title: “Computing NCA Parameters for Theophylline” author: “Bill Denney” output: html_document: toc: false

toc_depth: 2

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
my.conc <- 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")
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 
my.dose <- 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

my.data.automatic <- PKNCAdata(my.conc, my.dose)
knitr::kable(PKNCA.options("single.dose.aucs"))
start end auclast aucall aumclast aumcall cmax cmin tmax tlast tfirst clast.obs f mrt mrt.last cav ctrough ptr tlag half.life r.squared adj.r.squared lambda.z lambda.z.time.first lambda.z.n.points clast.pred span.ratio thalf.eff kel aucinf aumcinf aucpext cl vz vss vd
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
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 
knitr::kable(my.data.automatic$intervals)
start end auclast aucall aumclast aumcall cmax cmin tmax tlast tfirst clast.obs f mrt mrt.last cav ctrough ptr tlag half.life r.squared adj.r.squared lambda.z lambda.z.time.first lambda.z.n.points clast.pred span.ratio thalf.eff kel aucinf aumcinf aucpext cl vz vss vd Subject
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 1
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 1
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 2
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 2
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 3
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 3
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 4
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 4
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 5
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 5
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 6
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 6
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 7
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 7
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 8
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 8
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 9
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 9
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 10
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 10
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 11
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE 11
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 12
0 Inf FALSE FALSE FALSE FALSE TRUE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE FALSE TRUE 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 AUC~0-\(\infinity\)~, you do not have to specify it in the parameters requested.

my.intervals <- data.frame(start=0,
                           end=Inf,
                           cmax=TRUE,
                           tmax=TRUE,
                           aucinf=TRUE,
                           auclast=TRUE)
my.data.manual <- PKNCAdata(my.conc, my.dose,
                            intervals=my.intervals)
knitr::kable(my.data.manual$intervals)
start end auclast aucall aumclast aumcall cmax cmin tmax tlast tfirst clast.obs f mrt mrt.last cav ctrough ptr tlag half.life r.squared adj.r.squared lambda.z lambda.z.time.first lambda.z.n.points clast.pred span.ratio thalf.eff kel aucinf aumcinf aucpext cl vz vss vd
0 Inf TRUE 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 TRUE 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.

my.results.automatic <- pk.nca(my.data.automatic)
knitr::kable(head(my.results.automatic$result))
start end Subject PPTESTCD PPORRES
0 24 1 auclast 92.3654416
0 Inf 1 cmax 10.5000000
0 Inf 1 tmax 1.1200000
0 Inf 1 tlast 24.3700000
0 Inf 1 lambda.z 0.0484570
0 Inf 1 r.squared 0.9999997 
summary(my.results.automatic)
start end auclast cmax tmax half.life aucinf
0 24 74.6 [24.3] . . . .
0 Inf . 8.65 [17.0] 1.14 [0.630, 3.55] 8.18 [2.12] 115 [28.4] 
my.results.manual <- pk.nca(my.data.manual)
knitr::kable(head(my.results.manual$result))
start end Subject PPTESTCD PPORRES
0 Inf 1 auclast 147.2347485
0 Inf 1 cmax 10.5000000
0 Inf 1 tmax 1.1200000
0 Inf 1 tlast 24.3700000
0 Inf 1 lambda.z 0.0484570
0 Inf 1 r.squared 0.9999997 
summary(my.results.manual)
start end auclast cmax tmax aucinf
0 Inf 98.7 [22.5] 8.65 [17.0] 1.14 [0.630, 3.55] 115 [28.4]