least the inter-dose interval. You can adjust the timing by the wait option.

Combining event tables with rbind

You may combine event tables with rbind. This does not consider the event times when combining the event tables, but keeps them the same times. If you space the event tables by a waiting period, it also does not consider the inter-dose interval.

Using the previous seq you can clearly see the difference. Here was the sequence:

## bid for 5 days
bid <- et(timeUnits="hr") %>%
       et(amt=10000,ii=12,until=set_units(5, "days"))

## qd for 5 days
qd <- et(timeUnits="hr") %>%
      et(amt=20000,ii=24,until=set_units(5, "days"))

et <- seq(bid,qd) %>%
    et(seq(0,18*24,length.out=500));

rxSolve(m1, et) %>% plot(C2)

But if you bind them together with rbind

## bid for 5 days
et <- rbind(bid,qd) %>%
    et(seq(0,18*24,length.out=500));

rxSolve(m1, et) %>% plot(C2)

Still the waiting period applies (but does not consider the inter-dose interval)

et <- rbind(bid,wait=set_units(10,days),qd) %>%
    et(seq(0,18*24,length.out=500));

rxSolve(m1, et) %>% plot(C2)

You can also bind the tables together and make each ID in the event table unique; This can be good to combine cohorts with different expected dosing and sampling times. This requires the id="unique" option; Using the first example shows how this is different in this case:

## bid for 5 days
et <- etRbind(bid,qd, id="unique") %>%
    et(seq(0,150,length.out=500));

library(ggplot2)
rxSolve(m1, et) %>% plot(C2) + facet_wrap( ~ id)

Bolus Doses

A bolus dose is the default type of dose in RxODE and only requires the amt/dose

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12,until=24) %>%
    et(seq(0, 24, length.out=100))

ev

rxSolve(m1, ev) %>% plot(C2) +
    xlab("Time")

Constant Infusion (in terms of duration and rate)

The next type of event is an infusion; There are two ways to specify an infusion; The first is the dur keyword.

An example of this is:

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12,until=24, dur=8) %>%
    et(seq(0, 24, length.out=100))

ev

rxSolve(m1, ev) %>% plot(depot, C2) +
    xlab("Time")

It can be also specified by the rate component:

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12,until=24, rate=10000/8) %>%
    et(seq(0, 24, length.out=100))

ev

rxSolve(m1, ev) %>% plot(depot, C2) +
    xlab("Time")

These are the same with the exception of how bioavailability changes the infusion.

In the case of modeling rate, a bioavailability decrease, decreases the infusion duration, as in NONMEM. For example:

rxSolve(m1, ev, c(fdepot=0.25)) %>% plot(depot, C2) +
    xlab("Time")

Similarly increasing the bioavailability increases the infusion duration. 

rxSolve(m1, ev, c(fdepot=1.25)) %>% plot(depot, C2) +
    xlab("Time")

The rationale for this behavior is that the rate and amt are specified by the event table, so the only thing that can change with a bioavailability increase is the duration of the infusion.

If you specify the amt and dur components in the event table, bioavailability changes affect the rate of infusion.

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12,until=24, dur=8) %>%
    et(seq(0, 24, length.out=100))

You can see the side-by-side comparison of bioavailability changes affecting rate instead of duration with these records in the following plots:

library(ggplot2)
library(gridExtra)

p1 <- rxSolve(m1, ev, c(fdepot=1.25)) %>% plot(depot) +
    xlab("Time") + ylim(0,5000)

p2 <- rxSolve(m1, ev, c(fdepot=0.25)) %>% plot(depot) +
    xlab("Time")+ ylim(0,5000)

grid.arrange(p1,p2, nrow=1)

Modeled Rate and Duration of Infusion

You can model the duration, which is equivalent to NONMEM's rate=-2. As a mnemonic you can use the dur=model instead of rate=-2

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12,until=24, dur=model) %>%
    et(seq(0, 24, length.out=100))

ev

rxSolve(m1, ev, c(durDepot=7)) %>% plot(depot, C2) +
    xlab("Time")

Similarly, you may also model rate. This is equivalent to NONMEM's rate=-1 and is how RxODE's event table specifies the data item as well. You can also use rate=model as a mnemonic:

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12,until=24, rate=model) %>%
    et(seq(0, 24, length.out=100))

ev

rxSolve(m1, ev, c(rateDepot=10000/3)) %>% plot(depot, C2) +
    xlab("Time")

Steady State

Steady state doses; These doses are solved until a steady state is reached with a constant inter-dose interval.

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12, ss=1) %>%
    et(seq(0, 24, length.out=100))

ev

rxSolve(m1, ev) %>% plot(C2)

Steady state for complex dosing

By using the ss=2 flag, you can use the super-positioning principle in linear kinetics to get steady state nonstandard dosing (i.e. morning 100 mg vs evening 150 mg). This is done by:

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=24, ss=1) %>%
    et(time=12, amt=15000, ii=24, ss=2) %>%
    et(time=24, amt=10000, ii=24, addl=3) %>%
    et(time=36, amt=15000, ii=24, addl=3) %>%
    et(seq(0, 64, length.out=500))

library(ggplot2)

rxSolve(m1, ev,maxsteps=10000) %>% plot(C2) +
    annotate("rect", xmin=0, xmax=24, ymin=-Inf, ymax=Inf, alpha=0.2) +
    annotate("text", x=12.5, y=7, label="Initial Steady State Period") +
    annotate("text", x=44,   y=7, label="Steady State AM/PM dosing")

You can see that it takes a full dose cycle to reach the true complex steady state dosing.

Steady state for constant infusion or zero order processes

The last type of steady state that RxODE supports is steady-state constant infusion rate. This can be specified the same way as NONMEM, that is:

Note that rate=-2 where we model the duration of infusion doesn't make much sense since we are solving the infusion until steady state. The duration is specified by the steady state solution.

Also note that bioavailability changes on this steady state infusion also do not make sense because they neither change the rate or the duration of the steady state infusion. Hence modeled bioavailability on this type of dosing event is ignored.

Here is an example:

ev <- et(timeUnits="hr") %>%
    et(amt=0, ss=1,rate=10000/8)

p1 <- rxSolve(m1, ev) %>% plot(C2, eff)


ev <- et(timeUnits="hr") %>%
    et(amt=200000, rate=10000/8) %>%
    et(0, 250, length.out=1000)

p2 <- rxSolve(m1, ev) %>% plot(C2, eff)


grid.arrange(p1,p2, ncol=1)

Not only can this be used for PK, it can be used for steady-state disease processes.

Reset Events

Reset events are implemented by evid=3 or evid=reset, for reset and evid=4 for reset and dose.

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12, addl=3) %>%
    et(time=6, evid=reset) %>%
    et(seq(0, 24, length.out=100))

ev

The solving show what happens in this system when the system is reset at 6 hours post-dose.

rxSolve(m1, ev) %>% plot(depot,C2, eff)

You can see all the compartments are reset to their initial values. The next dose start the dosing cycle over.

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12, addl=3) %>%
    et(time=6, amt=10000, evid=4) %>%
    et(seq(0, 24, length.out=100))

ev

In this case, the whole system is reset and the dose is given

rxSolve(m1, ev) %>% plot(depot,C2, eff)

Turning off compartments

You may also turn off a compartment, which is similar to a reset event.

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12, addl=3) %>%
    et(time=6, cmt="-depot", evid=2) %>%
    et(seq(0, 24, length.out=100))

ev

Solving shows what this does in the system:

rxSolve(m1, ev) %>% plot(depot,C2, eff)

In this case, the depot is turned off, and the compartment concentrations are set to the initial values but the other compartment concentrations/levels are not reset. When another dose to the depot is administered the depot compartment is turned back on.

Note that a dose to a compartment only turns back on the compartment that was dosed. Hence if you turn off the effect compartment, it continues to be off after another dose to the depot.

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12, addl=3) %>%
    et(time=6, cmt="-eff", evid=2) %>%
    et(seq(0, 24, length.out=100))

rxSolve(m1, ev) %>% plot(depot,C2, eff)

To turn back on the compartment, a zero-dose to the compartment or a evid=2 with the compartment would be needed.

ev <- et(timeUnits="hr") %>%
    et(amt=10000, ii=12, addl=3) %>%
    et(time=6, cmt="-eff", evid=2) %>%
    et(time=12,cmt="eff",evid=2) %>%
    et(seq(0, 24, length.out=100))

rxSolve(m1, ev) %>% plot(depot,C2, eff)

Classic RxODE evid values

While RxODE still supports these values, this is primarily provided for historic information, and we recommend using the normal NONMEM dataset standard that is used by many modeling tools like NONMEM, Monolix and nlmixr, described above.

Classically, RxODE supported event coding in a single event id evid described in the following table.

| 100+ cmt | Infusion/Event Flag | <99 Cmt | SS flag & Turning of Compartment | |----------|-------------------------------|----------|-----------------------------------------------------------| | 100+ cmt | 0 = bolus dose | < 99 cmt | 1 = dose | | | 1 = infusion (rate) | | 10 = Steady state 1 (equivalent to SS=1) | | | 2 = infusion (dur) | | 20 = Steady state 2 (equivalent to SS=2) | | | 6 = turn off modeled duration | | 30 = Turn off a compartment (equivalent to -CMT w/EVID=2) | | | 7 = turn off modeled rate | | | | | 8 = turn on modeled duration | | | | | 9 = turn on modeled rate | | | | | 4 = replace event | | | | | 5 = multiply event | | |

The classic EVID concatenate the numbers in the above table, so an infusion would to compartment 1 would be 10101 and an infusion to compartment 199 would be 119901.

EVID = 0 (observations), EVID=2 (other type event) and EVID=3 are all supported. Internally an EVID=9 is a non-observation event and makes sure the system is initialized to zero; EVID=9 should not be manually set. EVID 10-99 represents modeled time interventions, similar to NONMEM's MTIME. This along with amount (amt) and time columns specify the events in the ODE system.

For infusions specified with EVIDs > 100 the amt column represents the rate value.

For Infusion flags 1 and 2 +amt turn on the infusion to a specific compartment -amt turn off the infusion to a specific compartment. To specify a dose/duration you place the dosing records at the time the duration starts or stops.

For modeled rate/duration infusion flags the on infusion flag must be followed by an off infusion record.

These number are concatenated together to form a full RxODE event ID, as shown in the following examples:

Bolus Dose Examples

A 100 bolus dose to compartment #1 at time 0

| time | evid | amt | |------|------|-----| | 0 | 101 | 100 | | 0.5 | 0 | 0 | | 1 | 0 | 0 |

A 100 bolus dose to compartment #99 at time 0

| time | evid | amt | |------|------|-----| | 0 | 9901 | 100 | | 0.5 | 0 | 0 | | 1 | 0 | 0 |

A 100 bolus dose to compartment #199 at time 0

| time | evid | amt | |------|--------|-----| | 0 | 109901 | 100 | | 0.5 | 0 | 0 | | 1 | 0 | 0 |

Infusion Event Examples

Bolus infusion with rate 50 to compartment 1 for 1.5 hr, (modeled bioavailability changes duration of infusion)

| time | evid | amt | |------|-------|-----| | 0 | 10101 | 50 | | 0.5 | 0 | 0 | | 1 | 0 | 0 | | 1.5 | 10101 | -50 |

Bolus infusion with rate 50 to compartment 1 for 1.5 hr (modeled bioavailability changes rate of infusion)

| time | evid | amt | |------|-------|-----| | 0 | 20101 | 50 | | 0.5 | 0 | 0 | | 1 | 0 | 0 | | 1.5 | 20101 | -50 |

Modeled rate with amount of 50

| time | evid | amt | |------|-------|-----| | 0 | 90101 | 50 | | 0 | 70101 | 50 | | 0.5 | 0 | 0 | | 1 | 0 | 0 |

Modeled duration with amount of 50

| time | evid | amt | |------|-------|-----| | 0 | 80101 | 50 | | 0 | 60101 | 50 | | 0.5 | 0 | 0 | | 1 | 0 | 0 |

Steady State for classic RxODE EVID example

Steady state dose to cmt 1

| time | evid | amt | |------|------|-----| | 0 | 110 | 50 |

Steady State with super-positioning principle for am 50 and pm 100 dose

| time | evid | amt | |------|------|-----| | 0 | 110 | 50 | | 12 | 120 | 100 |

Turning off a compartment with classic RxODE EVID

Turn off the first compartment at time 12

| time | evid | amt | |------|------|-----| | 0 | 110 | 50 | | 12 | 130 | NA |

Event coding in RxODE is encoded in a single event number evid. For compartments under 100, this is coded as:

For compartments greater or equal to 100, the 100s place and above digits are transferred to the 100,000th place digit. For doses to the 99th compartment the evid for a bolus dose would be 9901 and the evid for an infusion would be 19901. For a bolus dose to the 199th compartment the evid for the bolus dose would be 109901. An infusion dosing record for the 199th compartment would be 119901.



nlmixrdevelopment/RxODE.doc documentation built on Oct. 17, 2019, 1:27 a.m.

R Package Documentation

rdrr.io home R language documentation Run R code online

Browse R Packages

CRAN packages Bioconductor packages R-Forge packages GitHub packages

We want your feedback!

Note that we can't provide technical support on individual packages. You should contact the package authors for that.
GitHub issue tracker
ian@mutexlabs.com
Personal blog

 
Embedding an R snippet on your website

Add the following code to your website.

For more information on customizing the embed code, read Embedding Snippets.

Close