I have a basic question relating to a plasma concentration time curve. I enter a plasma concentration time curve into Phoenix and stipulate a plasma concentration say 10 ng/mL at which point, when exceeded, there is a therapeutic response. I see the program presents the time the plasma concentrations are below this level and the time the plasma concentrations are above this level. I am reading the manual on page 36 concerning therapeutic response. The times appear to be OK.
For the profile I want to obtain the AUC for the concentrations under the stipulated threshold value for the profile and also the AUC when the concentrations are higher than this level. I cannot make sense of the values presented for AUC ‘high’ and ‘low’. They do not appear to be correct when I graph the profile and look at it. The AUC segment for less than 10 ng/mL “low” is too high.
I attach an example. I realize that this feature was part of the original WinNonlin, however, I never used it in those days. Am I trying to do something that the program does not do?
Or am I in error the way I am using the program incorrectly.
HI Angus, I haven’t had problems with this in the past myself so I would need to see your example, however for some reason I don’t see your attachment, can you please either edit your first post to attach it, or email it to me directly and i will do it for you.
Thanks Simon; I have rebooted the computer this morning now things are OK. Basically the AUC for the low zone (below the threshold) is OK, since when you add the AUC of the amount below the threshold to the AUC above the threshold then you get AUC0-t from the NCA. I had difficulty attaching the file as well, but i think I now do not need to.
I am looking at the flooding in Yorkshire; it seems the rain is exceeding the anticipated upper limits.
Glad you got it sorted, if not I had some test data to use from the monitoring station nearest my house! the previous level of 2.68m was set in 1866! Typical range is 1.44 to 1.90m, it got to somewhere around 3.28m
Apologies for the off topic but it was quite exciting here in Leeds over Christmas, this is the train viaduct crossing what is normally the main road from Kirkstall to Leeds!
Thankfully the levels have dropped to normal levels and although a lot of businesses suffered flooding there is very little residential property in the flood plain in my are area, although downstream some new city centre flats did suffer.
There is an analogy between the rain levels and what I am doing. My AUC question is resolved but I still have a question that I need to be sure about. Can I send out a profile by email?
For example let us take an actual example of amoxicillin. I know that often in the literature to maintain a specific concentration for 9.6 hours above the MIC threshold is the target concentration to achieve in order to eradicate the infection. Let us take an example of amoxicillin plasma concentrations that I have from a formulation (immediate release). The MIC of my microorganism is 0.4 micro-grams /mL. To my mind the threshold is this 0.4 micro grams/mL, since this is what we must exceed. Baseline is not in the picture for this example so it is not applicable. So I have not used this.
From what you describe you are trying to do it looks like you have it set up fine, e.g. your Tonset is reported as 0.06h i.e. less than 4 min. And Time_above_T gives you 8.53h
I’ve made a few cosmetive improvements that might be interesting to consider e.g. log for declining slope since is in fact PK Data. Also adding a reference line for MIC to the NCA plot
Thank you Simon I think this is a better example for other people to look at, since it is real data. The MIC threshold is a well know criterion for threshold for onset when reached. It is better defined than other PD endpoints. Yes; it could be merged as an explanatory example.
Amoxicillin is a good example that the AUC sometimes is of little importance in BE, and the Cmax of none. Guidelines are guidelines… I once had to deal with a major variation of a formulation which required a bridging BE study. After some discussions with one of the European authorities we agreed to look primarily at the “Occupancy Time” (i.e., the time above some threshold). AUC and Cmax were just reported. Liked it.
One point to note: PHX (and “classical” WNL as well) always interpolate the intersection of the target concentration between two ascending concentrations linear, and between two descending ones log-linear – independent from the trapezoidal method you might have selected. Of course this algo is consistent only for the lin-up/log-down method. Yet another good reason to make it your standard.
[hr]Skelly JP, Barr WH. Biopharmaceutic consideration in designing and evaluating novel drug delivery systems.Clin Res Pract Drug Reg Aff 1985:3;501–39.
In case you don’t have Jerome’s antique, a quote:
Occupancy Time
Where a therapeutic window exists, ‘Therapeutic Occupancy Time’, the time that the plasma concentration stays within the thera peu tic range, becomes an important criterion. In steady-state, the percentage of time the drug concentrations lies within the thera peutic window is important. In the cited example, the drug lies within the therapeutic window for the subject population about 80% of the time.
Amoxicillin, from what I recall has a very low volume of distribution and a huge amount of work has been done to come up with a definition of MIC for microorganisms as it applies to therapeutic effect. I recall about 9.6 hours of a dosing interval above the MIC for a given organism is needed for the clinical response over a period of time. I have difficulty applying the MIC concept to the PK_PD of other drugs where e.g. drug receptor interaction mechanisms are invoked, since there there is so much variability in PK and PD at the receptor level and clinical response to receptor occupancy. I am thinking that amoxicillin quite simply reacts chemically with the bacterial cell wall and causes cell death?
