Computing NCA Parameters for Theophylline

Bill Denney

Source: vignettes/Example-theophylline.Rmd

Examples simplify understanding. Below is an example of how to use the theophylline dataset to generate NCA parameters.

Load the data 

## It is always a good idea to look at the data
knitr::kable(head(datasets::Theoph))
Subject Wt Dose Time conc
1 79.6 4.02 0.00 0.74
1 79.6 4.02 0.25 2.84
1 79.6 4.02 0.57 6.57
1 79.6 4.02 1.12 10.50
1 79.6 4.02 2.02 9.66
1 79.6 4.02 3.82 8.58

The columns that we will be interested in for our analysis are conc, Time, and Subject in the concentration data set and Dose, Time, and Subject for the dosing data set.

## By default it is groupedData; convert it to a data frame for use
conc_obj <- PKNCAconc(as.data.frame(datasets::Theoph), conc~Time|Subject)

## Dosing data needs to only have one row per dose, so subset for
## that first.
d_dose <- unique(datasets::Theoph[datasets::Theoph$Time == 0,
                                  c("Dose", "Time", "Subject")])
knitr::kable(d_dose,
             caption="Example dosing data extracted from theophylline data set")
Example dosing data extracted from theophylline data set
Dose Time Subject
1 4.02 0 1
12 4.40 0 2
23 4.53 0 3
34 4.40 0 4
45 5.86 0 5
56 4.00 0 6
67 4.95 0 7
78 4.53 0 8
89 3.10 0 9
100 5.50 0 10
111 4.92 0 11
122 5.30 0 12 
dose_obj <- PKNCAdose(d_dose, Dose~Time|Subject)

Merge the Concentration and Dose

After loading the data, they must be combined to prepare for parameter calculation. Intervals for calculation will automatically be selected based on the single.dose.aucs setting in PKNCA.options

data_obj_automatic <- PKNCAdata(conc_obj, dose_obj)
knitr::kable(PKNCA.options("single.dose.aucs"))
start end auclast aucall aumclast aumcall aucint.last aucint.last.dose aucint.all aucint.all.dose c0 cmax cmin tmax tlast tfirst clast.obs cl.last cl.all f mrt.last mrt.iv.last vss.last vss.iv.last cav ctrough ptr tlag deg.fluc swing ceoi ae clr.last clr.obs clr.pred fe sparse_auclast time_above aucivlast aucivall aucivint.last aucivint.all aucivpbextlast aucivpbextall aucivpbextint.last aucivpbextint.all half.life r.squared adj.r.squared lambda.z lambda.z.time.first lambda.z.n.points clast.pred span.ratio thalf.eff.last thalf.eff.iv.last kel.last kel.iv.last aucinf.obs aucinf.pred aumcinf.obs aumcinf.pred aucint.inf.obs aucint.inf.obs.dose aucint.inf.pred aucint.inf.pred.dose aucivinf.obs aucivinf.pred aucivpbextinf.obs aucivpbextinf.pred aucpext.obs aucpext.pred cl.obs cl.pred mrt.obs mrt.pred mrt.iv.obs mrt.iv.pred mrt.md.obs mrt.md.pred vz.obs vz.pred vss.obs vss.pred vss.iv.obs vss.iv.pred vss.md.obs vss.md.pred vd.obs vd.pred thalf.eff.obs thalf.eff.pred thalf.eff.iv.obs thalf.eff.iv.pred kel.obs kel.pred kel.iv.obs kel.iv.pred auclast.dn aucall.dn aucinf.obs.dn aucinf.pred.dn aumclast.dn aumcall.dn aumcinf.obs.dn aumcinf.pred.dn cmax.dn cmin.dn clast.obs.dn clast.pred.dn cav.dn ctrough.dn
0 24 TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE
0 Inf FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE 
knitr::kable(data_obj_automatic$intervals)
start end auclast aucall aumclast aumcall aucint.last aucint.last.dose aucint.all aucint.all.dose c0 cmax cmin tmax tlast tfirst clast.obs cl.last cl.all f mrt.last mrt.iv.last vss.last vss.iv.last cav ctrough ptr tlag deg.fluc swing ceoi ae clr.last clr.obs clr.pred fe sparse_auclast time_above aucivlast aucivall aucivint.last aucivint.all aucivpbextlast aucivpbextall aucivpbextint.last aucivpbextint.all half.life r.squared adj.r.squared lambda.z lambda.z.time.first lambda.z.n.points clast.pred span.ratio thalf.eff.last thalf.eff.iv.last kel.last kel.iv.last aucinf.obs aucinf.pred aumcinf.obs aumcinf.pred aucint.inf.obs aucint.inf.obs.dose aucint.inf.pred aucint.inf.pred.dose aucivinf.obs aucivinf.pred aucivpbextinf.obs aucivpbextinf.pred aucpext.obs aucpext.pred cl.obs cl.pred mrt.obs mrt.pred mrt.iv.obs mrt.iv.pred mrt.md.obs mrt.md.pred vz.obs vz.pred vss.obs vss.pred vss.iv.obs vss.iv.pred vss.md.obs vss.md.pred vd.obs vd.pred thalf.eff.obs thalf.eff.pred thalf.eff.iv.obs thalf.eff.iv.pred kel.obs kel.pred kel.iv.obs kel.iv.pred auclast.dn aucall.dn aucinf.obs.dn aucinf.pred.dn aumclast.dn aumcall.dn aumcinf.obs.dn aumcinf.pred.dn cmax.dn cmin.dn clast.obs.dn clast.pred.dn cav.dn ctrough.dn Subject
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0 Inf FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE 12

Intervals for calculation can also be specified manually. Manual specification requires at least columns for start time, end time, and the parameters requested. The manual specification can also include any grouping factors from the concentration data set. Column order of the intervals is not important. When intervals are manually specified, they are expanded to the full interval set when added to a PKNCAdata object (in other words, a column is created for each parameter. Also, PKNCA automatically calculates parameters required for the NCA, so while lambda.z is required for calculating AUC0-\(\infty\), you do not have to specify it in the parameters requested.

intervals_manual <- data.frame(start=0,
                               end=Inf,
                               cmax=TRUE,
                               tmax=TRUE,
                               aucinf.obs=TRUE,
                               auclast=TRUE)
data_obj_manual <- PKNCAdata(conc_obj, dose_obj,
                             intervals=intervals_manual)
knitr::kable(data_obj_manual$intervals)
start end auclast aucall aumclast aumcall aucint.last aucint.last.dose aucint.all aucint.all.dose c0 cmax cmin tmax tlast tfirst clast.obs cl.last cl.all f mrt.last mrt.iv.last vss.last vss.iv.last cav ctrough ptr tlag deg.fluc swing ceoi ae clr.last clr.obs clr.pred fe sparse_auclast time_above aucivlast aucivall aucivint.last aucivint.all aucivpbextlast aucivpbextall aucivpbextint.last aucivpbextint.all half.life r.squared adj.r.squared lambda.z lambda.z.time.first lambda.z.n.points clast.pred span.ratio thalf.eff.last thalf.eff.iv.last kel.last kel.iv.last aucinf.obs aucinf.pred aumcinf.obs aumcinf.pred aucint.inf.obs aucint.inf.obs.dose aucint.inf.pred aucint.inf.pred.dose aucivinf.obs aucivinf.pred aucivpbextinf.obs aucivpbextinf.pred aucpext.obs aucpext.pred cl.obs cl.pred mrt.obs mrt.pred mrt.iv.obs mrt.iv.pred mrt.md.obs mrt.md.pred vz.obs vz.pred vss.obs vss.pred vss.iv.obs vss.iv.pred vss.md.obs vss.md.pred vd.obs vd.pred thalf.eff.obs thalf.eff.pred thalf.eff.iv.obs thalf.eff.iv.pred kel.obs kel.pred kel.iv.obs kel.iv.pred auclast.dn aucall.dn aucinf.obs.dn aucinf.pred.dn aumclast.dn aumcall.dn aumcinf.obs.dn aumcinf.pred.dn cmax.dn cmin.dn clast.obs.dn clast.pred.dn cav.dn ctrough.dn
0 Inf TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE

Compute the parameters

Parameter calculation will automatically split the data by the grouping factor(s), subset by the interval, calculate all required parameters, record all options used for the calculations, and include data provenance to show that the calculation was performed as described. For all this, just call the pk.nca function with your PKNCAdata object.

results_obj_automatic <- pk.nca(data_obj_automatic)
knitr::kable(head(as.data.frame(results_obj_automatic)))
Subject start end PPTESTCD PPORRES exclude
1 0 24 auclast 92.365442 NA
1 0 Inf cmax 10.500000 NA
1 0 Inf tmax 1.120000 NA
1 0 Inf tlast 24.370000 NA
1 0 Inf clast.obs 3.280000 NA
1 0 Inf lambda.z 0.048457 NA 
summary(results_obj_automatic)
start end N auclast cmax tmax half.life aucinf.obs
0 24 12 74.6 [24.3] . . . .
0 Inf 12 . 8.65 [17.0] 1.14 [0.630, 3.55] 8.18 [2.12] 115 [28.4] 
results_obj_manual <- pk.nca(data_obj_manual)
knitr::kable(head(as.data.frame(results_obj_manual)))
Subject start end PPTESTCD PPORRES exclude
6 0 Inf auclast 71.6970150 NA
6 0 Inf cmax 6.4400000 NA
6 0 Inf tmax 1.1500000 NA
6 0 Inf tlast 23.8500000 NA
6 0 Inf clast.obs 0.9200000 NA
6 0 Inf lambda.z 0.0877957 NA 
summary(results_obj_manual)
start end N auclast cmax tmax aucinf.obs
0 Inf 12 98.7 [22.5] 8.65 [17.0] 1.14 [0.630, 3.55] 115 [28.4]

Multiple Dose Example

Assessing multiple dose pharmacokinetics is conceptually the same as single-dose in PKNCA.

To assess multiple dose PK, the theophylline data will be extended from single to multiple doses using superposition (see the Superposition vignette for more information).

d_conc <- PKNCAconc(as.data.frame(Theoph), conc~Time|Subject)
conc_obj_multi <-
  PKNCAconc(
    superposition(d_conc,
                  tau=168,
                  dose.times=seq(0, 144, by=24),
                  n.tau=1,
                  check.blq=FALSE),
    conc~time|Subject)
conc_obj_multi
## Formula for concentration:
##  conc ~ time | Subject
## Data are dense PK.
## With 12 subjects defined in the 'Subject' column.
## Nominal time column is not specified.
## 
## First 6 rows of concentration data:
##  Subject     conc time exclude volume duration
##        1  0.74000 0.00    <NA>     NA        0
##        1  2.84000 0.25    <NA>     NA        0
##        1  4.23875 0.37    <NA>     NA        0
##        1  6.57000 0.57    <NA>     NA        0
##        1 10.50000 1.12    <NA>     NA        0
##        1  9.66000 2.02    <NA>     NA        0
dose_obj_multi <- PKNCAdose(expand.grid(Subject=unique(conc_obj_multi$data$Subject),
                                      time=seq(0, 144, by=24)),
                          ~time|Subject)
dose_obj_multi
## Formula for dosing:
##  ~time | Subject
## Nominal time column is not specified.
## 
## First 6 rows of dosing data:
##  Subject time exclude         route duration
##        1    0    <NA> extravascular        0
##        2    0    <NA> extravascular        0
##        3    0    <NA> extravascular        0
##        4    0    <NA> extravascular        0
##        5    0    <NA> extravascular        0
##        6    0    <NA> extravascular        0

The superposition-simulated scenario is not especially realistic as it includes dense sampling on every day. With this scenario, the intervals automatically selected have an interval for every subject on every day.

data_obj <- PKNCAdata(conc_obj_multi, dose_obj_multi)
data_obj$intervals[,c("Subject", "start", "end")]
## # A tibble: 84 × 3
##    Subject start   end
##    <ord>   <dbl> <dbl>
##  1 1           0    24
##  2 1          24    48
##  3 1          48    72
##  4 1          72    96
##  5 1          96   120
##  6 1         120   144
##  7 1         144   168
##  8 2           0    24
##  9 2          24    48
## 10 2          48    72
## # … with 74 more rows

In a more realistic scenario, dense PK sampling occurs for every subject on the first and last days. To select those intervals manually, specify the intervals of interest in the intervals argument to the PKNCAdata function call. The intervals are automatically expanded not to calculate anything that was not requested.

intervals_manual <- data.frame(start=c(0, 144),
                               end=c(24, 168),
                               cmax=TRUE,
                               auclast=TRUE)
data_obj <- PKNCAdata(conc_obj_multi, dose_obj_multi,
                      intervals=intervals_manual)
data_obj$intervals
##   start end auclast aucall aumclast aumcall aucint.last aucint.last.dose
## 1     0  24    TRUE  FALSE    FALSE   FALSE       FALSE            FALSE
## 2   144 168    TRUE  FALSE    FALSE   FALSE       FALSE            FALSE
##   aucint.all aucint.all.dose    c0 cmax  cmin  tmax tlast tfirst clast.obs
## 1      FALSE           FALSE FALSE TRUE FALSE FALSE FALSE  FALSE     FALSE
## 2      FALSE           FALSE FALSE TRUE FALSE FALSE FALSE  FALSE     FALSE
##   cl.last cl.all     f mrt.last mrt.iv.last vss.last vss.iv.last   cav ctrough
## 1   FALSE  FALSE FALSE    FALSE       FALSE    FALSE       FALSE FALSE   FALSE
## 2   FALSE  FALSE FALSE    FALSE       FALSE    FALSE       FALSE FALSE   FALSE
##     ptr  tlag deg.fluc swing  ceoi    ae clr.last clr.obs clr.pred    fe
## 1 FALSE FALSE    FALSE FALSE FALSE FALSE    FALSE   FALSE    FALSE FALSE
## 2 FALSE FALSE    FALSE FALSE FALSE FALSE    FALSE   FALSE    FALSE FALSE
##   sparse_auclast time_above aucivlast aucivall aucivint.last aucivint.all
## 1          FALSE      FALSE     FALSE    FALSE         FALSE        FALSE
## 2          FALSE      FALSE     FALSE    FALSE         FALSE        FALSE
##   aucivpbextlast aucivpbextall aucivpbextint.last aucivpbextint.all half.life
## 1          FALSE         FALSE              FALSE             FALSE     FALSE
## 2          FALSE         FALSE              FALSE             FALSE     FALSE
##   r.squared adj.r.squared lambda.z lambda.z.time.first lambda.z.n.points
## 1     FALSE         FALSE    FALSE               FALSE             FALSE
## 2     FALSE         FALSE    FALSE               FALSE             FALSE
##   clast.pred span.ratio thalf.eff.last thalf.eff.iv.last kel.last kel.iv.last
## 1      FALSE      FALSE          FALSE             FALSE    FALSE       FALSE
## 2      FALSE      FALSE          FALSE             FALSE    FALSE       FALSE
##   aucinf.obs aucinf.pred aumcinf.obs aumcinf.pred aucint.inf.obs
## 1      FALSE       FALSE       FALSE        FALSE          FALSE
## 2      FALSE       FALSE       FALSE        FALSE          FALSE
##   aucint.inf.obs.dose aucint.inf.pred aucint.inf.pred.dose aucivinf.obs
## 1               FALSE           FALSE                FALSE        FALSE
## 2               FALSE           FALSE                FALSE        FALSE
##   aucivinf.pred aucivpbextinf.obs aucivpbextinf.pred aucpext.obs aucpext.pred
## 1         FALSE             FALSE              FALSE       FALSE        FALSE
## 2         FALSE             FALSE              FALSE       FALSE        FALSE
##   cl.obs cl.pred mrt.obs mrt.pred mrt.iv.obs mrt.iv.pred mrt.md.obs mrt.md.pred
## 1  FALSE   FALSE   FALSE    FALSE      FALSE       FALSE      FALSE       FALSE
## 2  FALSE   FALSE   FALSE    FALSE      FALSE       FALSE      FALSE       FALSE
##   vz.obs vz.pred vss.obs vss.pred vss.iv.obs vss.iv.pred vss.md.obs vss.md.pred
## 1  FALSE   FALSE   FALSE    FALSE      FALSE       FALSE      FALSE       FALSE
## 2  FALSE   FALSE   FALSE    FALSE      FALSE       FALSE      FALSE       FALSE
##   vd.obs vd.pred thalf.eff.obs thalf.eff.pred thalf.eff.iv.obs
## 1  FALSE   FALSE         FALSE          FALSE            FALSE
## 2  FALSE   FALSE         FALSE          FALSE            FALSE
##   thalf.eff.iv.pred kel.obs kel.pred kel.iv.obs kel.iv.pred auclast.dn
## 1             FALSE   FALSE    FALSE      FALSE       FALSE      FALSE
## 2             FALSE   FALSE    FALSE      FALSE       FALSE      FALSE
##   aucall.dn aucinf.obs.dn aucinf.pred.dn aumclast.dn aumcall.dn aumcinf.obs.dn
## 1     FALSE         FALSE          FALSE       FALSE      FALSE          FALSE
## 2     FALSE         FALSE          FALSE       FALSE      FALSE          FALSE
##   aumcinf.pred.dn cmax.dn cmin.dn clast.obs.dn clast.pred.dn cav.dn ctrough.dn
## 1           FALSE   FALSE   FALSE        FALSE         FALSE  FALSE      FALSE
## 2           FALSE   FALSE   FALSE        FALSE         FALSE  FALSE      FALSE

After the data is ready, the calculations and summary can progress.

results_obj <- pk.nca(data_obj)
print(results_obj)
## $result
## # A tibble: 48 × 6
##    Subject start   end PPTESTCD PPORRES exclude
##    <ord>   <dbl> <dbl> <chr>      <dbl> <chr>  
##  1 6           0    24 auclast    71.8  NA     
##  2 6           0    24 cmax        6.44 NA     
##  3 6         144   168 auclast    82.2  NA     
##  4 6         144   168 cmax        7.37 NA     
##  5 7           0    24 auclast    89.0  NA     
##  6 7           0    24 cmax        7.09 NA     
##  7 7         144   168 auclast   101.   NA     
##  8 7         144   168 cmax        8.07 NA     
##  9 8           0    24 auclast    86.7  NA     
## 10 8           0    24 cmax        7.56 NA     
## # … with 38 more rows
## 
## $data
## Formula for concentration:
##  conc ~ time | Subject
## Data are dense PK.
## With 12 subjects defined in the 'Subject' column.
## Nominal time column is not specified.
## 
## First 6 rows of concentration data:
##  Subject     conc time exclude volume duration
##        1  0.74000 0.00    <NA>     NA        0
##        1  2.84000 0.25    <NA>     NA        0
##        1  4.23875 0.37    <NA>     NA        0
##        1  6.57000 0.57    <NA>     NA        0
##        1 10.50000 1.12    <NA>     NA        0
##        1  9.66000 2.02    <NA>     NA        0
## Formula for dosing:
##  ~time | Subject
## Nominal time column is not specified.
## 
## First 6 rows of dosing data:
##  Subject time exclude         route duration
##        1    0    <NA> extravascular        0
##        2    0    <NA> extravascular        0
##        3    0    <NA> extravascular        0
##        4    0    <NA> extravascular        0
##        5    0    <NA> extravascular        0
##        6    0    <NA> extravascular        0
## 
## With 2 rows of AUC specifications.
## Options changed from default are:
## $adj.r.squared.factor
## [1] 1e-04
## 
## $max.missing
## [1] 0.5
## 
## $auc.method
## [1] "lin up/log down"
## 
## $conc.na
## [1] "drop"
## 
## $conc.blq
## $conc.blq$first
## [1] "keep"
## 
## $conc.blq$middle
## [1] "drop"
## 
## $conc.blq$last
## [1] "keep"
## 
## 
## $first.tmax
## [1] TRUE
## 
## $allow.tmax.in.half.life
## [1] FALSE
## 
## $min.hl.points
## [1] 3
## 
## $min.span.ratio
## [1] 2
## 
## $max.aucinf.pext
## [1] 20
## 
## $min.hl.r.squared
## [1] 0.9
## 
## $tau.choices
## [1] NA
## 
## $single.dose.aucs
##   start end auclast aucall aumclast aumcall aucint.last aucint.last.dose
## 1     0  24    TRUE  FALSE    FALSE   FALSE       FALSE            FALSE
## 2     0 Inf   FALSE  FALSE    FALSE   FALSE       FALSE            FALSE
##   aucint.all aucint.all.dose    c0  cmax  cmin  tmax tlast tfirst clast.obs
## 1      FALSE           FALSE FALSE FALSE FALSE FALSE FALSE  FALSE     FALSE
## 2      FALSE           FALSE FALSE  TRUE FALSE  TRUE FALSE  FALSE     FALSE
##   cl.last cl.all     f mrt.last mrt.iv.last vss.last vss.iv.last   cav ctrough
## 1   FALSE  FALSE FALSE    FALSE       FALSE    FALSE       FALSE FALSE   FALSE
## 2   FALSE  FALSE FALSE    FALSE       FALSE    FALSE       FALSE FALSE   FALSE
##     ptr  tlag deg.fluc swing  ceoi    ae clr.last clr.obs clr.pred    fe
## 1 FALSE FALSE    FALSE FALSE FALSE FALSE    FALSE   FALSE    FALSE FALSE
## 2 FALSE FALSE    FALSE FALSE FALSE FALSE    FALSE   FALSE    FALSE FALSE
##   sparse_auclast time_above aucivlast aucivall aucivint.last aucivint.all
## 1          FALSE      FALSE     FALSE    FALSE         FALSE        FALSE
## 2          FALSE      FALSE     FALSE    FALSE         FALSE        FALSE
##   aucivpbextlast aucivpbextall aucivpbextint.last aucivpbextint.all half.life
## 1          FALSE         FALSE              FALSE             FALSE     FALSE
## 2          FALSE         FALSE              FALSE             FALSE      TRUE
##   r.squared adj.r.squared lambda.z lambda.z.time.first lambda.z.n.points
## 1     FALSE         FALSE    FALSE               FALSE             FALSE
## 2     FALSE         FALSE    FALSE               FALSE             FALSE
##   clast.pred span.ratio thalf.eff.last thalf.eff.iv.last kel.last kel.iv.last
## 1      FALSE      FALSE          FALSE             FALSE    FALSE       FALSE
## 2      FALSE      FALSE          FALSE             FALSE    FALSE       FALSE
##   aucinf.obs aucinf.pred aumcinf.obs aumcinf.pred aucint.inf.obs
## 1      FALSE       FALSE       FALSE        FALSE          FALSE
## 2       TRUE       FALSE       FALSE        FALSE          FALSE
##   aucint.inf.obs.dose aucint.inf.pred aucint.inf.pred.dose aucivinf.obs
## 1               FALSE           FALSE                FALSE        FALSE
## 2               FALSE           FALSE                FALSE        FALSE
##   aucivinf.pred aucivpbextinf.obs aucivpbextinf.pred aucpext.obs aucpext.pred
## 1         FALSE             FALSE              FALSE       FALSE        FALSE
## 2         FALSE             FALSE              FALSE       FALSE        FALSE
##   cl.obs cl.pred mrt.obs mrt.pred mrt.iv.obs mrt.iv.pred mrt.md.obs mrt.md.pred
## 1  FALSE   FALSE   FALSE    FALSE      FALSE       FALSE      FALSE       FALSE
## 2  FALSE   FALSE   FALSE    FALSE      FALSE       FALSE      FALSE       FALSE
##   vz.obs vz.pred vss.obs vss.pred vss.iv.obs vss.iv.pred vss.md.obs vss.md.pred
## 1  FALSE   FALSE   FALSE    FALSE      FALSE       FALSE      FALSE       FALSE
## 2  FALSE   FALSE   FALSE    FALSE      FALSE       FALSE      FALSE       FALSE
##   vd.obs vd.pred thalf.eff.obs thalf.eff.pred thalf.eff.iv.obs
## 1  FALSE   FALSE         FALSE          FALSE            FALSE
## 2  FALSE   FALSE         FALSE          FALSE            FALSE
##   thalf.eff.iv.pred kel.obs kel.pred kel.iv.obs kel.iv.pred auclast.dn
## 1             FALSE   FALSE    FALSE      FALSE       FALSE      FALSE
## 2             FALSE   FALSE    FALSE      FALSE       FALSE      FALSE
##   aucall.dn aucinf.obs.dn aucinf.pred.dn aumclast.dn aumcall.dn aumcinf.obs.dn
## 1     FALSE         FALSE          FALSE       FALSE      FALSE          FALSE
## 2     FALSE         FALSE          FALSE       FALSE      FALSE          FALSE
##   aumcinf.pred.dn cmax.dn cmin.dn clast.obs.dn clast.pred.dn cav.dn ctrough.dn
## 1           FALSE   FALSE   FALSE        FALSE         FALSE  FALSE      FALSE
## 2           FALSE   FALSE   FALSE        FALSE         FALSE  FALSE      FALSE
## 
## 
## $exclude
## [1] "exclude"
## 
## attr(,"class")
## [1] "PKNCAresults" "list"        
## attr(,"provenance")
## Provenance hash ee687a520af821aa354fef62aa53cba0 generated on 2022-10-04 20:57:48 with R version 4.2.1 (2022-06-23).
summary(results_obj)
##  start end  N     auclast        cmax
##      0  24 12 98.8 [23.0] 8.65 [17.0]
##    144 168 12  115 [28.4] 10.0 [21.0]
## 
## Caption: auclast, cmax: geometric mean and geometric coefficient of variation