auditor
★

India,
2012-02-28 08:59
(3395 d 23:00 ago)

Posting: # 8173
Views: 8,000

## Pre dose concentration [Regulatives / Guidelines]

Dear All,

As per recent EU guideline for BA/BE, clear statement given for not to withdraw any subject in which >5% Cmax concentration observed after dosing endogenous molecule.

I am looking for such kind of clarity in US FDA guidance. Can any one please let me know is the same thing can be followed in US submission?

Regards,

Auditor
drgunasakaran1
★★

2012-02-28 11:36
(3395 d 20:23 ago)

(edited by drgunasakaran1 on 2012-02-28 12:11)
@ auditor
Posting: # 8174
Views: 7,279

## Pre dose concentration

Dear Mr.Auditor,

As per FDA's Individual Product Bioequivalence Recommendation for Ergocalciferol, an endogenous substance, any subject with pre-dose concentration more than 5% of their Cmax should be excluded from BE statistical analysis.

Dr S Gunasakaran MBBS MD
Disclaimer: The replies/posts are my personal opinions and it does not represent my company views on the same.
d_labes
★★★

Berlin, Germany,
2012-02-28 12:03
(3395 d 19:56 ago)

@ auditor
Posting: # 8176
Views: 7,230

Dear Auditor,

did you read the FDA guidances?

Guidance for Industry
"Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations" 2003
page 25 of 26
Heading "Subjects with predose plasma concentrations:"

Or search the Forum and you would find this post and others.

Regards,

Detlew
auditor
★

India,
2012-02-28 12:08
(3395 d 19:51 ago)

@ d_labes
Posting: # 8178
Views: 7,239

The suggested reference is not giving any clarity about endogenous product. Please again read my post as clearly mentioned about reference for endogenous product.

d_labes
★★★

Berlin, Germany,
2012-02-28 12:49
(3395 d 19:10 ago)

@ auditor
Posting: # 8179
Views: 7,251

## Sorry

Dear Auditor,

» The suggested reference is not giving any clarity about endogenous product. Please again read my post as clearly mentioned about reference for endogenous product.

Mea culpa

Regards,

Detlew
Helmut
★★★

Vienna, Austria,
2012-02-28 14:09
(3395 d 17:50 ago)

@ auditor
Posting: # 8180
Views: 7,310

Dear Auditor!

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

No‽

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.

Appendix
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:

• When the body produces the compound, we recommend that you measure multiple baseline concentrations in the time period before administration of the study drug and subtract the baseline in an appropriate manner consistent with the pharmacokinetic properties of the drug.
• In addition, when there is dietary intake of the compound, we recommend that you strictly control the intake both before and during the study. Subjects should be housed at a clinic before the study and served standardized meals containing an amount of the compound similar to that in the meals to be served on the pharmacokinetic sampling day.

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.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
d_labes
★★★

Berlin, Germany,
2012-02-28 16:40
(3395 d 15:19 ago)

@ Helmut
Posting: # 8181
Views: 7,354

## 5% Cmax rule and endogenous drugs - EMA

Dear Helmut!

Full ACK with all your points.
But one doubt:

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

Seems there is an ambiguity in the EMA guidance. On page 15 of 27 under the heading Carry-over effects it is stated:
"... If there are any subjects for whom the pre-dose concentration is greater than 5 percent of the Cmax value for the subject in that period ... ...
This approach does not apply to endogenous drugs."

It is not quite clear for me if they talk there about the original concentrations only. Common sense would tell us yes.
But it's not always common sense what characterizes the guideline .

Regards,

Detlew
Helmut
★★★

Vienna, Austria,
2012-02-28 17:18
(3395 d 14:41 ago)

@ d_labes
Posting: # 8182
Views: 7,300

## My interpretation + (lenghty) example

Dear Detlew!

» Seems there is an ambiguity in the EMA guidance. On page 15 of 27 under the heading Carry-over effects it is stated:
» "... If there are any subjects for whom the pre-dose concentration is greater than 5 percent of the Cmax value for the subject in that period ... ...
» This approach does not apply to endogenous drugs."
»
» It is not quite clear for me if they talk there about the original concentrations only. Common sense would tell us yes.
» But it's not always common sense what characterizes the guideline .

Right. My common-sense-interpretion is: “This approach [= excluding subjects with measured pre-dose concentrations of >5% before baseline-correction] does not apply to endogenous drugs.”

“In bioequivalence studies with endogenous substances, it cannot be directly assessed whether carryover has occurred, so extra care should be taken to ensure that the washout period is of an adequate duration.”

It can’t?
OK, directly = uncorrected; IMHO this implies that it can be done indirectly = corrected (see also the FDA’s guidance).

Example:
Averaged pre-dose 30 ng/mL, Cmax of endogenous profile 200 ng/mL, theoretical Cmax after dosing 100 ng/mL. Note that the pre-dose is already 15% of the blank profile’s Cmax. Following the naïve/savage assumption1 that the shape of the blank profile is similar to the (theoretical) one after administration, we measure a Cmax of 300 ng/mL and estimate the pre-dose with 0 and Cmax with 270 ng/mL (simple correction); following the logic of excluding subjects with uncorrected pre-dose values of >5% Cmax we would have to exclude many (all?) subjects, since 30 ng/mL = 10% of 200+100 ng/mL. Thus it does not make (common-)sense to deal with uncorrected data.
Let’s go further: Theoretical Cmax of the reference 100 ng/mL and of the test 90 ng/mL (T/R 90%). We measure 300 ng/mL (R) / 290 ng/mL (T) and estimate Cmax 270 ng/mL (R) / 260 ng/mL (T). Our T/R ratio will be 96.3% instead of the correct 90%: the method is not sensitive to detect true differences between formulations. In such a case it is mandatory to subtract a complete profile.

Another pitfall: We have to test the most sensitive dose.2 With endogenous compounds we may experience nasty feedback-loops! The highest dose may downregulate the system or rocket it to a nonlinear state…

1. Endogenous compounds can be quite complicated: (sometimes distorted) sinusoidals and/or flip-flop PK depending on prandial state.
2. GL, p.11: “If a separation in exposure following administration of different doses of a particular endogenous substance has not been previously established this should be demonstrated, either in a pilot study or as part of the pivotal bioequivalence study using different doses of the reference formulation, in order to ensure that the dose used for the bioequivalence comparison is sensitive to detect potential differences between formulations.”

Not for an initiate like you, but the archive.
Green line: sinusoidal baseline + release of endogenous compound triggered by food (depending on caloric content) at 4, 9, and 13 h post dose (Cmax 200, tmax 5.7 h). Thin black lines show the model’s components.
Red line: theoretical PK after administration (Cmax 100, tmax 3 h, t½ 5.78 h).
Blue line: measured total concentration (Cmax 285, tmax 5.4 h, t½ ??).

That’s nasty. The theoretical Cmax is 50% of the baseline, the AUC 52%, and the tmax occurs 2.7 h earlier.

Now let’s see. Pre-doses are 30, the concentrations at -8 152 and at -16 166. Mean 94.4.

If we subtract only the pre-dose we get the pink line. Note the increasing profile after 23 h.
If we subtract the mean we get the gray line. Oh, a lag-time!
Only if we subtract the entire blank profile we get the ‘true’ values.
Note the bias in Cmax and AUC, the shifted tmax, and the crazy t½:
         -blank    -mean   -profile   theoret. Cmax      255.2     190.8     100.0     100.0 tmax        5.4       5.4       3.0       3.0 AUCt     2522.3    1430.3    1108.8    1108.9 t½          0.14      0.13      5.77      5.78 AUC∞     2524.3    1430.3    1188.6    1188.8

Lesson learned: Never follow simple methods if you don’t understand the PK of the drug.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
d_labes
★★★

Berlin, Germany,
2012-02-29 08:33
(3394 d 23:26 ago)

@ Helmut
Posting: # 8184
Views: 7,119

## Well done!

Dear Helmut!

» Lesson learned: Never follow simple methods if you don’t understand the PK of the drug.

That's really a Sundays exhortation ("Wort zum Sonntag"). SCNR.

Regards,

Detlew
Helmut
★★★

Vienna, Austria,
2012-02-29 14:19
(3394 d 17:40 ago)

@ d_labes
Posting: # 8189
Views: 7,098

Dear Detlew!

» That's really a Sundays exhortation ("Wort zum Sonntag"). SCNR.

Well, I’ve seen such crazy profiles in the – not so remote – past. Can you guess the country of origin? Add some scatter and .
In the log-plots an amazing mixture of convex phases and increasing values. Some self-appointed ‘experts’ extrapolated anyhow (excluding data-points they didn’t like, t½-ranges of 0.1 – 8 h). In all these studies naïve subtraction was applied.

You can’t fix by analysis
what you bungled by design.
Richard J. Light, Judith D. Singer, John B. Willett

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes