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Simulate New dosing from Monolix model

simulate-new-dosing.Rmd

This page shows a simple work-flow for directly simulating a different dosing paradigm than what was modeled.

Step 1: Import the model 

library(monolix2rx)
library(rxode2)

# You use the path to the monolix mlxtran file

# In this case we will us the theophylline project included in monolix2rx
pkgTheo <- system.file("theo/theophylline_project.mlxtran", package="monolix2rx")

# Note you have to setup monolix2rx to use the model library or save
# the model as a separate file
mod <- monolix2rx(pkgTheo)
#> ℹ integrated model file 'oral1_1cpt_kaVCl.txt' into mlxtran object
#> ℹ updating model values to final parameter estimates
#> ℹ done
#> ℹ reading run info (# obs, doses, Monolix Version, etc) from summary.txt
#> ℹ done
#> ℹ reading covariance from FisherInformation/covarianceEstimatesLin.txt
#> ℹ done
#> Warning in .dataRenameFromMlxtran(data, .mlxtran): NAs introduced by coercion
#> ℹ imported monolix and translated to rxode2 compatible data ($monolixData)
#> ℹ imported monolix ETAS (_SAEM) imported to rxode2 compatible data ($etaData)
#> ℹ imported monolix pred/ipred data to compare ($predIpredData)
#> ℹ solving ipred problem
#> ℹ done
#> ℹ solving pred problem
#> ℹ done

print(mod)
#>  ── rxode2-based free-form 2-cmt ODE model ────────────────────────────────────── 
#>  ── Initalization: ──  
#> Fixed Effects ($theta): 
#>      ka_pop       V_pop      Cl_pop           a           b 
#>  0.42699448 -0.78635157 -3.21457598  0.43327956  0.05425953 
#> 
#> Omega ($omega): 
#>           omega_ka    omega_V   omega_Cl
#> omega_ka 0.4503145 0.00000000 0.00000000
#> omega_V  0.0000000 0.01594701 0.00000000
#> omega_Cl 0.0000000 0.00000000 0.07323701
#> 
#> States ($state or $stateDf): 
#>   Compartment Number Compartment Name
#> 1                  1            depot
#> 2                  2          central
#>  ── μ-referencing ($muRefTable): ──  
#>    theta      eta level
#> 1 ka_pop omega_ka    id
#> 2  V_pop  omega_V    id
#> 3 Cl_pop omega_Cl    id
#> 
#>  ── Model (Normalized Syntax): ── 
#> function() {
#>     description <- "The administration is extravascular with a first order absorption (rate constant ka).\nThe PK model has one compartment (volume V) and a linear elimination (clearance Cl).\nThis has been modified so that it will run without the model library"
#>     dfObs <- 120
#>     dfSub <- 12
#>     thetaMat <- lotri({
#>         ka_pop ~ 0.09785
#>         V_pop ~ c(0.00082606, 0.00041937)
#>         Cl_pop ~ c(-4.2833e-05, -6.7957e-06, 1.1318e-05)
#>         omega_ka ~ c(omega_ka = 0.022259)
#>         omega_V ~ c(omega_ka = -7.6443e-05, omega_V = 0.0014578)
#>         omega_Cl ~ c(omega_ka = 3.062e-06, omega_V = -1.2912e-05, 
#>             omega_Cl = 0.0039578)
#>         a ~ c(omega_ka = -0.0001227, omega_V = -6.5914e-05, omega_Cl = -0.00041194, 
#>             a = 0.015333)
#>         b ~ c(omega_ka = -1.3886e-05, omega_V = -3.1105e-05, 
#>             omega_Cl = 5.2805e-05, a = -0.0026458, b = 0.00056232)
#>     })
#>     validation <- c("ipred relative difference compared to Monolix ipred: 0.04%; 95% percentile: (0%,0.52%); rtol=0.00038", 
#>         "ipred absolute difference compared to Monolix ipred: 95% percentile: (0.000362, 0.00848); atol=0.00254", 
#>         "pred relative difference compared to Monolix pred: 0%; 95% percentile: (0%,0%); rtol=6.6e-07", 
#>         "pred absolute difference compared to Monolix pred: 95% percentile: (1.6e-07, 1.27e-05); atol=3.66e-06", 
#>         "iwres relative difference compared to Monolix iwres: 0%; 95% percentile: (0.06%,32.22%); rtol=0.0153", 
#>         "iwres absolute difference compared to Monolix pred: 95% percentile: (0.000403, 0.0138); atol=0.00305")
#>     ini({
#>         ka_pop <- 0.426994483535611
#>         V_pop <- -0.786351566327091
#>         Cl_pop <- -3.21457597916301
#>         a <- c(0, 0.433279557549051)
#>         b <- c(0, 0.0542595276206251)
#>         omega_ka ~ 0.450314511978718
#>         omega_V ~ 0.0159470121255372
#>         omega_Cl ~ 0.0732370098834837
#>     })
#>     model({
#>         cmt(depot)
#>         cmt(central)
#>         ka <- exp(ka_pop + omega_ka)
#>         V <- exp(V_pop + omega_V)
#>         Cl <- exp(Cl_pop + omega_Cl)
#>         d/dt(depot) <- -ka * depot
#>         d/dt(central) <- +ka * depot - Cl/V * central
#>         Cc <- central/V
#>         CONC <- Cc
#>         CONC ~ add(a) + prop(b) + combined1()
#>     })
#> }

Step 2: Look at a different dosing paradigm

Lets say that in this case instead of a single dose, we want to see what the concentration profile is with a single day of BID dosing. In this case is done by creating a quick event table:

ev <- et(amt=4, ii=12, until=24) %>%
  et(list(c(0, 2), # add observations in windows
          c(4, 6),
          c(8, 12),
          c(14, 18),
          c(20, 26),
          c(28, 32),
          c(32, 36),
          c(36, 44))) %>%
  et(id=1:10)

Step 3: solve using rxode2

In this step, we solve the model with the new event table for the 10 subjects:

s <- rxSolve(mod, ev)
#> ℹ using locf interpolation like Monolix, specify directly to change
#> ℹ using Monolix specified atol=1e-06
#> ℹ using Monolix specified rtol=1e-06
#> ℹ Since Monolix doesn't use ssRtol, set ssRtol=100
#> ℹ Since Monolix doesn't use ssRtol, set ssAtol=100
#> ℹ Since Monolix uses a set number of doses for steady state use maxSS=8, minSS=7
#> using C compiler: ‘gcc (Ubuntu 11.4.0-1ubuntu1~22.04) 11.4.0’

Note that since this is a nonmem2rx model, the default solving will match the tolerances and methods specified in your NONMEM model.

Step 4: exploring the simulation (by plotting)

This solved object acts the same as any other rxode2 solved object, so you can use the plot() function to see the individual profiles you simulated:

library(ggplot2)
plot(s, ipredSim) +
  ylab("Concentrations")