Bioequivalence and Bioavailability Forum • PK profile outlier

avinash
★

India,
2013-05-02 16:48
(4409 d 07:45 ago)

Posting: # 10525
Views: 5,794

PK profile outlier [Bioanalytics]

Dear Members,

The following query is with regard to concentration profile:

In subject concentration profile there is a sudden increase in concentration of one sample in elimination phase which is not in line with the rest of the profiles.

Same sample was reanalyzed as a part of investigation and the results were not matching with initial analysis (difference was found to be 175%).

Please suggest how to handle this situation.

Thanks & Regards,
Avinash Jain

Edit: Subject line changed. [Helmut]

Helmut
★★★

Vienna, Austria,
2013-05-02 16:56
(4409 d 07:38 ago)

@ avinash
Posting: # 10526
Views: 4,850

IS response?

Post reply

Hi Avinash,

which regulatory agency is your “target”?

For the FDA and HPFB/TPD you can repeat a sample based on PK grounds and report the repeated value – if you have an SOP for the entire procedure.
Bad luck with EMA (and countries adapting its rules: Australia & New Zealand).

Did you compared the IS response of the original value with the repeat’s? If in the original analysis IS addition was incomplete, you will get a higher analyte/IS ratio → concentration.

—
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

avinash ★ India, 2013-05-02 17:09 (4409 d 07:24 ago) @ Helmut Posting: # 10527 Views: 4,843	IS response? Post reply
	Hi thanks for the reply. its for FDA submission. Best regards, Avinash

Helmut
★★★

Vienna, Austria,
2013-05-02 17:17
(4409 d 07:16 ago)

@ avinash
Posting: # 10528
Views: 4,939

DB Summary Table 9

Post reply

Hi Avinash!

❝ its for FDA submission.

OK, though FDA accepts PK repeats that doesn’t imply that they like it. I hope you have an SOP. Report the outcome in Table 9 (2013 version).

Other ideas:

Do you control the transfer volume(s) in your method? If yes, you could construct an external calibration curve (peak area instead of analyte/IR-ratio vs. concentrations). If the suspect value fits now into the PK profile you have some additional evidence that IS addition was not correct. Don’t forget that an IS only protects against errors in sample transfer – relying on the assumption of error-free IS addition. It’s always a good idea to transfer volumes as accurate as possible (like in an ES method). An IS is no excuse for sloppy work.
See also this old (and lengthy) thread.
You said the suspect value is in the elimination phase. If you have to deal with an FDA assessor who likes EMA’s GLs (note: FDA’s guidance is currently under revision), keep the original value for the calculation of AUC_t, but exclude it from the estimation of λ_z (→ AUC_∞). In the worst case exclude the subject from the AUC-assessment but keep him/her for the comparison of C_max.

—
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

AngusMcLean ★★ USA, 2013-05-15 02:38 (4396 d 21:55 ago) @ Helmut Posting: # 10584 Views: 4,672	DB Summary Table 9 Post reply
	Pharmacokinetic outlier I think it is important to have an SOP in place and issued prior to running the study. It should be defined what the criteria are for identifying a "pharmacokinetic outlier" and repeat of the assay. The repeat data should be examined in accord with the lab. SOP for accepting and rejecting repeat assays. The FDA will review above. Angus