Recently I have been asked to look into the generation of a "NCA best practices" document for clinical PK analysis. This seems to be a tricky subject, as most of the time the analysis is very subjective, with the need to be looked at on a case-by-case basis. Nevertheless we would like to have a uniform best-practices starting ground to work from. The best practices NCA would be applied to biologics (mAbs, ADCs, etc) and small molecules.
I was wondering if you might be able to provide any input, or if you may happen to have any reference documents you could share with me to assist in my endeavor.
Some of the items I was considering to possibly include are described below:
1) Rsq < 0.80, HL lambda Z is excluded.
2) %extrapolation of AUCinf >20 is excluded.
3) At least 3 timepoints in the terminal phase (not including cmax) to calculated HL lambda Z.
4) Actual timepoint differences from nominal , >30% are excluded (not sure about this rule, in my past experience we followed this rule, but currently we have a much less stringent criteria of 200% or so, because we do not want to exclude observations, what do you typically apply).
5) Actual dose differences from nominal , >30% are excluded.
6) Outlier exclusion test for NCA parameters, exclude extreme statistical outliers, defined as those records outside the range of (first quartile -3.0X interquartile range, third quartile +3.0X interquartile range), where interquartile range is calculated using individual patient parameter values stratified by treatment arm.
7) The test described above is great at catching outliers whose records are >3.0X IQR, but is not good at capturing <3.0X IQR, because the lower limit is usually negative, as such we usually may exclude individuals with extremely poor exposure due to X rationale, for example (AUCinf <40X the median) etc.
8) pre-dose positive samples (prior to the first dose) are usually excluded from the analysis.
What is your take on the criteria, are there any other items that are worthy of mentioning, or things you agree with or disagree with, or what general guidance do you follow for clinical PK analysis?
Not sure if there are any colleagues working in any regulatory setting, but if so, what are the health authorities typically looking for? Would appreciate any comments.
Thanks greatly for your assistance.
Edited by csheme, 16 January 2018 - 05:37 PM.