# Divergent transitions in PK models

#21

Rate = -2 is a NONMEM convention, allowing you to specify in the model, rather than the data, the rate/duration

Rate = -1 means it will expect a hard-coded rate
Rate = -2 means look to a hard coded duration

so you can specify `D_<CMT>` = 1 which is interpreted as, give a 1 hour infusion for all amounts specied to that particular compartment. This isn’t terribly hard to calculate in this day and age, so (potentially) may not be needed in stan, but it can be nice when you have a consistent clinical guidance, and don’t have to go through the motion of df %>% mutate(RATE = AMT/inf_length)

#22

nice. I can provide a more expansive “real” .dataset for you to chew on. Obviously can’t share the real data online, bu maybe we should discuss offline. I’d spoken with Charles about a nonmem vs stan comparison, with a combination of simulated scenarios (know the truth) and real data (see where/if there are differences). We should talk a little offline to figure out if we can get a data sharing agreement in place.

#23

Rate = -2 is a NONMEM convention, allowing you to specify in the model, rather than the data, the rate/duration

Rate = -1 means it will expect a hard-coded rate
Rate = -2 means look to a hard coded duration

Thanks for the details on NONMEM. Torsten currently works in the Rate = -1 regime. You can always specify a rate when you hand-code an ODE system in the functions block or a constant rate matrix. Less flexibility when you call a built-in analytical solution.

#24

I assume that amt=30 and rate=-2 in csv means unknown duration. Is this
feature included in torsten? NONMEM suggests to model it as a random effect
around nominal duration. Are there any better approaches?

#25

Yes it could be estimated, both with or without a random effect, but does not have to. This can be valuable when you want to fit, for example, a zero-order process, so you can just provide the amount you are aware will enter the system and the profile and let the duration be sorted out to optimize the fit. For complex absorption processes such as tablets with release profiles or intramuscular injections this is a great way to estimate such processes. In such cases, as NONMEM suggests, estimating both a nominal duration with a random effect can be valuable, however if there isn’t that much information about the absorption process sometimes this is not feasible and you can only use a fixed effect (though STAN it would probably be reasonable to apply a reasonable prior based on physiochemical/in vitro characteristics, given it is more flexible than nonmem)

or like in this case with Vanco, everyone just gives a 1 hour infusion, do rather than calculating the rates for each individual, it can just be hard coded.

The rule of thumb will generally come back to physiology and mechanistic plausibility. If you have a intramuscular injection that is injected in the glute for lipophilic (fat loving) compound, it stands to reason that you could have gender differences, and will almost certainly have differences between patients based on their body composition near the injection site. A morbidly obese woman (women have slightly higher fat contents) vs an athletic man could have drastically difference release profiles. On the flip side, some new microsphere formulations are really good for controlled release that don’t vary much between patients (maybe only 10%), in that case, having no random effect would be a reasonably simplification.

#26

Here is a profile for 422. I didn’t expect it to be so good. I have assumed
IV duration of 1h, 1cmp. Brown lines denote the start of IV, red circles -
actual observations, green - median of true conc, blue - 95% CI of true
conc. I suspect it will be even better after modeling of correlation
between parameters - it looks like there is a correlation between cl and
egfr. I used additive error model - perhaps this could be improved as well.
Not sure if duration should have a random effect - still didn’t grasp how
to incorporate it.

Should we talk offline to fit more patients?

#27

good job! A couple things:

1. the error model is best to be multiplicative/proportional for concentration data. Generally such constant CV residual error models are appropriate for concentration-time data. For individual fits, you can generally ‘get away’ with additive, since the range for this individual, however the misspecification of the residual error model will become very visible over larger concentration ranges. This can be inspected by looking at residuals vs predicted concentration. If you see a fanning pattern (larger magnitude of residuals for higher concs) you’ll definitely know you need proportional error model.

When you can have concentrations near the lower limit of quantitation (LLOQ) then it can also be helpful to also have some additive component to allow the model to stabilize. Else the constant CV error model will have problems as even slight misses between predicted/observed can cause issues. I am not sure how to code such a model in STAN

in nonmem it is basically

Y = IPRED*(1 + PROP_ERROR) + ADD_ERROR where the error is specified as a normal distribution with mean 0 and variance PROP_ERROR/ADD_ERROR

so it will be something like 0.2-0.3 for prop error and add_error around the value of the LLOQ (so like 1 mg/L in this case).

perhaps @Bob_Carpenter or others can provide insight for how to appropriately handle such a residual error model. (and again apologize for my lack of formal statistical specifications/equations).

1. With regards to correlation, yes there is massive correlation between egfr and CL - thats baked into the equation for CL - thats also we use hierarchical modeling, such prognostic factors can effectively guide what the likely range of CL for a patient will be, before collecting any data.

shoot me an email at devin (dot) pastoor (at) gmail.com and we can look at figuring out some more real datasets and get the results on github where it will be easier to share and discuss the models/outputs.

#28

stan handles well add+proportional error (as in nonmem):

Maybe it would be of interest to forum how to handle uncertain durations.

#29