Bioequivalence and Bioavailability Forum • 0 hr Pre-dose concentration but less than 5% of Cmax

jag009
★★★

NJ,
2012-03-29 21:34
(4805 d 08:06 ago)

Posting: # 8349
Views: 12,168

0 hr Pre-dose concentration but less than 5% of Cmax [Regulatives / Guidelines]

Hi everyone,

Regarding the FDA guidance on pre-dose concentration:

"If the predose concentration is less than or equal to 5 percent of Cmax value in that subject, the subjects data without any adjustments can be included in all pharmacokinetic measurements and calculations. If the predose value is greater than 5 percent of Cmax, the subject should be dropped from all BE study evaluations."

What if a subject has a pre-dose concentration in period 1? Should the subject still be kept or needs to be removed since he shouldn't have any pre-dose concentration in period 1.

Clinic shows no deviations and data was reviewed.

Thanks

John

Helmut
★★★

Vienna, Austria,
2012-03-29 21:50
(4805 d 07:50 ago)

@ jag009
Posting: # 8350
Views: 10,996

0 hr Pre-dose concentration but less than 5% of Cmax

Post reply

Dear John!

❝ What if a subject has a pre-dose concentration in period 1? Should the subject still be kept or needs to be removed since he shouldn't have any pre-dose concentration in period 1.

❝

❝ Clinic shows no deviations and data was reviewed.

Shit happens. But:

The guidance does not distinguish between period 1 and the others. Though you are right that pre-dose values in period 1 are less likely (carry-over due to too short wash-out are possible in higher ones).
If you have an SOP for pharmacokinetic repeats in place perform a reanalysis. Maybe the value will not be confirmed.
Remember the requirements for testing interferences in method validation: none out of six independent sources of matrix. If 0/6 is OK does that imply that 1/7 is OK as well? In other words even if your method was validated – in a large study you may see interferences. Keep the subject.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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

jag009
★★★

NJ,
2012-03-29 22:10
(4805 d 07:31 ago)

@ Helmut
Posting: # 8351
Views: 10,986

0 hr Pre-dose concentration but less than 5% of Cmax

Post reply

Thanks Helmut

❝ Shit happens. But:

The guidance does not distinguish between period 1 and the others. Though you are right that pre-dose values in period 1 are less likely (carry-over due to too short wash-out are possible in higher ones).
❝
If you have an SOP for pharmacokinetic repeats in place perform a reanalysis. Maybe the value will not be confirmed.
❝
Remember the requirements for testing interferences in method validation: none out of six independent sources of matrix. If 0/6 is OK does that imply that 1/7 is OK as well? In other words even if your method was validated – in a large study you may see interferences. Keep the subject.

That's what I thought as well (Keeping the subject) since the guidance just stated the 5% rule but nothing about period 1 or period n.

John

Helmut
★★★

Vienna, Austria,
2012-03-30 01:17
(4805 d 04:23 ago)

@ jag009
Posting: # 8352
Views: 10,984

Reanalysis if possible

Post reply

Dear John!

❝ That's what I thought as well (Keeping the subject) since the guidance just stated the 5% rule but nothing about period 1 or period n.

OK, but if ever possible perform a reanalysis in duplicate. If the value was not too far away from the LLOQ it may have been pure chance as well.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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

jag009
★★★

NJ,
2012-03-30 17:06
(4804 d 12:34 ago)

@ Helmut
Posting: # 8354
Views: 10,872

Reanalysis if possible

Post reply

Hi Helmut,

❝ OK, but if ever possible perform a reanalysis in duplicate. If the value was not too far away from the LLOQ it may have been pure chance as well.

Thanks. Yes the lab did reanalysis and came to the same conclusion (as per their SOP). It's just kind of strange to see value at 0 on period 1 that's all.

Have you seen CROs which go the full length and pre-screen subjects for exposure to the study drug prior to the first dosing day?

Thanks

John

Helmut
★★★

Vienna, Austria,
2012-03-30 17:16
(4804 d 12:25 ago)

@ jag009
Posting: # 8355
Views: 10,879

>6 sources of matrix

Post reply

Dear John!

❝ Yes the lab did reanalysis and came to the same conclusion (as per their SOP). It's just kind of strange to see value at 0 on period 1 that's all.

OK, at least you know now that it wasn’t pure chance but at true interference.

❝ Have you seen CROs which go the full length and pre-screen subjects for exposure to the study drug prior to the first dosing day?

Only once (in 30+ years) – drug was Δ⁹-THC. :smoke:

Another time I came across a very difficult ligand-binding assay where matrix effects were common. During method development the CRO screened ~60 subjects and in validation another 30.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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

jag009 ★★★ NJ, 2012-03-30 22:40 (4804 d 07:01 ago) @ Helmut Posting: # 8360 Views: 10,975	>6 sources of matrix Post reply
	Hi Helmut ❝ Only once (in 30+ years) – drug was Δ⁹-THC. ❝ Another time I came across a very difficult ligand-binding assay where matrix effects were common. During method development the CRO screened ~60 subjects and in validation another 30. Haha, figures! Don't tell me you ran the study in Amsterdam John

Helmut ★★★ Vienna, Austria, 2012-03-31 02:23 (4804 d 03:17 ago) @ jag009 Posting: # 8362 Views: 10,842	>6 sources of matrix Post reply
	Hi John! ❝ ❝ […] drug was Δ⁹-THC. ❝ Haha, figures! Don't tell me you ran the study in Amsterdam Austrian volunteers are also a funny bunch. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes

jag009
★★★

NJ,
2012-04-04 18:32
(4799 d 11:08 ago)

@ Helmut
Posting: # 8382
Views: 10,754

>6 sources of matrix

Post reply

Hi Helmut,

❝ ❝ Yes the lab did reanalysis and came to the same conclusion (as per their SOP). It's just kind of strange to see value at 0 on period 1 that's all.

❝

❝ OK, at least you know now that it wasn’t pure chance but at true interference.

This just popped into my head (flashback... Nightmare, whatever you called it)...

Should the lab adjust the concentration profile to remove the residual levels caused by the pre-dose concentration???? ie. using the t1/2 and determine the amount of pre-dose concentration remaining throughout the timepoints and subtract it from the respective concentrations.

I remember one lab doing this and they said it's part of their SOP...

Thanks

John

Helmut
★★★

Vienna, Austria,
2012-04-05 18:10
(4798 d 11:30 ago)

@ jag009
Posting: # 8386
Views: 10,942

Flashback

Post reply

Hi John!

❝ This just popped into my head (flashback... Nightmare, whatever you called it)...

For me – flashback. We performed a pilot study of a drug with a nice average [sic] half-life of ~50 hours, sampling up to 216 hours (since truncated AUC wasn’t common at that time), washout 2 weeks. No predose concentrations… The pivotal was a 6×3 in 36 subjects, but:

only ½ of the dose of the pilot was administered and
the LLOQ of analytical method was improved by a factor of 9 [sic].

Result: We measured pre-dose values (maximum 7.8% of C_max) in 54% of samples of periods 2 & 3 (none in period 1). Since we had a blinded plausibility review in place we were able to come up with a statistical amendment while analytics were still running:

Primary analysis based on period 1’s data as a parallel design. The sponsor had too much money – so the cross-over was extremely overpowered. The total CV was quite low and we expected still ~75% power. Since no pretesting (sequence or unequal carry-over) was done (Grizzle’s flawed method), the patient’s risk was not compromised.
Exploratory 1: Ignoring the carry-over and performing the comparison as originally planned. Nowadays we would go a similar track: 86% of the subjects with pre-dose values <5% would stay in the analysis.
Exploratory 2: Estimating λ_z not only from data of the respective treatment, but including the pre-dose value of the next period. Subtracting estimated concentrations of the next period from measured ones.

Results:

Confirmatory: AUC passed, upper limit of C_max failed.
Exploratory 1 & 2: AUC and C_max passed easily.

Lessons learned: Never base the washout on mean-values (large studies not even on x±SD) and think twice if you improve the analytical method too much. ;-)

P.S.: The product was approved based on this study in the EU in 2002 and by the FDA in 2003.

❝ Should the lab adjust the concentration profile to remove the residual levels caused by the pre-dose concentration???? ie. using the t1/2 and determine the amount of pre-dose concentration remaining throughout the timepoints and subtract it from the respective concentrations.

See above. I cannot imaging that any regulatory agency would accept this (any more).

❝ I remember one lab doing this and they said it's part of their SOP...

Referring to an SOP is alway the worst (pseudo-)justification I can think of.

“Hey, let’s jump from the cliff!” Lemming’s SOP

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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

jag009
★★★

NJ,
2012-04-05 19:51
(4798 d 09:50 ago)

@ Helmut
Posting: # 8388
Views: 10,624

Flashback

Post reply

Hi Helmut,

❝ ❝ Should the lab adjust the concentration profile to remove the residual levels caused by the pre-dose concentration???? ie. using the t1/2 and determine the amount of pre-dose concentration remaining throughout the timepoints and subtract it from the respective concentrations.

❝

❝ See above. I cannot imaging that any regulatory agency would accept this (any more).

Question, can the pre-dose (0 hr) concentration be set to 0 if it is less than 5% of Cmax? FDA that is...

Thanks

John

Helmut
★★★

Vienna, Austria,
2012-04-05 20:08
(4798 d 09:32 ago)

@ jag009
Posting: # 8390
Views: 10,748

No correction if ≤5% Cmax

Post reply

Hi John!

❝ […] can the pre-dose (0 hr) concentration be set to 0 if it is less than 5% of Cmax? FDA that is...

Can? Technically, yes. But I wouldn’t recommend it (see the [image]

2003 guidance):

If the predose concentration is ≤ 5 percent of C_max value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements and calculations.

(my emphasis; interpreting “can” as “should”…)

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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

navoday
☆

India,
2012-08-15 22:37
(4666 d 07:03 ago)

@ Helmut
Posting: # 9070
Views: 10,128

No correction if ≤5% Cmax

Post reply

❝ ❝ […] can the pre-dose (0 hr) concentration be set to 0 if it is less than 5% of Cmax? FDA that is...

Dear Helmut...

wishing you and all members of forum a very happy independence day (india)

should we submit statistical data with inclusion and exclusion of that subject having predose concentration more than 5% of C_max or simply delete that subject from all analysis? what if study is partial replicate (3WSABE)and that subject has completed TR sequence? as it may help for estimating t1/2 and tmax if average bioequivalence is there.

Helmut
★★★

Vienna, Austria,
2012-08-16 18:36
(4665 d 11:05 ago)

@ navoday
Posting: # 9073
Views: 10,191

excluded period(s)

Post reply

Hi Navoday!

❝ should we submit statistical data with inclusion and exclusion of that subject having predose concentration more than 5% of C_max or simply delete that subject from all analysis?

Even complying with the guidance I always state the planned procedure in the protocol. I report the PK data (in order to give the assessor a mean to check them) but exclude the subject in a 2×2 cross-over from comparative assessments. If the pre-dose concentration is observed not in all periods and the study is either a replicate or a higher-order cross-over, I proceed as following:

Replicate: Keep the data if at least one period after test and reference is available and the study is analyzed by mixed effects model.
Higher-order (e.g., one tests and two references): If the pre-dose concentration is observed after one of the references, keep the other data.

❝ what if study is partial replicate (3WSABE)and that subject has completed TR sequence? as it may help for estimating t1/2 and tmax if average bioequivalence is there.

Since according to the FDA a partial replicate has to be analyzed by SAS Proc GLM (or similar) IMHO all data of the subject will be dropped from the analysis (even if you observe a pre-dose concentration in just one period).

❝ as it may help for estimating t1/2 and tmax if average bioequivalence is there.

Don’t understand what you mean here. :confused:

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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

rajasekharkakarla
☆

India,
2019-09-20 09:57
(2074 d 19:44 ago)

@ Helmut
Posting: # 20630
Views: 5,810

excluded period(s)

Post reply

Hi Helmut sir!

❝ Since according to the FDA a partial replicate has to be analyzed by SAS Proc GLM (or similar) IMHO all data of the subject will be dropped from the analysis (even if you observe a pre-dose concentration in just one period).

if we get the Swr less than 0.294 then we need to go for ABE approach in that can can we include those subjects in ABE calculation if subject completed 1 test and 1 reference treatment period.

what about in case of fully replicated designs, if we got the 5 % cmax in 4th period with 2 reference periods completed or one Test and Reference treatment period completed.

please help me..