Reading rounding from NONMEM

One of the things that can be helpful is reading NONMEM with rounding errors.

For this example we will take some of the test examples from babelmixr2 to translate to show examples of rounding errors that can be read in to help diagnose what could be happening with the model.

library(nonmem2rx)
library(babelmixr2)

Step 1: Have a NONMEM model with rounding errors (and `.phi` or other information about the `etas`)

The first step is to load a model with rounding errors using nonmem2rx():

# Unzip example with rounding error
# included, but can be accessed with nlmixr2
#
# unzip(system.file("tests/testthat/pk.turnover.emax3-nonmem.zip", package="babelmixr2"))
# Load the model with `nonmem2rx`:
mod <- nonmem2rx("pk.turnover.emax3-nonmem/pk.turnover.emax3.nmctl")
#> ℹ getting information from  'pk.turnover.emax3-nonmem/pk.turnover.emax3.nmctl'
#> ℹ reading in xml file
#> ℹ done
#> ℹ reading in ext file
#> ℹ done
#> ℹ reading in phi file
#> ℹ done
#> ℹ reading in lst file
#> ℹ abbreviated list parsing
#> ℹ done
#> ℹ reading in grd file
#> ℹ done
#> ℹ splitting control stream by records
#> ℹ done
#> ℹ Processing record $INPUT
#> ℹ Processing record $MODEL
#> ℹ Processing record $gTHETA
#> ℹ Processing record $OMEGA
#> ℹ Processing record $SIGMA
#> ℹ Processing record $PROBLEM
#> ℹ Processing record $DATA
#> ℹ Processing record $SUBROUTINES
#> ℹ Processing record $PK
#> ℹ Processing record $DES
#> ℹ Processing record $ERROR
#> ℹ Processing record $ESTIMATION
#> ℹ Ignore record $ESTIMATION
#> ℹ Processing record $COVARIANCE
#> ℹ Ignore record $COVARIANCE
#> ℹ Processing record $TABLE
#> ℹ change initial estimate of `theta1` to `6.24053043162953e-07`
#> ℹ change initial estimate of `theta2` to `-3.00642760553675e-06`
#> ℹ change initial estimate of `theta3` to `-2.00405074386117`
#> ℹ change initial estimate of `theta4` to `2.05188410700476`
#> ℹ change initial estimate of `theta5` to `0.0985804613565218`
#> ℹ change initial estimate of `theta6` to `0.511625249037084`
#> ℹ change initial estimate of `theta7` to `6.4184983102259`
#> ℹ change initial estimate of `theta8` to `0.140763261319656`
#> ℹ change initial estimate of `theta9` to `-2.9534704318737`
#> ℹ change initial estimate of `theta10` to `4.57045413136592`
#> ℹ change initial estimate of `theta11` to `3.71714384851537`
#> ℹ change initial estimate of `eta1` to `0.558129815059436`
#> ℹ change initial estimate of `eta2` to `0.558402321309217`
#> ℹ change initial estimate of `eta3` to `0.0785849119252598`
#> ℹ change initial estimate of `eta4` to `0.0508226905750953`
#> ℹ change initial estimate of `eta5` to `5e-05`
#> ℹ change initial estimate of `eta6` to `0.18426809257979`
#> ℹ change initial estimate of `eta7` to `0.0083631531443303`
#> ℹ change initial estimate of `eta8` to `0.00274561514766752`
#> ℹ read in nonmem input data (for model validation): /home/runner/work/nonmem2rx/nonmem2rx/vignettes/articles/pk.turnover.emax3-nonmem/pk.turnover.emax3.csv
#> ℹ ignoring lines that begin with a letter (IGNORE=@)
#> ℹ applying names specified by $INPUT
#> ℹ renaming 'ytype' to 'nmytype'
#> ℹ renaming 'dvid' to 'nmdvid'
#> ℹ done
#> ℹ read in nonmem IPRED data (for model validation): /home/runner/work/nonmem2rx/nonmem2rx/vignettes/articles/pk.turnover.emax3-nonmem/pk.turnover.emax3.pred
#> ℹ done
#> ℹ changing most variables to lower case
#> ℹ done
#> ℹ replace theta names
#> ℹ done
#> ℹ replace eta names
#> ℹ done
#> ℹ renaming compartments
#> ℹ done
#> ℹ solving ipred problem
#> ℹ done
#> ℹ solving pred problem
#> ℹ done
mod
#>  ── rxode2-based free-form 4-cmt ODE model ────────────────────────────────────── 
#>  ── Initalization: ──  
#> Fixed Effects ($theta): 
#>          tktr           tka           tcl            tv      prop.err 
#>  6.240530e-07 -3.006428e-06 -2.004051e+00  2.051884e+00  9.858046e-02 
#>     pkadd.err         temax         tec50         tkout           te0 
#>  5.116252e-01  6.418498e+00  1.407633e-01 -2.953470e+00  4.570454e+00 
#>     pdadd.err 
#>  3.717144e+00 
#> 
#> Omega ($omega): 
#>            eta.ktr    eta.ka     eta.cl      eta.v eta.emax  eta.ec50
#> eta.ktr  0.5581298 0.0000000 0.00000000 0.00000000    0e+00 0.0000000
#> eta.ka   0.0000000 0.5584023 0.00000000 0.00000000    0e+00 0.0000000
#> eta.cl   0.0000000 0.0000000 0.07858491 0.00000000    0e+00 0.0000000
#> eta.v    0.0000000 0.0000000 0.00000000 0.05082269    0e+00 0.0000000
#> eta.emax 0.0000000 0.0000000 0.00000000 0.00000000    5e-05 0.0000000
#> eta.ec50 0.0000000 0.0000000 0.00000000 0.00000000    0e+00 0.1842681
#> eta.kout 0.0000000 0.0000000 0.00000000 0.00000000    0e+00 0.0000000
#> eta.e0   0.0000000 0.0000000 0.00000000 0.00000000    0e+00 0.0000000
#>             eta.kout      eta.e0
#> eta.ktr  0.000000000 0.000000000
#> eta.ka   0.000000000 0.000000000
#> eta.cl   0.000000000 0.000000000
#> eta.v    0.000000000 0.000000000
#> eta.emax 0.000000000 0.000000000
#> eta.ec50 0.000000000 0.000000000
#> eta.kout 0.008363153 0.000000000
#> eta.e0   0.000000000 0.002745615
#> 
#> States ($state or $stateDf): 
#>   Compartment Number Compartment Name
#> 1                  1            DEPOT
#> 2                  2              GUT
#> 3                  3           CENTER
#> 4                  4           EFFECT
#>  ── Model (Normalized Syntax): ── 
#> function() {
#>     NULL
#>     description <- c("translated from babelmixr2", "; comments show mu referenced model in ui$getSplitMuModel")
#>     dfObs <- 483
#>     dfSub <- 32
#>     sigma <- lotri({
#>         eps1 ~ 1
#>     })
#>     validation <- c("IPRED relative difference compared to Nonmem IPRED: 0%; 95% percentile: (0%,0%); rtol=6.13e-06", 
#>         "IPRED absolute difference compared to Nonmem IPRED: 95% percentile: (3.12e-06, 0.000497); atol=6.17e-05", 
#>         "PRED relative difference compared to Nonmem PRED: 0%; 95% percentile: (0%,0%); rtol=6.18e-06", 
#>         "PRED absolute difference compared to Nonmem PRED: 95% percentile: (3.79e-07,0.00313) atol=6.18e-06")
#>     ini({
#>         tktr <- 6.24053043162953e-07
#>         label("1 - tktr")
#>         tka <- -3.00642760553675e-06
#>         label("2 - tka")
#>         tcl <- -2.00405074386117
#>         label("3 - tcl")
#>         tv <- 2.05188410700476
#>         label("4 - tv")
#>         prop.err <- c(0, 0.0985804613565218)
#>         label("5 - prop.err")
#>         pkadd.err <- c(0, 0.511625249037084)
#>         label("6 - pkadd.err")
#>         temax <- 6.4184983102259
#>         label("7 - temax")
#>         tec50 <- 0.140763261319656
#>         label("8 - tec50")
#>         tkout <- -2.9534704318737
#>         label("9 - tkout")
#>         te0 <- 4.57045413136592
#>         label("10 - te0")
#>         pdadd.err <- c(0, 3.71714384851537)
#>         label("11 - pdadd.err")
#>         eta.ktr ~ 0.558129815059436
#>         eta.ka ~ 0.558402321309217
#>         eta.cl ~ 0.0785849119252598
#>         eta.v ~ 0.0508226905750953
#>         eta.emax ~ 5e-05
#>         eta.ec50 ~ 0.18426809257979
#>         eta.kout ~ 0.0083631531443303
#>         eta.e0 ~ 0.00274561514766752
#>     })
#>     model({
#>         cmt(DEPOT)
#>         cmt(GUT)
#>         cmt(CENTER)
#>         cmt(EFFECT)
#>         mu_1 <- tktr
#>         mu_2 <- tka
#>         mu_3 <- tcl
#>         mu_4 <- tv
#>         mu_5 <- temax
#>         mu_6 <- tec50
#>         mu_7 <- tkout
#>         mu_8 <- te0
#>         ktr <- exp(mu_1 + eta.ktr)
#>         ka <- exp(mu_2 + eta.ka)
#>         cl <- exp(mu_3 + eta.cl)
#>         v <- exp(mu_4 + eta.v)
#>         emax <- ((1) - (0)) * (1/(1 + exp(-(mu_5 + eta.emax)))) + 
#>             (0)
#>         ec50 <- exp(mu_6 + eta.ec50)
#>         kout <- exp(mu_7 + eta.kout)
#>         e0 <- exp(mu_8 + eta.e0)
#>         rxini.rxddta4. <- e0
#>         EFFECT(0) <- rxini.rxddta4.
#>         dcp <- CENTER/v
#>         rxdz001 <- (ec50 + dcp)
#>         if (rxdz001 >= 0 && rxdz001 <= 1e-06) {
#>             rxdz001 <- 1e-06
#>         }
#>         if (rxdz001 >= -1e-06 && rxdz001 < 0) {
#>             rxdz001 <- -1e-06
#>         }
#>         pd <- 1 - emax * dcp/rxdz001
#>         kin <- e0 * kout
#>         d/dt(DEPOT) <- -ktr * DEPOT
#>         d/dt(GUT) <- ktr * DEPOT - ka * GUT
#>         d/dt(CENTER) <- ka * GUT - cl/v * CENTER
#>         d/dt(EFFECT) <- kin * pd - kout * EFFECT
#>         cp <- CENTER/v
#>         f <- DEPOT
#>         rxe_dcp <- CENTER/v
#>         rxdze001 <- (ec50 + rxe_dcp)
#>         if (rxdze001 >= 0 && rxdze001 <= 1e-06) {
#>             rxdze001 <- 1e-06
#>         }
#>         if (rxdze001 >= -1e-06 && rxdze001 < 0) {
#>             rxdze001 <- -1e-06
#>         }
#>         rxe_pd <- 1 - emax * rxe_dcp/rxdze001
#>         rxe_kin <- e0 * kout
#>         rxe_cp <- CENTER/v
#>         rx_pf1 <- rxe_cp
#>         rx_pf2 <- EFFECT
#>         rx_ip1 <- rx_pf1
#>         rx_p1 <- rx_ip1
#>         w1 <- sqrt((pkadd.err)^2 + (rx_pf1)^2 * (prop.err)^2)
#>         if (w1 == 0) 
#>             w1 <- 1
#>         rx_ip2 <- rx_pf2
#>         rx_p2 <- rx_ip2
#>         w2 <- sqrt((pdadd.err)^2)
#>         if (w2 == 0) 
#>             w2 <- 1
#>         ipred <- rx_ip1
#>         w <- w1
#>         if (nmdvid == 2) {
#>             ipred <- rx_ip2
#>             w <- w2
#>         }
#>         y <- ipred + w * eps1
#>     })
#> }
#>  ── nonmem2rx translation notes ($notes): ──  
#>    • some etas defaulted to non-mu referenced, possible parsing error: eta.emax as a work-around try putting the mu-referenced expression on a simple line 
#>    • some etas defaulted to non-mu referenced, possible parsing error: eta5 as a work-around try putting the mu-referenced expression on a simple line 
#>    • some NONMEM input has tied times; they are offset by a small offset 
#>    • is.na() applied to non-(list or vector) of type 'language' 
#>    • 'dvid' variable has special meaning in rxode2, renamed to 'nmdvid', rename/copy in your data too 
#>    • $MODEL NCOMPARTMENTS/NEQUILIBRIUM/NPARAMETERS statement(s) ignored 
#>  ── nonmem2rx extra properties: ──  
#> 
#> Sigma ($sigma): 
#>      eps1
#> eps1    1
#> 
#> other properties include: $nonmemData, $etaData
#> captured NONMEM table outputs: $predData, $ipredData
#> NONMEM/rxode2 comparison data: $iwresCompare, $predCompare, $ipredCompare
#> NONMEM/rxode2 composite comparison: $predAtol, $predRtol, $ipredAtol, $ipredRtol, $iwresAtol, $iwresRtol

Step 2: Convert `rxode2` model to model with endpoints/residuals specified like `nlmixr2`

This example has rounding errors and isn’t a fully qualified nlmixr2 model (even though it was generated from nlmixr2).

We can use the model and create an equivalent model with as.nonmem2rx()

mod2 <- function() {
  ini({
    tktr <- 6.24053043162953e-07
    label("1 - tktr")
    tka <- -3.00642760553675e-06
    label("2 - tka")
    tcl <- -2.00405074386117
    label("3 - tcl")
    tv <- 2.05188410700476
    label("4 - tv")
    prop.err <- c(0, 0.0985804613565218)
    label("5 - prop.err")
    pkadd.err <- c(0, 0.511625249037084)
    label("6 - pkadd.err")
    temax <- 6.4184983102259
    label("7 - temax")
    tec50 <- 0.140763261319656
    label("8 - tec50")
    tkout <- -2.9534704318737
    label("9 - tkout")
    te0 <- 4.57045413136592
    label("10 - te0")
    pdadd.err <- c(0, 3.71714384851537)
    label("11 - pdadd.err")
    eta.ktr ~ 0.558129815059436
    eta.ka ~ 0.558402321309217
    eta.cl ~ 0.0785849119252598
    eta.v ~ 0.0508226905750953
    eta.emax ~ 5e-05
    eta.ec50 ~ 0.18426809257979
    eta.kout ~ 0.0083631531443303
    eta.e0 ~ 0.00274561514766752
  })
  model({
    cmt(DEPOT)
    cmt(GUT)
    cmt(CENTER)
    cmt(EFFECT)
    ktr <- exp(tktr + eta.ktr)
    ka <- exp(tka   + eta.ka)
    cl <- exp(tcl   + eta.cl)
    v <- exp(tv     + eta.v)
    emax <- expit(temax + eta.emax) 
    ec50 <- exp(tec50 + eta.ec50)
    kout <- exp(tkout + eta.kout)
    e0 <- exp(te0 + eta.e0)
    EFFECT(0) <- e0
    dcp <- CENTER/v
    pd <- 1 - emax * dcp/(ec50 + dcp)
    kin <- e0 * kout
    d/dt(DEPOT) <- -ktr * DEPOT
    d/dt(GUT) <- ktr * DEPOT - ka * GUT
    d/dt(CENTER) <- ka * GUT - cl/v * CENTER
    d/dt(EFFECT) <- kin * pd - kout * EFFECT
    eff <- EFFECT
    dcp ~ add(pkadd.err)+prop(prop.err)
    eff ~ add(pdadd.err)
  })
}

In the model above, the following modifications were made:

The code for protecting for rounding errors was removed
Endpoints/residual specifications were added
Duplicate code in NONMEM’s $ERROR block was removed from imported model
All the rx and nlmixr prefixed items were removed from the model. It is possible that not removing these variables can causenlmixr2 conversion to fail. It is best practice to remove them completely.

Also, it is good practice to make sure the model parses correctly before trying to validate/convert the model. If you find that your model doesn’t parse correctly it definitely won’t validate (and the error may not be as easy to track-down).

The first step is to validate if the translation is correct. This is done below:

new <- as.nonmem2rx(mod, mod2)
#> ℹ parameter labels from comments are typically ignored in non-interactive mode
#> ℹ Need to run with the source intact to parse comments
#> ℹ copy 'dfSub' to nonmem2rx model
#> ℹ copy 'dfObs' to nonmem2rx model
#> ℹ merging 'dvid' with nlmixr2 'cmt' definition
#> ℹ solving ipred problem
#> ℹ done
#> ℹ solving pred problem
#> ℹ done
print(new)
#>  ── rxode2-based free-form 4-cmt ODE model ────────────────────────────────────── 
#>  ── Initalization: ──  
#> Fixed Effects ($theta): 
#>          tktr           tka           tcl            tv      prop.err 
#>  6.240530e-07 -3.006428e-06 -2.004051e+00  2.051884e+00  9.858046e-02 
#>     pkadd.err         temax         tec50         tkout           te0 
#>  5.116252e-01  6.418498e+00  1.407633e-01 -2.953470e+00  4.570454e+00 
#>     pdadd.err 
#>  3.717144e+00 
#> 
#> Omega ($omega): 
#>            eta.ktr    eta.ka     eta.cl      eta.v eta.emax  eta.ec50
#> eta.ktr  0.5581298 0.0000000 0.00000000 0.00000000    0e+00 0.0000000
#> eta.ka   0.0000000 0.5584023 0.00000000 0.00000000    0e+00 0.0000000
#> eta.cl   0.0000000 0.0000000 0.07858491 0.00000000    0e+00 0.0000000
#> eta.v    0.0000000 0.0000000 0.00000000 0.05082269    0e+00 0.0000000
#> eta.emax 0.0000000 0.0000000 0.00000000 0.00000000    5e-05 0.0000000
#> eta.ec50 0.0000000 0.0000000 0.00000000 0.00000000    0e+00 0.1842681
#> eta.kout 0.0000000 0.0000000 0.00000000 0.00000000    0e+00 0.0000000
#> eta.e0   0.0000000 0.0000000 0.00000000 0.00000000    0e+00 0.0000000
#>             eta.kout      eta.e0
#> eta.ktr  0.000000000 0.000000000
#> eta.ka   0.000000000 0.000000000
#> eta.cl   0.000000000 0.000000000
#> eta.v    0.000000000 0.000000000
#> eta.emax 0.000000000 0.000000000
#> eta.ec50 0.000000000 0.000000000
#> eta.kout 0.008363153 0.000000000
#> eta.e0   0.000000000 0.002745615
#> 
#> States ($state or $stateDf): 
#>   Compartment Number Compartment Name
#> 1                  1            DEPOT
#> 2                  2              GUT
#> 3                  3           CENTER
#> 4                  4           EFFECT
#>  ── Multiple Endpoint Model ($multipleEndpoint): ──  
#>   variable                cmt                dvid*
#> 1  dcp ~ … cmt='dcp' or cmt=5 dvid='dcp' or dvid=1
#> 2  eff ~ … cmt='eff' or cmt=6 dvid='eff' or dvid=2
#>   * If dvids are outside this range, all dvids are re-numered sequentially, ie 1,7, 10 becomes 1,2,3 etc
#> 
#>  ── μ-referencing ($muRefTable): ──  
#>   theta      eta level
#> 1  tktr  eta.ktr    id
#> 2   tka   eta.ka    id
#> 3   tcl   eta.cl    id
#> 4    tv    eta.v    id
#> 5 temax eta.emax    id
#> 6 tec50 eta.ec50    id
#> 7 tkout eta.kout    id
#> 8   te0   eta.e0    id
#> 
#>  ── Model (Normalized Syntax): ── 
#> function() {
#>     description <- c("translated from babelmixr2", "; comments show mu referenced model in ui$getSplitMuModel")
#>     dfObs <- 483
#>     dfSub <- 32
#>     validation <- c("IPRED relative difference compared to Nonmem IPRED: 0%; 95% percentile: (0%,0%); rtol=6.13e-06", 
#>         "IPRED absolute difference compared to Nonmem IPRED: 95% percentile: (3.12e-06, 0.000497); atol=6.17e-05", 
#>         "PRED relative difference compared to Nonmem PRED: 0%; 95% percentile: (0%,0%); rtol=6.18e-06", 
#>         "PRED absolute difference compared to Nonmem PRED: 95% percentile: (3.79e-07,0.00313) atol=6.18e-06")
#>     ini({
#>         tktr <- 6.24053043162953e-07
#>         label("1 - tktr")
#>         tka <- -3.00642760553675e-06
#>         label("2 - tka")
#>         tcl <- -2.00405074386117
#>         label("3 - tcl")
#>         tv <- 2.05188410700476
#>         label("4 - tv")
#>         prop.err <- c(0, 0.0985804613565218)
#>         label("5 - prop.err")
#>         pkadd.err <- c(0, 0.511625249037084)
#>         label("6 - pkadd.err")
#>         temax <- 6.4184983102259
#>         label("7 - temax")
#>         tec50 <- 0.140763261319656
#>         label("8 - tec50")
#>         tkout <- -2.9534704318737
#>         label("9 - tkout")
#>         te0 <- 4.57045413136592
#>         label("10 - te0")
#>         pdadd.err <- c(0, 3.71714384851537)
#>         label("11 - pdadd.err")
#>         eta.ktr ~ 0.558129815059436
#>         eta.ka ~ 0.558402321309217
#>         eta.cl ~ 0.0785849119252598
#>         eta.v ~ 0.0508226905750953
#>         eta.emax ~ 5e-05
#>         eta.ec50 ~ 0.18426809257979
#>         eta.kout ~ 0.0083631531443303
#>         eta.e0 ~ 0.00274561514766752
#>     })
#>     model({
#>         cmt(DEPOT)
#>         cmt(GUT)
#>         cmt(CENTER)
#>         cmt(EFFECT)
#>         ktr <- exp(tktr + eta.ktr)
#>         ka <- exp(tka + eta.ka)
#>         cl <- exp(tcl + eta.cl)
#>         v <- exp(tv + eta.v)
#>         emax <- expit(temax + eta.emax, 0, 1)
#>         ec50 <- exp(tec50 + eta.ec50)
#>         kout <- exp(tkout + eta.kout)
#>         e0 <- exp(te0 + eta.e0)
#>         EFFECT(0) <- e0
#>         dcp <- CENTER/v
#>         pd <- 1 - emax * dcp/(ec50 + dcp)
#>         kin <- e0 * kout
#>         d/dt(DEPOT) <- -ktr * DEPOT
#>         d/dt(GUT) <- ktr * DEPOT - ka * GUT
#>         d/dt(CENTER) <- ka * GUT - cl/v * CENTER
#>         d/dt(EFFECT) <- kin * pd - kout * EFFECT
#>         eff <- EFFECT
#>         dcp ~ add(pkadd.err) + prop(prop.err)
#>         eff ~ add(pdadd.err)
#>     })
#> }
#>  ── nonmem2rx extra properties: ──  
#> other properties include: $nonmemData, $etaData, $thetaMat
#> captured NONMEM table outputs: $predData, $ipredData
#> NONMEM/rxode2 comparison data: $iwresCompare, $predCompare, $ipredCompare
#> NONMEM/rxode2 composite comparison: $predAtol, $predRtol, $ipredAtol, $ipredRtol, $iwresAtol, $iwresRtol

Step 3: Convert new model to nlmixr2 fit with `as.nlmixr2()`

Once the translation is complete, and it is validated, you can convert the fit to a full nlmixr2 fit object.

fit <- as.nlmixr2(new)
#> → loading into symengine environment...
#> → pruning branches (`if`/`else`) of full model...
#> ✔ done
#> → optimizing duplicate expressions in EBE model (2 chunks)...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → compiling EBE model...
#> ✔ done
#> rxode2 5.1.4 using 2 threads (see ?getRxThreads)
#>   no cache: create with `rxCreateCache()`
#> → Calculating residuals/tables
#> ✔ done

# Once it is loaded remove the directory (we don't need the files any
# more for this example)
#
# In this example, we don't remove, but note where it can be removed
#
# unlink("pk.turnover.emax3-nonmem", recursive = TRUE)

Note this object does not rerun an estimation, but rather imports everything it knows about the fit to rerun the nlmixr2 table steps to calculate the things you need.

Step 4: Explore the data/fit as if it came from `nlmixr2`

With this information you can see about the properties of the model:

print(fit)
#> ── nlmixr² nonmem2rx reading NONMEM ver 7.4.3 ──
#> 
#>               OBJF     AIC      BIC Log-likelihood
#> nonmem2rx 439.2156 1364.91 1444.331      -663.4551
#> 
#> ── Time (sec $time): ──
#> 
#>             setup postprocess table compress NONMEM as.nlmixr2
#> elapsed 0.6350346       0.022 0.046    0.001 320.27      2.422
#> 
#> ── Population Parameters ($parFixed or $parFixedDf): ──
#> 
#>                Parameter      Est. SE %RSE Back-transformed(95%CI)
#> tktr            1 - tktr  6.241e-7                           1.000
#> tka              2 - tka -3.006e-6                           1.000
#> tcl              3 - tcl    -2.004                          0.1348
#> tv                4 - tv     2.052                           7.783
#> prop.err    5 - prop.err   0.09858                         0.09858
#> pkadd.err  6 - pkadd.err    0.5116                          0.5116
#> temax          7 - temax     6.418                          0.9984
#> tec50          8 - tec50    0.1408                           1.151
#> tkout          9 - tkout    -2.953                         0.05216
#> te0             10 - te0     4.570                           96.59
#> pdadd.err 11 - pdadd.err     3.717                           3.717
#>           BSV(CV% or SD) Shrink(SD)%
#> tktr               86.45      59.84 
#> tka                86.48      59.84 
#> tcl                28.59      1.340 
#> tv                 22.83      6.442 
#> prop.err                            
#> pkadd.err                           
#> temax           0.007071      99.99 
#> tec50              44.98      6.065 
#> tkout              9.164      32.42 
#> te0                5.243      18.09 
#> pdadd.err                           
#>  
#>   No correlations in between subject variability (BSV) matrix
#>   Full BSV covariance ($omega) or correlation ($omegaR; diagonals=SDs) 
#>   Distribution stats (mean/skewness/kurtosis/p-value) available in $shrink 
#>   Censoring ($censInformation): No censoring
#>   Minimization message ($message):  
#>     
#> 
#>  WARNINGS AND ERRORS (IF ANY) FOR PROBLEM    1
#> 
#>  (WARNING  2) NM-TRAN INFERS THAT THE DATA ARE POPULATION.
#> 
#>     
#> 0MINIMIZATION TERMINATED
#>  DUE TO ROUNDING ERRORS (ERROR=134)
#>  NO. OF FUNCTION EVALUATIONS USED:     1088
#>  NO. OF SIG. DIGITS UNREPORTABLE
#> 0PARAMETER ESTIMATE IS NEAR ITS BOUNDARY
#> 
#>     IPRED relative difference compared to Nonmem IPRED: 0%; 95% percentile: (0%,0%); rtol=5.09e-06
#>     PRED relative difference compared to Nonmem PRED: 0%; 95% percentile: (0%,0%); rtol=5.29e-06
#>     IPRED absolute difference compared to Nonmem IPRED: 95% percentile: (2.2e-06, 0.000454); atol=3.03e-05
#>     PRED absolute difference compared to Nonmem PRED: 95% percentile: (4.72e-07,0.00361); atol=5.29e-06
#>     there are solving errors during optimization (see '$prderr')
#>     nonmem2rx model file: 'pk.turnover.emax3-nonmem/pk.turnover.emax3.nmctl' 
#> 
#> ── Fit Data (object is a modified tibble): ──
#> # A tibble: 483 × 35
#>   ID     TIME CMT      DV  PRED   RES IPRED   IRES  IWRES eta.ktr eta.ka eta.cl
#>   <fct> <dbl> <fct> <dbl> <dbl> <dbl> <dbl>  <dbl>  <dbl>   <dbl>  <dbl>  <dbl>
#> 1 1       0.5 dcp     0    1.16 -1.16 0.444 -0.444 -0.864  -0.506 -0.506  0.699
#> 2 1       1   dcp     1.9  3.37 -1.47 1.45   0.446  0.840  -0.506 -0.506  0.699
#> 3 1       2   dcp     3.3  7.51 -4.21 3.96  -0.660 -1.03   -0.506 -0.506  0.699
#> # ℹ 480 more rows
#> # ℹ 23 more variables: eta.v <dbl>, eta.emax <dbl>, eta.ec50 <dbl>,
#> #   eta.kout <dbl>, eta.e0 <dbl>, dcp <dbl>, eff <dbl>, DEPOT <dbl>, GUT <dbl>,
#> #   CENTER <dbl>, EFFECT <dbl>, ktr <dbl>, ka <dbl>, cl <dbl>, v <dbl>,
#> #   emax <dbl>, ec50 <dbl>, kout <dbl>, e0 <dbl>, pd <dbl>, kin <dbl>,
#> #   tad <dbl>, dosenum <dbl>

In this model you can see:

High shrinkage in temax, ktr, ka and moderate shrinkage in kout

By removing these parameters, you could possibly get a successful NONMEM run.

If you want, you can use model piping to remove these parameters as follows:

mod3 <-  fit %>%
  model(ktr <- exp(tktr)) %>%
  model(ka <- exp(tka)) %>%
  model(emax <- expit(temax)) %>%
  model(kout <- exp(tkout))
#> ! remove between subject variability `eta.ktr`
#> ! remove between subject variability `eta.ka`
#> ! remove between subject variability `eta.emax`
#> ! remove between subject variability `eta.kout`

mod3
#>  ── rxode2-based free-form 4-cmt ODE model ────────────────────────────────────── 
#>  ── Initalization: ──  
#> Fixed Effects ($theta): 
#>          tktr           tka           tcl            tv      prop.err 
#>  6.240530e-07 -3.006428e-06 -2.004051e+00  2.051884e+00  9.858046e-02 
#>     pkadd.err         temax         tec50         tkout           te0 
#>  5.116252e-01  6.418498e+00  1.407633e-01 -2.953470e+00  4.570454e+00 
#>     pdadd.err 
#>  3.717144e+00 
#> 
#> Omega ($omega): 
#>              eta.cl      eta.v  eta.ec50      eta.e0
#> eta.cl   0.07858491 0.00000000 0.0000000 0.000000000
#> eta.v    0.00000000 0.05082269 0.0000000 0.000000000
#> eta.ec50 0.00000000 0.00000000 0.1842681 0.000000000
#> eta.e0   0.00000000 0.00000000 0.0000000 0.002745615
#> 
#> States ($state or $stateDf): 
#>   Compartment Number Compartment Name
#> 1                  1            DEPOT
#> 2                  2              GUT
#> 3                  3           CENTER
#> 4                  4           EFFECT
#>  ── Multiple Endpoint Model ($multipleEndpoint): ──  
#>   variable                cmt                dvid*
#> 1  dcp ~ … cmt='dcp' or cmt=5 dvid='dcp' or dvid=1
#> 2  eff ~ … cmt='eff' or cmt=6 dvid='eff' or dvid=2
#>   * If dvids are outside this range, all dvids are re-numered sequentially, ie 1,7, 10 becomes 1,2,3 etc
#> 
#>  ── μ-referencing ($muRefTable): ──  
#>   theta      eta level
#> 1   tcl   eta.cl    id
#> 2    tv    eta.v    id
#> 3 tec50 eta.ec50    id
#> 4   te0   eta.e0    id
#> 
#>  ── Model (Normalized Syntax): ── 
#> function() {
#>     description <- c("translated from babelmixr2", "; comments show mu referenced model in ui$getSplitMuModel")
#>     dfObs <- 483
#>     dfSub <- 32
#>     validation <- c("IPRED relative difference compared to Nonmem IPRED: 0%; 95% percentile: (0%,0%); rtol=6.13e-06", 
#>         "IPRED absolute difference compared to Nonmem IPRED: 95% percentile: (3.12e-06, 0.000497); atol=6.17e-05", 
#>         "PRED relative difference compared to Nonmem PRED: 0%; 95% percentile: (0%,0%); rtol=6.18e-06", 
#>         "PRED absolute difference compared to Nonmem PRED: 95% percentile: (3.79e-07,0.00313) atol=6.18e-06")
#>     ini({
#>         tktr <- 6.24053043162953e-07
#>         label("1 - tktr")
#>         tka <- -3.00642760553675e-06
#>         label("2 - tka")
#>         tcl <- -2.00405074386117
#>         label("3 - tcl")
#>         tv <- 2.05188410700476
#>         label("4 - tv")
#>         prop.err <- c(0, 0.0985804613565218)
#>         label("5 - prop.err")
#>         pkadd.err <- c(0, 0.511625249037084)
#>         label("6 - pkadd.err")
#>         temax <- 6.4184983102259
#>         label("7 - temax")
#>         tec50 <- 0.140763261319656
#>         label("8 - tec50")
#>         tkout <- -2.9534704318737
#>         label("9 - tkout")
#>         te0 <- 4.57045413136592
#>         label("10 - te0")
#>         pdadd.err <- c(0, 3.71714384851537)
#>         label("11 - pdadd.err")
#>         eta.cl ~ 0.0785849119252598
#>         eta.v ~ 0.0508226905750953
#>         eta.ec50 ~ 0.18426809257979
#>         eta.e0 ~ 0.00274561514766752
#>     })
#>     model({
#>         cmt(DEPOT)
#>         cmt(GUT)
#>         cmt(CENTER)
#>         cmt(EFFECT)
#>         ktr <- exp(tktr)
#>         ka <- exp(tka)
#>         cl <- exp(tcl + eta.cl)
#>         v <- exp(tv + eta.v)
#>         emax <- expit(temax, 0, 1)
#>         ec50 <- exp(tec50 + eta.ec50)
#>         kout <- exp(tkout)
#>         e0 <- exp(te0 + eta.e0)
#>         EFFECT(0) <- e0
#>         dcp <- CENTER/v
#>         pd <- 1 - emax * dcp/(ec50 + dcp)
#>         kin <- e0 * kout
#>         d/dt(DEPOT) <- -ktr * DEPOT
#>         d/dt(GUT) <- ktr * DEPOT - ka * GUT
#>         d/dt(CENTER) <- ka * GUT - cl/v * CENTER
#>         d/dt(EFFECT) <- kin * pd - kout * EFFECT
#>         eff <- EFFECT
#>         dcp ~ add(pkadd.err) + prop(prop.err)
#>         eff ~ add(pdadd.err)
#>     })
#> }

Since you have babelmixr2 you could use babelmixr2 to run the model for you in NONMEM (if you have it setup to run NONMEM), or even run the model from nlmixr2 itself. In this example we will choose to use nlmixr2 (since the babelmixr2 example runs NONMEM and shows a reduction in shrinkage)

fit2 <- nlmixr(mod3, new$nonmemData, "focei", foceiControl(print=0))
#> → loading into symengine environment...
#> → pruning branches (`if`/`else`) of full model...
#> ✔ done
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → calculate sensitivities
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → calculate ∂(f)/∂(η)
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → calculate ∂(R²)/∂(η)
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → finding duplicate expressions in inner model...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → optimizing duplicate expressions in inner model...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → optimizing duplicate expressions in EBE model (2 chunks)...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → compiling inner model...
#> ✔ done
#> → finding duplicate expressions in FD model...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → optimizing duplicate expressions in FD model...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → compiling EBE model...
#> ✔ done
#> → compiling events FD model...
#> ✔ done
#> calculating covariance matrix
#> [====|====|====|====|====|====|====|====|====|====] 0:00:28 
#> done
#> → Calculating residuals/tables
#> ✔ done

fit2
#> ── nlmixr² FOCEi (outer: bobyqa) ──
#> 
#>           OBJF      AIC      BIC Log-likelihood Condition#(Cov) Condition#(Cor)
#> FOCEi 1423.043 2340.738 2403.438      -1155.369      1966036839        499851.9
#> 
#> ── Time (sec fit2$time): ──
#> 
#>            setup optimize covariance preprocess postprocess table compress
#> elapsed 9.105813 20.45482   52.78919      0.033       0.017 0.064    0.001
#>             other
#> elapsed 0.1281705
#> 
#> ── Population Parameters (fit2$parFixed or fit2$parFixedDf): ──
#> 
#>                Parameter    Est.      SE   %RSE    Back-transformed(95%CI)
#> tktr            1 - tktr 0.05093  0.1584  311.0      1.052 (0.7715, 1.435)
#> tka              2 - tka 0.05071  0.1113  219.4      1.052 (0.8459, 1.308)
#> tcl              3 - tcl  -1.996 0.05169  2.589    0.1358 (0.1227, 0.1503)
#> tv                4 - tv   2.055 0.04506  2.193       7.807 (7.147, 8.528)
#> prop.err    5 - prop.err  0.1606 0.03124  19.46   0.1606 (0.09932, 0.2218)
#> pkadd.err  6 - pkadd.err  0.5847 0.07771  13.29    0.5847 (0.4324, 0.7370)
#> temax          7 - temax   9.209  0.6280  6.819     0.9999 (0.9997, 1.000)
#> tec50          8 - tec50  0.1286 0.09121  70.90      1.137 (0.9511, 1.360)
#> tkout          9 - tkout  -2.964 0.02378 0.8024 0.05162 (0.04927, 0.05409)
#> te0             10 - te0   4.572 0.01129 0.2470       96.72 (94.60, 98.88)
#> pdadd.err 11 - pdadd.err   3.809  0.3318  8.711       3.809 (3.159, 4.460)
#>           BSV(CV%) Shrink(SD)%
#> tktr                          
#> tka                           
#> tcl          27.90      2.995 
#> tv           23.67      9.924 
#> prop.err                      
#> pkadd.err                     
#> temax                         
#> tec50        42.50      7.298 
#> tkout                         
#> te0          5.254      18.80 
#> pdadd.err                     
#>  
#>   Covariance Type (fit2$covMethod): |r|,|s|
#>   No correlations in between subject variability (BSV) matrix
#>   Full BSV covariance (fit2$omega) or correlation (fit2$omegaR; diagonals=SDs) 
#>   Distribution stats (mean/skewness/kurtosis/p-value) available in fit2$shrink 
#>   Information about run found (fit2$runInfo):
#>    • gradient problems with covariance; see $scaleInfo 
#>    • since sandwich matrix is corrected, you may compare to $covR or $covS if you wish 
#>    • S matrix non-positive definite but corrected by S = sqrtm(S%*%S) 
#>    • R matrix non-positive definite but corrected by R = sqrtm(R%*%R) 
#>    • last objective function was not at minimum, possible problems in optimization 
#>    • ETAs were reset to zero during optimization; (Can control by foceiControl(resetEtaP=.)) 
#>   Censoring (fit2$censInformation): No censoring
#>   Minimization message (fit2$message):  
#>     Normal exit from bobyqa 
#> 
#> ── Fit Data (object fit2 is a modified tibble): ──
#> # A tibble: 483 × 33
#>   ID     TIME CMT      DV  PRED   RES  WRES IPRED   IRES IWRES CPRED  CRES CWRES
#>   <fct> <dbl> <fct> <dbl> <dbl> <dbl> <dbl> <dbl>  <dbl> <dbl> <dbl> <dbl> <dbl>
#> 1 1       0.5 dcp     0    1.25 -1.25 -1.83 0.994 -0.994 -1.64  1.23 -1.23 -1.89
#> 2 1       1   dcp     1.9  3.61 -1.71 -1.45 2.85  -0.952 -1.28  3.52 -1.62 -1.64
#> 3 1       2   dcp     3.3  7.83 -4.53 -1.99 6.16  -2.86  -2.49  7.66 -4.36 -2.40
#> # ℹ 480 more rows
#> # ℹ 20 more variables: eta.cl <dbl>, eta.v <dbl>, eta.ec50 <dbl>, eta.e0 <dbl>,
#> #   DEPOT <dbl>, GUT <dbl>, CENTER <dbl>, EFFECT <dbl>, ktr <dbl>, ka <dbl>,
#> #   cl <dbl>, v <dbl>, emax <dbl>, ec50 <dbl>, kout <dbl>, e0 <dbl>, pd <dbl>,
#> #   kin <dbl>, tad <dbl>, dosenum <dbl>

With these modifications the shrinkage is also reduced (just like in the NONMEM case)

Step 5: Get the covariance of the model

Another thing that can be helpful when the fit has been imported into a nlmixr2 fit is to get the variance/covariance matrix. This can be especially helpful to diagnose things to help simplify your model

getVarCov(fit)
#> → loading into symengine environment...
#> → pruning branches (`if`/`else`) of full model...
#> ✔ done
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → calculate sensitivities
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → calculate ∂(f)/∂(η)
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → optimizing duplicate expressions in inner model (2 chunks)...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → optimizing duplicate expressions in EBE model (2 chunks)...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → compiling inner model...
#> ✔ done
#> → finding duplicate expressions in FD model...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → optimizing duplicate expressions in FD model...
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00
#> → compiling EBE model...
#> ✔ done
#> → compiling events FD model...
#> ✔ done
#> calculating covariance matrix
#> [====|====|====|====|====|====|====|====|====|====] 0:00:14
#> Warning in foceiFitCpp_(.ret): using R matrix to calculate covariance, can
#> check sandwich or S matrix with $covRS and $covS
#> Warning in foceiFitCpp_(.ret): gradient problems with covariance; see
#> $scaleInfo
#> Updated original fit object fit
#>                      tktr           tka           tcl            tv
#> tktr         7.117551e-04  1.226477e-05 -3.804048e-06  6.487412e-05
#> tka          1.226477e-05  2.236301e-05 -2.268007e-08  3.241752e-06
#> tcl         -3.804048e-06 -2.268007e-08  1.312454e-04  5.156170e-06
#> tv           6.487412e-05  3.241752e-06  5.156170e-06  1.358642e-04
#> prop.err    -3.082560e-05 -1.442396e-06 -7.446109e-06  1.872193e-05
#> pkadd.err    8.311740e-05  4.054890e-06  1.535522e-04 -5.614444e-05
#> temax        5.679707e-04 -3.312004e-05 -9.245357e-05  3.105047e-04
#> tec50        2.472474e-05  5.848648e-07 -1.832133e-04  5.324455e-05
#> tkout        1.872373e-05  1.134966e-06 -5.305420e-05  5.375822e-05
#> te0          2.884045e-06  1.400669e-07 -6.109209e-06  5.554689e-06
#> pdadd.err    9.726719e-05  5.108921e-06 -1.542511e-04  1.752999e-04
#> om.eta.ktr   2.491142e-04  1.141137e-06  2.494431e-06  4.145592e-05
#> om.eta.ka   -8.426159e-05  5.947916e-06  4.340370e-06  1.161604e-05
#> om.eta.cl    2.440707e-08  3.289216e-09  9.727122e-07  7.122064e-07
#> om.eta.v    -1.674692e-06 -7.593511e-08  1.140494e-06  8.963284e-07
#> om.eta.emax  4.795794e-08 -2.689360e-09 -1.166710e-08  3.074419e-08
#> om.eta.ec50 -4.866894e-07 -8.373748e-09  4.179315e-06 -1.233600e-06
#> om.eta.kout  2.407474e-07  1.302878e-08 -3.906939e-07  6.013430e-07
#> om.eta.e0    3.777665e-08  1.987335e-09 -6.333809e-08  7.562325e-08
#>                  prop.err     pkadd.err         temax         tec50
#> tktr        -3.082560e-05  8.311740e-05  5.679707e-04  2.472474e-05
#> tka         -1.442396e-06  4.054890e-06 -3.312004e-05  5.848648e-07
#> tcl         -7.446109e-06  1.535522e-04 -9.245357e-05 -1.832133e-04
#> tv           1.872193e-05 -5.614444e-05  3.105047e-04  5.324455e-05
#> prop.err     9.528457e-05 -2.713613e-04  2.375178e-05  1.943147e-05
#> pkadd.err   -2.713613e-04  2.909074e-03 -4.038898e-04 -2.473354e-04
#> temax        2.375178e-05 -4.038898e-04  3.717483e+00  2.238245e-02
#> tec50        1.943147e-05 -2.473354e-04  2.238245e-02  8.847216e-04
#> tkout        1.136123e-05 -9.152552e-05 -9.514660e-03  7.993296e-05
#> te0          1.151226e-06 -1.013283e-05 -1.240086e-04 -6.412860e-05
#> pdadd.err    3.701360e-05 -1.204600e-04 -2.332204e-02  1.637766e-04
#> om.eta.ktr   5.186590e-05 -2.695553e-06 -2.868540e-04  6.178644e-06
#> om.eta.ka    6.404873e-05 -3.681776e-05 -5.645412e-04 -5.485836e-06
#> om.eta.cl    5.078831e-07  1.587141e-05 -6.701757e-06 -1.149177e-06
#> om.eta.v     4.724737e-06  2.997372e-06 -2.589168e-05 -1.641539e-06
#> om.eta.emax  3.712916e-09 -3.135457e-08  2.996180e-04  1.831847e-06
#> om.eta.ec50 -5.294395e-07  3.677414e-05 -6.559946e-04 -1.575773e-05
#> om.eta.kout  1.669907e-07  9.224099e-07 -6.580260e-05  1.471163e-06
#> om.eta.e0    2.018697e-08 -3.971365e-08 -8.564827e-06  1.589712e-07
#>                     tkout           te0     pdadd.err    om.eta.ktr
#> tktr         1.872373e-05  2.884045e-06  9.726719e-05  2.491142e-04
#> tka          1.134966e-06  1.400669e-07  5.108921e-06  1.141137e-06
#> tcl         -5.305420e-05 -6.109209e-06 -1.542511e-04  2.494431e-06
#> tv           5.375822e-05  5.554689e-06  1.752999e-04  4.145592e-05
#> prop.err     1.136123e-05  1.151226e-06  3.701360e-05  5.186590e-05
#> pkadd.err   -9.152552e-05 -1.013283e-05 -1.204600e-04 -2.695553e-06
#> temax       -9.514660e-03 -1.240086e-04 -2.332204e-02 -2.868540e-04
#> tec50        7.993296e-05 -6.412860e-05  1.637766e-04  6.178644e-06
#> tkout        3.165048e-04  2.651478e-05  1.940087e-04  1.404801e-05
#> te0          2.651478e-05  4.413047e-05  1.230731e-05  1.388562e-06
#> pdadd.err    1.940087e-04  1.230731e-05  3.976383e-02  2.987240e-04
#> om.eta.ktr   1.404801e-05  1.388562e-06  2.987240e-04  9.253453e-02
#> om.eta.ka    5.450136e-06  6.522215e-08  2.492119e-04  2.965039e-02
#> om.eta.cl   -1.954464e-07 -3.521995e-08  5.635618e-06  2.059001e-05
#> om.eta.v    -3.300434e-07 -4.206716e-08  1.521112e-05  1.625102e-05
#> om.eta.emax -7.694311e-07 -1.462942e-08 -1.478714e-06 -6.780320e-09
#> om.eta.ec50 -4.223933e-06 -5.115733e-07  2.801966e-04  6.768802e-06
#> om.eta.kout  1.272296e-06 -1.942521e-07  5.322319e-05  4.488374e-06
#> om.eta.e0    6.589633e-08 -4.893808e-08  1.442266e-05  1.732708e-07
#>                 om.eta.ka     om.eta.cl      om.eta.v   om.eta.emax
#> tktr        -8.426159e-05  2.440707e-08 -1.674692e-06  4.795794e-08
#> tka          5.947916e-06  3.289216e-09 -7.593511e-08 -2.689360e-09
#> tcl          4.340370e-06  9.727122e-07  1.140494e-06 -1.166710e-08
#> tv           1.161604e-05  7.122064e-07  8.963284e-07  3.074419e-08
#> prop.err     6.404873e-05  5.078831e-07  4.724737e-06  3.712916e-09
#> pkadd.err   -3.681776e-05  1.587141e-05  2.997372e-06 -3.135457e-08
#> temax       -5.645412e-04 -6.701757e-06 -2.589168e-05  2.996180e-04
#> tec50       -5.485836e-06 -1.149177e-06 -1.641539e-06  1.831847e-06
#> tkout        5.450136e-06 -1.954464e-07 -3.300434e-07 -7.694311e-07
#> te0          6.522215e-08 -3.521995e-08 -4.206716e-08 -1.462942e-08
#> pdadd.err    2.492119e-04  5.635618e-06  1.521112e-05 -1.478714e-06
#> om.eta.ktr   2.965039e-02  2.059001e-05  1.625102e-05 -6.780320e-09
#> om.eta.ka    9.146140e-02  2.015145e-05  1.648622e-05 -3.141669e-08
#> om.eta.cl    2.015145e-05  3.900522e-04  2.332449e-07 -2.095038e-10
#> om.eta.v     1.648622e-05  2.332449e-07  1.672595e-04 -7.648997e-10
#> om.eta.emax -3.141669e-08 -2.095038e-10 -7.648997e-10  3.371466e-03
#> om.eta.ec50  6.857673e-06  2.113917e-06  6.300933e-07  1.267573e-07
#> om.eta.kout  4.297694e-06  6.795138e-08  2.175756e-07  1.868036e-09
#> om.eta.e0    1.523645e-07  5.359341e-09  8.067423e-09 -4.033401e-10
#>               om.eta.ec50   om.eta.kout     om.eta.e0
#> tktr        -4.866894e-07  2.407474e-07  3.777665e-08
#> tka         -8.373748e-09  1.302878e-08  1.987335e-09
#> tcl          4.179315e-06 -3.906939e-07 -6.333809e-08
#> tv          -1.233600e-06  6.013430e-07  7.562325e-08
#> prop.err    -5.294395e-07  1.669907e-07  2.018697e-08
#> pkadd.err    3.677414e-05  9.224099e-07 -3.971365e-08
#> temax       -6.559946e-04 -6.580260e-05 -8.564827e-06
#> tec50       -1.575773e-05  1.471163e-06  1.589712e-07
#> tkout       -4.223933e-06  1.272296e-06  6.589633e-08
#> te0         -5.115733e-07 -1.942521e-07 -4.893808e-08
#> pdadd.err    2.801966e-04  5.322319e-05  1.442266e-05
#> om.eta.ktr   6.768802e-06  4.488374e-06  1.732708e-07
#> om.eta.ka    6.857673e-06  4.297694e-06  1.523645e-07
#> om.eta.cl    2.113917e-06  6.795138e-08  5.359341e-09
#> om.eta.v     6.300933e-07  2.175756e-07  8.067423e-09
#> om.eta.emax  1.267573e-07  1.868036e-09 -4.033401e-10
#> om.eta.ec50  2.228655e-03  1.293380e-06  2.576137e-07
#> om.eta.kout  1.293380e-06  6.463107e-06  2.914145e-08
#> om.eta.e0    2.576137e-07  2.914145e-08  5.463700e-07
fit
#> ── nlmixr² nonmem2rx reading NONMEM ver 7.4.3 ──
#> 
#>               OBJF     AIC      BIC Log-likelihood Condition#(Cov)
#> nonmem2rx 439.2156 1364.91 1444.331      -663.4551         6871556
#>           Condition#(Cor)
#> nonmem2rx        10.42427
#> 
#> ── Time (sec fit$time): ──
#> 
#>             setup postprocess table compress NONMEM as.nlmixr2 covariance
#> elapsed 0.6350346       0.022 0.046    0.001 320.27      2.422      52.57
#> 
#> ── Population Parameters (fit$parFixed or fit$parFixedDf): ──
#> 
#>                Parameter      Est.       SE    %RSE    Back-transformed(95%CI)
#> tktr            1 - tktr  6.241e-7  0.09734 1.560e7      1.000 (0.8263, 1.210)
#> tka              2 - tka -3.006e-6  0.09745 3241000      1.000 (0.8261, 1.210)
#> tcl              3 - tcl    -2.004  0.01155  0.5764    0.1348 (0.1318, 0.1379)
#> tv                4 - tv     2.052  0.01261  0.6148       7.783 (7.592, 7.977)
#> prop.err    5 - prop.err   0.09858 0.009993   10.14  0.09858 (0.07899, 0.1182)
#> pkadd.err  6 - pkadd.err    0.5116  0.05401   10.56    0.5116 (0.4058, 0.6175)
#> temax          7 - temax     6.418    1.955   30.46     0.9984 (0.9300, 1.000)
#> tec50          8 - tec50    0.1408  0.03075   21.84       1.151 (1.084, 1.223)
#> tkout          9 - tkout    -2.953  0.01787  0.6050 0.05216 (0.05036, 0.05402)
#> te0             10 - te0     4.570 0.006660  0.1457       96.59 (95.34, 97.86)
#> pdadd.err 11 - pdadd.err     3.717   0.1974   5.311       3.717 (3.330, 4.104)
#>           BSV(CV% or SD) Shrink(SD)%
#> tktr               86.45      59.84 
#> tka                86.48      59.84 
#> tcl                28.59      1.340 
#> tv                 22.83      6.442 
#> prop.err                            
#> pkadd.err                           
#> temax           0.007071      99.99 
#> tec50              44.98      6.065 
#> tkout              9.164      32.42 
#> te0                5.243      18.09 
#> pdadd.err                           
#>  
#>   Covariance Type (fit$covMethod): r
#>   No correlations in between subject variability (BSV) matrix
#>   Full BSV covariance (fit$omega) or correlation (fit$omegaR; diagonals=SDs) 
#>   Distribution stats (mean/skewness/kurtosis/p-value) available in fit$shrink 
#>   Censoring (fit$censInformation): No censoring
#>   Minimization message (fit$message):  
#>     
#> 
#>  WARNINGS AND ERRORS (IF ANY) FOR PROBLEM    1
#> 
#>  (WARNING  2) NM-TRAN INFERS THAT THE DATA ARE POPULATION.
#> 
#>     
#> 0MINIMIZATION TERMINATED
#>  DUE TO ROUNDING ERRORS (ERROR=134)
#>  NO. OF FUNCTION EVALUATIONS USED:     1088
#>  NO. OF SIG. DIGITS UNREPORTABLE
#> 0PARAMETER ESTIMATE IS NEAR ITS BOUNDARY
#> 
#>     IPRED relative difference compared to Nonmem IPRED: 0%; 95% percentile: (0%,0%); rtol=5.09e-06
#>     PRED relative difference compared to Nonmem PRED: 0%; 95% percentile: (0%,0%); rtol=5.29e-06
#>     IPRED absolute difference compared to Nonmem IPRED: 95% percentile: (2.2e-06, 0.000454); atol=3.03e-05
#>     PRED absolute difference compared to Nonmem PRED: 95% percentile: (4.72e-07,0.00361); atol=5.29e-06
#>     there are solving errors during optimization (see '$prderr')
#>     nonmem2rx model file: 'pk.turnover.emax3-nonmem/pk.turnover.emax3.nmctl' 
#> 
#> ── Fit Data (object fit is a modified tibble): ──
#> # A tibble: 483 × 35
#>   ID     TIME CMT      DV  PRED   RES IPRED   IRES  IWRES eta.ktr eta.ka eta.cl
#>   <fct> <dbl> <fct> <dbl> <dbl> <dbl> <dbl>  <dbl>  <dbl>   <dbl>  <dbl>  <dbl>
#> 1 1       0.5 dcp     0    1.16 -1.16 0.444 -0.444 -0.864  -0.506 -0.506  0.699
#> 2 1       1   dcp     1.9  3.37 -1.47 1.45   0.446  0.840  -0.506 -0.506  0.699
#> 3 1       2   dcp     3.3  7.51 -4.21 3.96  -0.660 -1.03   -0.506 -0.506  0.699
#> # ℹ 480 more rows
#> # ℹ 23 more variables: eta.v <dbl>, eta.emax <dbl>, eta.ec50 <dbl>,
#> #   eta.kout <dbl>, eta.e0 <dbl>, dcp <dbl>, eff <dbl>, DEPOT <dbl>, GUT <dbl>,
#> #   CENTER <dbl>, EFFECT <dbl>, ktr <dbl>, ka <dbl>, cl <dbl>, v <dbl>,
#> #   emax <dbl>, ec50 <dbl>, kout <dbl>, e0 <dbl>, pd <dbl>, kin <dbl>,
#> #   tad <dbl>, dosenum <dbl>

Note this covariance step is not 100% successful since it is not r, s. However, it can give some insights on which parameters are estimated well. In this case you can see that the emax parameter is more poorly estimated than other parameters, which means fixing the parameter or reducing other parameters may help your estimate progress in NONMEM.

Step 1: Have a NONMEM model with rounding errors (and .phi or other information about the etas)

Step 2: Convert rxode2 model to model with endpoints/residuals specified like nlmixr2

Step 3: Convert new model to nlmixr2 fit with as.nlmixr2()

Step 4: Explore the data/fit as if it came from nlmixr2

Step 5: Get the covariance of the model

Step 1: Have a NONMEM model with rounding errors (and `.phi` or other information about the `etas`)

Step 2: Convert `rxode2` model to model with endpoints/residuals specified like `nlmixr2`

Step 3: Convert new model to nlmixr2 fit with `as.nlmixr2()`

Step 4: Explore the data/fit as if it came from `nlmixr2`