ssk
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2006-08-12 17:01

Posting: # 206
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 water restriction before and after dosing [Regulatives / Guidelines]

why is there water restriction before and after dosing in a BA/BE study.why is only 240 ml of water is used during dosing
Helmut
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2006-08-12 18:21

@ ssk
Posting: # 207
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 water restriction before and after dosing

Hello ssk!

One of the main assumptions in a cross-over setting are constant clearances within study periods.
We have for the two treatments: (F1 × AUC1) / (D1 × CL1) and (F2 × AUC2) / (D2 × CL2), where

F  : Fraction absorbed
AUC: Area under the curve
D  : Dose
CL : Clearance

The indices are referring to treatments 1 and 2.

Now we may calculate
Frel(BA) = AUC1 / AUC2
only if we assume
D1 = D2 (or perform a dose correction, which is possible according to some guidelines (e.g., WHO, Canada),
and
CL1 = CL2.
The second assumption is the tricky one, because we can only try to achieve that by standardization accross treatment periods (nutrition, fluid intake, posture, physical activities, …).

The 240 ml (or 237 ml to be precise) originate from the ‘American standard cup’ which contains 8 fluid ounces (US). In other parts of the world less fluid is standard. I never heard of somebody trying to administer the study drugs together with more than 240 ml in a BE study (since this volume already troubles some subjects).
If I remember it correctly, the half life of water in the stomach is about 10 minutes, so it doesn't make a big difference anyhow.

The BCS assumes 250 ml as the standard volume for dissolution (which may be quite optimistic…).

Standardization of fluid intake pre-dose and post-dose is an attempt to keep the 'fluid-load' within periods level.
Published guidelines use almost identical wording to justify fluid restrictions. You may have a look at the Guidelines Page and a previous thread.

Cheers,
Helmut Schütz
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ssk
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2006-08-13 16:51

@ Helmut
Posting: # 208
Views: 10,114
 

 water restriction before and after dosing

hello sir,
Thanks for the reply. But I still couldn't understand the need for water restriction before and after dosing. If you can elaborate the answer or suggest some internet sites for this I will be grateful to you.
Thanking you,
ssk
Helmut
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2006-08-13 19:13

@ ssk
Posting: # 209
Views: 10,088
 

 water restriction before and after dosing

Hello ssk,

let’s put it the other way ’round. Why do you think water consumption will not influence BA?
Since you have posted in the category Regulatives / Guidelines and standardized fluid consumption is mentioned in virtually all guidelines, you should have strong arguments if you want to act against them.

Cheers,
Helmut Schütz
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drks
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2006-08-19 09:18

@ Helmut
Posting: # 227
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 water restriction before and after dosing

What will be the effect on the pharmacokinetic front if a particular subject was administered with only 230 ml of water in one period however, in another one, he was given 240 ml water. should this make significant difference in the bioequivalence estimation of the test formulation?
Please suggest...

thanks and regards
Kshitij


Please avoid full quotes and delete not required text. [Helmut]
Helmut
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2006-08-19 12:45

@ drks
Posting: # 228
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 water restriction before and after dosing

Hello Kshitij!

» What will be the effect on the pharmacokinetic front if a particular subject was administered with only 230 ml of water in one period however, in another one, he was given 240 ml water. should this make significant difference in the bioequivalence estimation of the test formulation?

I know the solvent front in thin layer chromatography, but what's the pharmacokinetic front? ;-)

OK, that’s a 4.2% difference in fluid volume. I would not bother a second about this! The main purpose of the fluid is not to supply a solvent in the stomach – which will be ‘gone’ within a short period of time anyway – but to get the formulations without problems down the throat (prevent sticking somwhere in the esophagus). If you watched it, make a note in the subject's CRF, and continue as usual (maybe you can try to convince the subject to swallow the remaining 10 ml as well).

The main assumption in a cross-over study for BE are constant clearances throughout treatment periods (for assumptions see this post); we have no means to verify this assumption anyway. So your difference in fluid volume may simply add just a little variability to the within-subject error.

If you find a real large difference in PK responses between occasions (statistical significant outlier), according to almost all guidelines you have the possibility to exclude the subject from the evaluation (because you are able to give a clinical explanation). As always, don’t forget to make such a statement a priori in the protocol.

Cheers,
Helmut Schütz
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Dr.Tarak Parikh
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India,
2007-04-06 09:27

@ Helmut
Posting: # 640
Views: 9,720
 

 water restriction before and after dosing

Dear,
I am totally agree with HS. I would like to appreciate his advise.
now the question was why 1 hr before dosing and 1 hr after dosing water restriction.
so in my opinion, as per pharmacokinetic and what we learned in medicine, water will do the distention of stomach which results in increase in surface area and thats why increases the absorption.

To maintain similarity guideline says only 240 ml of water should be given at the time of dosing. but if it is given less, then you have to mention protocol deviation and just to evaluate the PK parameters afterwards.from my experience i can tell you it will not hamper ur study results.

still que is there why only 240ml???

other wise i am agree with all.

regards
Dr.Tarak Parikh
MD,Physician
Helmut
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2007-04-06 15:34

@ Dr.Tarak Parikh
Posting: # 641
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 water restriction before and after dosing

Dear Tarak!

» now the question was why 1 hr before dosing and 1 hr after dosing water restriction.
» so in my opinion, as per pharmacokinetic and what we learned in medicine, water will do the distention of stomach which results in increase in surface area and thats why increases the absorption.

Sorry, IMHO this is not the case for the following reasons:
  1. In fasted state only 50 ml350 ml[/nb of the average volume of [nb]1500 ml are filled with liquid (where the distribution of volumes is verly likely skewed towards 50 ml), therefore no distention is to be expected,
  2. the stomach is not an absoption site for most drugs (except for ethanol), and
  3. even if we assume a neutral molecule, which would be equally absorbed throughout all pH-ranges (i.e., the entire GIT-tract would act as an absorption window), the stomach would play no significant role, since surface areas are 0.06 m² (stomach), 2 m² (duodenum), 180 m² (jejunum), 280 m² (ileum), and 1.5 m² (colon).

» To maintain similarity guideline says only 240 ml of water should be given at the time of dosing. but if it is given less, then you have to mention protocol deviation and just to evaluate the PK parameters afterwards.

Suggested water volumes vary according to different guidelines within 100 ml250 ml (see this post).

» still que is there why only 240ml???

Following the baseless rumour, that patients take their medication together with the (US) standard cup of water. :hungry:
I don’t know of a single study comparing plasma concentrations of any IR formulation administered with 240 ml v.s. a different volume.
BTW, according to the short average gastric emptying time of water in the stomach (15 minutes, see references), differences in volume would quickly level out anyway.

It’s nice that many colleagues follow the American roadshow (8 fluid ounces) unquestioned, but in the worlds largest economic area (the European Union based on GPD, 493 Mio citizens), Canada, Japan, and many other countries (not forgetting the WHO!), only 150ml are recommend…


References (Scintigraphy, epigastric impedance technique, or real time ultrasound measurements: values given for healthy controls)
Murphy, D.B., Sutton, J.A., Prescott, L.F., Murphy, M.B.
Opioid-induced Delay in Gastric Emptying: A Peripheral Mechanism in Humans
Anesthesiology. 87(4):765-770 (October 1997)
500 ml water (n=11): 5.5 ± 2.1 min
Murphy, D.B., Sutton, A., Prescott, L.F., Murphy, M.B.
A comparison of the effects of tramadol and morphine on gastric emptying in man
Anaesthesia. 52(12):1224-1229 (December 1997)
500 ml water (n=11): 7.7 ± 3.3 min
Chang, F.Y., Lu, C.L., Chen, C.Y., Lee, S.D., Tsai, D.S., Fu, S.E.
The Pharmacological Effect of Omeprazole on Water Gastric Emptying: A Study Based on an Impedance Measure
Pharmacology 63:50-57 (2001)
500ml water (n=15): 12.7 ± 5.1 min
Chang F.Y., Chen C.Y., Lu C.L., Luo J.C., Jiun K.L., Lee S.D., Wu C.W.
Undisturbed water gastric emptying in patients of stomach cancer
Hepatogastroenterology 51(58):1219-24 (2004 Jul-Aug)
500 ml water (n=28): 16.8 ± 2.1 min
J.F. Pedersen
Sonographic Comparison of Gastric Emptying of Broth and Water: Is There a Promoting Cephalic Factor?
Health Science, Cancer and Oncology and Medical Research 46(2):132-134 (April 2005)
350 ml water (n=12): 20.3 min (range 12–40)

Cheers,
Helmut Schütz
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drks
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2011-06-10 14:24

@ Helmut
Posting: # 7105
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 water restriction before and after dosing

Dear friends,

» BTW, according to the short average gastric emptying time of water in the stomach (15 minutes, see references), differences in volume would quickly level out anyway.

Considering this, what could be the variation that can be considered 'allowable' for various agencies (e.g. ANVISA)? For instance, Some investigator might have given 200 mL of water, but her/his measuring cylinder might not have been calibrated and/or would have been of plastic (increasing risk of variation with temperature). Should this be a cause of concern to the clinical team (CRO/sponsor)?

I presume a QA personnel may want cylinder to be calibrated to ensure no variance (or known variance) and contrarily, PK personnel may justify that it'd hardly make a difference; but from a regulatory submission point of view, I wonder what could be the best choice.

This may be too much thinking, but I guess it's good to think if big projects are at stake. ;-)

requesting your kind responses on this,

regards,
Kshitij
Ohlbe
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France,
2011-06-10 18:02

@ drks
Posting: # 7107
Views: 8,000
 

 Survey

Dear all,

» Considering this, what could be the variation that can be considered 'allowable' for various agencies (e.g. ANVISA)? For instance, Some investigator might have given 200 mL of water, but her/his measuring cylinder might not have been calibrated and/or would have been of plastic (increasing risk of variation with temperature). Should this be a cause of concern to the clinical team (CRO/sponsor)?

IMHO +/- 5 ml will really make no difference !

» [...] from a regulatory submission point of view, I wonder what could be the best choice.

OK, we have on this forum a pretty large panel of people from various companies and CROs, who have been inspected by various authorities (FDA, EU, ANVISA...). Can you share your experience ?

1. Was anybody asked during a regulatory inspection whether his measuring cylinder was calibrated ?

2. If yes, and it was not calibrated: was there any consequence ?

I don't think we'll get many positive answers for 1, and I'd be really surprised by positive answers to question 2 ! Better is sometimes just too much, and QA should sometimes take some distance and think.

Regards
Ohlbe

Regards
Ohlbe
Helmut
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2011-06-13 17:55

@ Ohlbe
Posting: # 7115
Views: 7,979
 

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Dear Ohlbe!

#1. No (Austria’s AGES PharmMed) - and therefore #2. (as you expected) was not applicable.

Cheers,
Helmut Schütz
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