ssk ● 2006-08-12 19:01 (6438 d 17:09 ago) Posting: # 206 Views: 14,135 |
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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 ★★★ Vienna, Austria, 2006-08-12 20:21 (6438 d 15:49 ago) @ ssk Posting: # 207 Views: 12,733 |
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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) , whereF : Fraction absorbed 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. — 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 |
ssk ● 2006-08-13 18:51 (6437 d 17:20 ago) @ Helmut Posting: # 208 Views: 12,529 |
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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 ★★★ Vienna, Austria, 2006-08-13 21:13 (6437 d 14:57 ago) @ ssk Posting: # 209 Views: 12,595 |
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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. — 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 |
drks ☆ 2006-08-19 11:18 (6432 d 00:52 ago) @ Helmut Posting: # 227 Views: 12,447 |
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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 ★★★ Vienna, Austria, 2006-08-19 14:45 (6431 d 21:26 ago) @ drks Posting: # 228 Views: 12,572 |
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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. — 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 |
Dr.Tarak Parikh ☆ India, 2007-04-06 11:27 (6202 d 00:44 ago) @ Helmut Posting: # 640 Views: 12,155 |
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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 ★★★ Vienna, Austria, 2007-04-06 17:34 (6201 d 18:37 ago) @ Dr.Tarak Parikh Posting: # 641 Views: 12,238 |
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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:
❝ 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 ml – 250 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. 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) — 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 |
drks ☆ 2011-06-10 16:24 (4675 d 19:46 ago) @ Helmut Posting: # 7105 Views: 10,460 |
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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 ★★★ France, 2011-06-10 20:02 (4675 d 16:08 ago) @ drks Posting: # 7107 Views: 10,343 |
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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 ★★★ Vienna, Austria, 2011-06-13 19:55 (4672 d 16:16 ago) @ Ohlbe Posting: # 7115 Views: 10,329 |
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Dear Ohlbe! #1. No (Austria’s AGES PharmMed) - and therefore #2. (as you expected) was not applicable. — 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 |