AUC0-tau differ from those calculated by WinNonlin,how to solve it?

[Su-2020]

I am a statistician. Recently, while using the pknca package, I noticed that the results for AUC0-tau differ from those calculated by WinNonlin. Previously, when calculating AUC0-last, I encountered a similar issue, which was resolved by setting AUC method = linear in the options. Could you please advise on how to resolve this? In theory, since I set it to linear, it should also apply to the calculation of AUC0-tau.

[billdenney]

Before running pk.nca(), you can set the AUC integration method to linear using one of these two methods:

1. (preferred) Use the options argument to PKNCAdata(): PKNCAdata(conc_obj, intervals = intervals, options = list(auc.method = "linear"))
2. (also works) Use PKNCA.options(auc.method = "linear") before calling pk.nca()

[Su-2020]

I had set it,but still not work. just wonder why occur this ?

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------------------ 原始邮件 ------------------ 发件人: "humanpred/pknca" ***@***.***>; 发送时间: 2025年6月9日(星期一) 晚上7:00 ***@***.***>; ***@***.******@***.***>; 主题: Re: [humanpred/pknca] AUC0-tau differ from those calculated by WinNonlin,how to solve it? (Discussion #431) Before running pk.nca(), you can set the AUC integration method to linear using one of these two methods: (preferred) Use the options argument to PKNCAdata(): PKNCAdata(conc_obj, intervals = intervals, options = list(auc.method = "linear")) (also works) Use PKNCA.options(auc.method = "linear") before calling pk.nca() — Reply to this email directly, view it on GitHub, or unsubscribe. You are receiving this because you authored the thread.Message ID: ***@***.***>

[billdenney]

Can you please provide a reproducible example (with made-up data, if necessary) that shows the disconnect?

[Su-2020]

if you have new progress, let me know.Thanks

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------------------ 原始邮件 ------------------ 发件人: "humanpred/pknca" ***@***.***>; 发送时间: 2025年6月9日(星期一) 晚上7:09 ***@***.***>; ***@***.******@***.***>; 主题: Re: [humanpred/pknca] AUC0-tau differ from those calculated by WinNonlin,how to solve it? (Discussion #431) Can you please provide a reproducible example (with made-up data, if necessary) that shows the disconnect? — Reply to this email directly, view it on GitHub, or unsubscribe. You are receiving this because you authored the thread.Message ID: ***@***.***>

[billdenney]

I don't know exactly what solution you're looking for without a reproducible example. Can you please provide an example with what is happening and what is different than you expect?

[js3110]

@billdenney I am also noticing this issue with AUCINT compared to Winonlin

Using this dummy dataset
example-ADNCA.csv

library(PKNCA)
library(dplyr)

# Load the data
data <- read.csv("example-ADNCA.csv", na.strings = c("", "NA"))

data <- data %>%
  filter(USUBJID == "S1-01",
         PARAM == "DrugA",
         PCSPEC == "SERUM")

# Load the PK concentration data
df_conc <- data

# Dosing dataset
df_dose <- df_conc %>%
  group_by(ATPTREF) %>%
  slice(1) %>%
  mutate(AFRLT = AFRLT - ARRLT)

# Create PKNCA objects
pknca_conc <- PKNCA::PKNCAconc(
  df_conc,
  formula = AVAL ~ AFRLT | STUDYID + PCSPEC + DOSETRT + USUBJID / PARAM,
  time.nominal = "NFRLT",
  concu = "AVALU",
  timeu = "RRLTU",
)

pknca_dose <- PKNCA::PKNCAdose(
  data = df_dose,
  formula = DOSEA ~ AFRLT | STUDYID + DOSETRT + USUBJID,
  route = "intravascular",
  time.nominal = "NFRLT",
  duration = "ADOSEDUR",
  doseu = "DOSEU"
)

intervals <-
  data.frame(
    start = 0, end = 24,
    ATPTREF = "DOSE1",
    auclast = TRUE,
    aucint.last = TRUE,
    clast.obs = TRUE,
    tlast = TRUE
  )


pknca_data_object <- PKNCA::PKNCAdata(
  data.conc = pknca_conc,
  data.dose = pknca_dose,
  intervals = intervals,
  options = list(
    auc.method = "lin up/log down",
    progress = FALSE,
    keep_interval_cols = "ATPTREF"
  ),
  impute = "start_conc0"
)
## Calculate the NCA parameters
results_obj <- as.data.frame(pk.nca(pknca_data_object))
print(results_obj)

If I run this code, AUCLast is 12.3 but AUCint is 20.1
In winlonlin, AUC 0 to 24 is 12.98.

Not sure what the reason for such a large difference is? Or which one is correct...
As far as I can tell I have followed the same method for both.

[billdenney]

It appears that WNL is reporting AUCall for the AUC0-24 since there are BLQ values starting at 12 hours in your dataset.

For the AUCint in PKNCA, PKNCA is interpolating between your two above limit of quantification measures at 7.59 and 24.654 hr. I think that this is a bug.

For "which one is correct", my opinion is that the answer is probably somewhere in between WNL and PKNCA's current behavior.

PKNCA's behavior should change in the following ways:

1. Be more dose-aware, and do not extrapolate over a dose with AUCint, unless the dose is within the interval (your dose occurs at 24.1 hr; so extrapolation should not use any data after that time, unless your interval were >24.1 hr)
2. If half-life is estimable, extrapolate using the half-life (this is currently done in other cases, but not the case here)
3. If half-life is not estimable, use AUCall

We can then use PPANMETH to clarify what method was used.