Issue with timing of change of time-varying variable (not related to nocb=T option)

[ssancheGH]

Hi,

I noticed an issue with the package (version 1.0.6). This concerns time-varying parameters/covariates (not related to the nocb option).

In dset (see attached image), ETA_F1_IOV is an interoccasion variability transformed into F_DEPOT for each dosing occasion using the .cpp equations. You can see from dset that the bioavailability parameter is meant to change at 168.0167 (then at 336.0, 504.0167, etc).

I then simulated concentrations using:
sdata.frame <- mod %>%
data_set(dset) %>%
idata_set(iparams) %>%
Req(CP,PPI,PctPPI,KA,F_DEPOT,DOSN) %>%
mrgsim_df(end=2000, nocb=F,delta=0.05)

The issue: I compared simulation outputs between NONMEM and mrgsolve and there was no match. After simulating and outputting the bioavailability values at the different time points, you can notice that F_DEPOT changes from 0.3518 to 0.4151 after 168.0167.

So the timing of the ETA_F1_IOV change is slightly off. It may not be an issue for most time-varying variables, but the timing of the change is quite important for bioavailability because I understand the total amount of absorbed drug is determined from the bioavailability at the time of dose administration. I solved the issue by adding 0 doses just before the timing of new doses and changing ETA_F1_IOV at that point (see attached). This resulted in a match between mrgsolve and NONMEM outputs.

Do you have enough information to fix the issue? Let me know!
Steven Sanche (PhD)
Associate Director IDD, Certara Inc.

[kylebaron]

Hi @ssancheGH -

Thanks for reaching out. If you could create a reproducible example for this that I could run with you, I could definitely look into this.

We do have tests for time-varying covariates here
https://github.com/mrgsolve/nmtests/blob/master/time-varying/time-varying-vignette.md

This test looks at time-varying covariates on disposition parameters.

I did open up an issue earlier that looked at how time-varying covariates should affect dosing events (like your example):
#808

At the end of that, I still couldn't tell if there was a problem or not and haven't had time to dig into it. I think if you can give me a minimal example that runs under NONMEM and mrgsolve it could give us a place to dig in and figure it out.

Thanks!
Kyle