jag009
★★★

NJ,
2013-09-09 21:12

Posting: # 11464
Views: 8,718

Hi guys,

If a blood draw has a time deviation which pushes it to overlap with the next blood draw time point, how do you deal with PK if you need to calculate partial AUC0-4?

3.5 hr blood draw has time deviation of +41 mins.
4 hr blood draw has time deviation of +2 mins.

John
Helmut
★★★

Vienna, Austria,
2013-09-13 00:55

@ jag009
Posting: # 11490
Views: 7,301

## A Nightmare on Elm Street

Hi John,

» It's not described on the protocol and CRO's SOP doesn't have this.

So in the protocol they simply copypasted from the guidance “AUC0-4, AUC4-t, AUC0-∞, and Cmax, where AUC0-4 is the area under the plasma-concentration vs. time curve from 0 to 4 hours, AUC4-t is area under the curve from 4 hours to the last measurable time point” without stating the algo? Brilliant. Which software are they using?

» They have the following:
» 3.5 hr with a time deviation of 45 mins; Reason - Restick
» 4 hr with a time deviation of 15 mins; Reason - Restick

Splendid. As you posted before I thought I have seen everything – but this?!

» The concentration values are different.

Sure. AP hits.

» How the hell do you tackle this??? Should I take the average of the two concentrations and use only the 4 hr time point?

The latter (OK, the second one at 4:15). Set the first one to “missing”, “not reportable“, or “oops”.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
jag009
★★★

NJ,
2013-09-13 15:26

@ Helmut
Posting: # 11491
Views: 7,251

## A Nightmare on Elm Street

» So in the protocol they simply copypasted from the guidance “AUC0-4, AUC4-t, AUC0-∞, and Cmax, where AUC0-4 is the area under the plasma-concentration vs. time curve from 0 to 4 hours, AUC4-t is area under the curve from 4 hours to the last measurable time point” without stating the algo? Brilliant. Which software are they using?

Exactly... Software wise I think they use both WinNonlin and SAS. I think they can do the interpolation by doing a protocol amendment? I have seen this before and FDA accepted it (not for partial AUC but for other things).
A lot of companies do this because they don't know whether their Kel elimination coding in SAS is "safe" so they need something that is officially validated.

» » They have the following:
» » 3.5 hr with a time deviation of 45 mins; Reason - Restick
» » 4 hr with a time deviation of 15 mins; Reason - Restick
»
» Splendid. As you posted before I thought I have seen everything – but this?!

YES! I told you I haven't seen EVERYTHING

» The latter (OK, the second one at 4:15). Set the first one to “missing”, “not reportable“, or “oops”.

Why the latter and not the first? If they have both samples and the numbers are different? I think they should take the average?

Thanks
John
Helmut
★★★

Vienna, Austria,
2013-09-13 16:00

@ jag009
Posting: # 11493
Views: 7,239

## A Nightmare on Elm Street

Hi John,

» Exactly... Software wise I think they use both WinNonlin and SAS. I think they can do the interpolation by doing a protocol amendment? I have seen this before and FDA accepted it (not for partial AUC but for other things).
» A lot of companies do this because they don't know whether their Kel elimination coding in SAS is "safe" so they need something that is officially validated.

Again: If you ask Phoenix/WinNonlin for partial AUCs they will be calculated up to/from the requested truncation time point – irrespective of time deviations (like in the plot above). I don’t think that you need an amendment.

» » The latter (OK, the second one at 4:15). Set the first one to “missing”, “not reportable“, or “oops”.
»
» Why the latter and not the first?

Gut feeling. I prefer a 15 min deviation over 45. I’m asking myself how they got two samples at the same time point. Two nurses sticking needles in the left and right arms of the subject competing on who finishes first?

» If they have both samples and the numbers are different?

Due to analytical variability the values are expected to be different.

» I think they should take the average?

Yes and no. Although the average should be more close to the “true value” you might open a can of worms. Some nitpicking assessor might tell you this value carries undue weight (since all other values are single determinations). Duno.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
jag009
★★★

NJ,
2013-09-13 19:57

@ Helmut
Posting: # 11496
Views: 7,173

## A Nightmare on Elm Street

Hi Helmut,

» » Why the latter and not the first?
»
» Gut feeling. I prefer a 15 min deviation over 45. I’m asking myself how they got two samples at the same time point. Two nurses sticking needles in the left and right arms of the subject competing on who finishes first?

Like Formula 1 GP. Photo finish... I don't know what they were thinking and I don't know why they persistent in collecting the 3.5 hr sample if they were unsuccessful after a few poke on the subject's arm...

John
jag009
★★★

NJ,
2013-09-10 16:13

@ Ohlbe
Posting: # 11470
Views: 7,366

## WTF ?

Hi Ohlbe,

» Unless the staff were kept busy by a serious adverse event and had more urgent things to do, I can't see how they managed to f... up that much. Even with a blocked canula they should be able to collect the sample via a fresh venipuncture. Or did they have no spare phlebotomist at hand ?
»
» OK, I know it doesn't help, sorry...

For 41 mins??? I still want to know how many holes they punched the poor subject with!

John
ElMaestro
★★★

Belgium?,
2013-09-10 18:31

@ jag009
Posting: # 11472
Views: 7,370

## monitor

Hi John,

» For 41 mins??? I still want to know how many holes they punched the poor subject with!

Did the monitor have any remarks in the report? Did (s)he visit on the day this happened?

I could be wrong, but...

Best regards,
ElMaestro

"Pass or fail" (D. Potvin et al., 2008)
jag009
★★★

NJ,
2013-09-10 22:48

@ ElMaestro
Posting: # 11473
Views: 7,333

## monitor

» » For 41 mins??? I still want to know how many holes they punched the poor subject with!
»
» Did the monitor have any remarks in the report? Did (s)he visit on the day this happened?

Waiting for their "explanation"... Study info to be released in upcoming weeks. So far the explanation is "restick". The clinic thought subjects were not hydrated adequately before dosing in Period 1 so they ask them to drink more the night before period 2. Problem solved? Sort of but nope, still had long time deivations...

In my opinion the subject should've been dropped. Its not ethical to keep on poking for blood for so long... It occured at 3.5-4 hr so the P.I. should've made a decision (A DOCTOR!)

John