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posted by Helmut Homepage – Vienna, Austria, 2012-02-28 14:09 (3740 d 04:21 ago) – Posting: # 8180
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Dear Auditor!

» The suggested reference is not giving any clarity about endogenous product.


Since ergocalciferol (vitamin D2) is an endogenous substance, for both fasting and fed studies, the plasma concentrations of ergocalciferol should be corrected for baseline endogenous levels by subtracting the mean value of four pre-dose levels at -24, -16, -8 and 0 hour baseline time points from each subsequent ergocalciferol concentration obtained after dosing and used for all pharmacokinetic calculations. Any negative values obtained from baseline correction at time 0 hour, should be designated as zero (0) and any subject with pre-dose concentration more than 5% of their Cmax should be excluded from BE statistical analysis and the 90% confidence intervals based on the remaining subjects.

Endogenous compounds are drugs that are already present in the body either because the body produces them or they are present in the normal diet. Because these compounds are identical to the drug that is being administered, determining the amount of drug released from the dosage form and absorbed by each subject can be difficult. We recommend that applicants measure and approximate the baseline endogenous levels in blood (plasma) and subtract these levels from the total concentrations measured from each subject after the drug product has been administered. In this way, you can achieve an estimate of BE of the products. Depending on whether the endogenous compound is naturally produced by the body or is present in the diet, the recommended approaches for determining BE differ as follows:

For both of the approaches above, we recommend that you determine baseline concentrations for each dosing period that are period specific. If a baseline correction results in a negative plasma concentration value, the value should be set equal to 0 before calculating the baseline-corrected AUC. Pharmacokinetic and statistical analysis should be performed on both uncorrected and corrected data. Determination of BE should be based on the baseline-corrected data.

FDA’s approach (subtracting the mean of four baseline concentrations measured at -24, -16, -8, and 0 h in every period) is suitable only if the compound shows fairly low circadian variability and might have to be adapted for other compounds. If you have high circadian variability it might be necessary to sample a full baseline profile (as suggested in the EMA’s guideline):

For endogenous substances, the sampling schedule should allow characterisation of the endogenous baseline profile for each subject in each period. Often, a baseline is determined from 2-3 samples taken before the drug products are administered. In other cases, sampling at regular intervals throughout 1-2 day(s) prior to administration may be necessary in order to account for fluctuations in the endogenous baseline due to circadian rhythms.

I’m not sure whether it makes sense to sample baseline profiles prior to each treatment period if the shape of profiles is similar and only the level is variable. It might be sufficient to sample only one profile prior to the first treatment period and correct this concentrations by the pre-dose value in every treatment period. If no literature data on the circadian rhythm of the compound is available a pilot study is highly recommended.

Of course the 5% Cmax rule for exclusion is applicable to the baseline-corrected concentrations only.

Now for the forum-internals. Obviously you are not willing to comply with the Forum’s Policies. The team of moderators had to edit >75% of your posts (final warning here).
Once this thread is closed, I will block your account for four weeks.

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