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Combining event tables

Source: vignettes/articles/rxode2-event-table-combine.Rmd
rxode2-event-table-combine.Rmd

Once single regimens are built with et() (see Building event tables with et()), they can be combined into more complex designs with c(), seq()/etSeq(), rep()/etRep() and rbind()/etRbind().

The examples use the model from the rxode2 tutorial:

library(rxode2)
#> rxode2 5.1.8.9000 using 2 threads (see ?getRxThreads)
#>   no cache: create with `rxCreateCache()`
library(units)
#> udunits database from /usr/share/xml/udunits/udunits2.xml
## Model from rxode2 tutorial
m1 <-function() {
  ini({
    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
  })
  model({
    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
  })
}

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)
#> ℹ parameter labels from comments are typically ignored in non-interactive mode
#> ℹ Need to run with the source intact to parse comments

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 rxode2 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)

Next steps