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ioanam ★ Romania, 2007-01-22 12:35 (6296 d 23:55 ago) Posting: # 477 Views: 8,929 |
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Dear Sir, I read a protocol for a Be study for an extended - release formulation. It was a single dose study(only in fasted conditions) and multi- dose study. In this study, the first period of the single dose study was followed by the first period of the steady – state study. The wash out period began after the last dose administered in the steady - state study. The second period was identical with the first one. Is correct this design for the study? I know that for extended - release formulations must be performed totally different studies (single dose and multi - dose studies) in different periods. Is this correct? Thank you. |
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Helmut ★★★   Vienna, Austria, 2007-01-22 19:32 (6296 d 16:57 ago) @ ioanam Posting: # 478 Views: 8,193 |
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Dear ioanam! ❝ It was a single dose study(only in fasted conditions) and multi- dose study. In this study, the first period of the single dose study was followed by the first period of the steady - state study. The wash out period began after the last dose administered in the steady - state study. The second period was identical with the first one. Is correct this design for the study? In this case the sponsor obviously tries to kill two birds with one stone  Let's go into the datails - if I got it wright: In steady state you measure for 24 hours, whereas in single dose your last sampling point is determined by the regulatory requirement to cover at least 80% of AUCinf (i.e., by the half life of the drug and the LLOQ of the assay). Therefore the saturation phase for the multiple dose part may only start as early as the time point of the last expected concentration above LLOQ in any of the subjects (otherwise you may jeopardize accurate estimate of AUCinf in this subject). Saturation up to steady state and the profile itself is pretty straightforward, but in order to get all drug cleared from the body (assuming accumulation) our washout to the second single dose period generally will be longer than for a 'conventional' single dose design. Have you ever thought about the blood loss in such a 'design'? What about statistics? Only if we close our eyes the comparisons for BE will come from 'periods 1&2' - because actually we have 4. BE will be calculated from 1&3 (single dose) and from 2&4 (steady state). We should incorporate this information in the model - and don't ask me about regulatory acceptance  What if one of the two parts fail to demonstrate BE? It will be impossible to 'split' your data... We are also loosing time: in a multiple dose steady we dont need a washout phase at all; we may directly switch from one formulation to the other. ❝ I know that for extended - release formulations must be performed totally different studies (single dose and multi - dose studies) in different periods. Is this correct? I would think so - see above — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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shabana ● 2007-01-31 06:16 (6288 d 06:13 ago) @ Helmut Posting: # 498 Views: 8,150 |
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Dear Ioanam i have some points to add to the discussion below. i am making certain assumptions regarding the study design ioanam mentioned. HS talks here about problem re steady state phase. of course, it depends on the drug, but you will rarely come across a drug that will not show concentrations above the LOQ on multiple dosing!!!!! and yes, the washout period will be longer than in the single dose, naturally. no regulatory body recommends a washout less than at least 7-10 half-lives in steady state studies. the fact that the study has been coducted as a crossover, shows that there was a possibility of an effective washout period. of course, if the drug has accumulated and not completely removed from body in the washout period, it will show up as significant pre-dose concentration in the next period,and there you are caught!!! then the second period will never be considered for PK and statistical analysis at all. HS has raised a point regarding blood loss. with new,more accurate and precise analytical methods coming up, you don't need to take 10ml or even 5ml blood to carry out analysis for such a long study. the only problem you would have to face here is subject compliance!!!!! and possibly ethical issues about taking so many ambulatory samples.  As to taking relevant data from respective periods, it is generally accepted that such issues can be predefined in the protocol to avoid regulatory problems. As to the last point re regulatory acceptance. i am sure the regulatory says "In addition to the single-dose studies described ........, a comparison should be made between .......................... at steady state." its how you interpret it. when you say "in addition to", does it mean in a separate trial, or a different phase? "musable" issues, if you ask me. i found a recent declaration by the DKMA quite amusing. it said that "the 90% confidence interval for the ratio test versus reference should include 100% irrespective of whether acceptance limits of 80-125% or narrower are employed.". looks like someone was playing hookey with the guidelines!!!! SN -- Edit: Full quote removed. [HS] |
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Helmut ★★★ Vienna, Austria, 2007-01-31 14:49 (6287 d 21:40 ago) @ shabana Posting: # 500 Views: 8,682 |
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Dear shabana! ❝ […] yes, the washout period will be longer than in the single dose, naturally. Why are you applying a washout at all? To quote myself… ❝ ❝ […] in a multiple dose steady we dont need a washout phase at all; we may directly switch from one formulation to the other. EMEA (EU), TGA (Australia): In steady-state studies wash out of the previous treatment last dose can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least three times the terminal half-life). BPFK (Malaysia): In steady-state studies washout of the last dose of the previous treatment can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least three (3) times the dominating half-life). ACCSQ (ASEAN States): In steady-state studies wash out of the previous treatment last dose can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least three times the terminal half-life). ❝ no regulatory body recommends a washout less than at least 7-10 half-lives in steady state studies. No one? Specific for steady-state studies (EU, AUS, MZ, ASEAN-States; see above) General about wash-outs: WHO: … more than five times the terminal half-life of the API. Japan: … should usually be more than 5 times the elimination half life of the parent drug or active metabolites. CDSCO (India): … two phases of treatment separated by an adequate washout period which should ideally be equal to or more than five half life's of the moieties to be measured. You are only right for Canada (a little bit outdated – 1996)… HPFB: The interval between study days should […] normally be not less than 10 times the mean terminal half-life of the drug (generally, the interval between study days should not exceed four weeks). Steady state is usually achieved when repeated doses of a formulation are administered over a period that exceeds five disposition half-lives of the modified-release form. … and ANVISA (Brazil): The interval between the periods must be, at least, of seven half-lives of the drug or the metabolite elimination. ❝ the fact that the study has been coducted as a crossover, shows that there was a possibility of an effective washout period.  ❝ of course, if the drug has accumulated and not completely removed from body in the washout period, it will show up as significant pre-dose concentration in the next period,and there you are caught!!! then the second period will never be considered for PK and statistical analysis at all. Forget about washouts in steady-state; they are just a waste of time, increasing the chance of subjects dropping out from the study (see above)! You may google for 'switch-over' design.  It's a basic principle in linear PK (superposition principle: AUCτ=AUC∞) that irrespective of the level we're starting from, we always obtain the same steady-state concentrations. ![[image]](img/uploaded/SwitchOver.png) To give you an example (1 compartment open, D=100, V/F=1, k01=0.6931, k10=0.06931, τ=24h). The green line shows the saturation phase after a wash-out (or in period 1), the red line shows what we would expect in a switch-over design where test=reference (starting from a residual concentration), and the blue line shows what we would expect if the BA of the formulation administered in period 1 is 2× the formulation we administer in period 2. Do you see any difference in steady-state levels? OK, to be precise, at 120h we get 25.966 (after washout), 25.972 (T=R), and 25.979 (P1=2×P2). ❝ As to the last point re regulatory acceptance. i am sure the regulatory says "In addition to the single-dose studies described ........, a comparison should be made between .......................... at steady state." its how you interpret it. when you say "in addition to", does it mean in a separate trial, or a different phase? ❝ "musable" issues, if you ask me. Appendix 1 of EMEA's NfG leaves no space for interpretation (clearly talks about studies, not study phases). ❝ i found a recent declaration by the DKMA quite amusing. it said that "the 90% confidence interval for the ratio test versus reference should include 100% irrespective of whether acceptance limits of 80-125% or narrower are employed.". looks like someone was playing hookey with the guidelines!!!! Not quite recent… … but in practice in Denmark (see also this post). In the last two years I had to handle quite a lot of deficiency letters from other European Regulatory Agencies as well concerning the '100% not included in the CI'-issue. All of them could be resolved, and you're true, I think it's just nuts. Actually there are only two possible reasons for such a result:
Edit: FDA-link corrected to latest archived copy. [Helmut] — 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 |
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shabana ● 2007-02-12 11:38 (6276 d 00:51 ago) (edited by HS on 2007-02-12 13:41) @ Helmut Posting: # 511 Views: 8,020 |
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Dear HS Thank you for your kind comments. I would like to add something here. As i understand washout periods are meant to "wash out" the drug from the body, completely remove it, or as nearly completely as possible (correct me here if I am wrong). Most PK scientists would tell us that the consensus on five half lives for washout period came from the fact that 96.9 % of the drug has been removed from the body by the time five half lives are over. Of course some regulatory bodies give you the option of applying at least three half-lives that emcompasses both washout and run-up. By three half-lives, 87.5% of the drug is lost, by four half-lives 93.5% of the drug is removed. So i guess if you are happy with 87.5 %(=three half-lives) of the drug lost from the body, no problems in accommodating with the design they suggest. Whether you call it "washout period" or "build-up", they are meant to remove the drug from the body. I meant it in that simple sense. I think the operative word here is "at least"; the regulatory recommends a lower margin, and puts no tabs on the upper margin. Its upto the sponsor to arrive on a judicious upper margin, balancing the effects of subject dropout and unacceptable results. I did not know about the "switchover design" you are talking about. thanks for telling me. I will check it out. When you say ❝ Forget about washouts in steady-state; they are just a waste of time, increasing the chance of subjects dropping out from the study do you mean you are totally against washout periods in biostudies involving steady state???? I wonder how this statement would go down with Ethics Committees??? And you have to agree that the regulatory bodies, in general, recommend a longer washout in steady-state studies as compared to single dose studies. ❝ you would get the same plasma concentrations no matter what initial concentration you start with. I am afraid i don't think this can be treated as a blanket statement, though it may be true in most cases. How will you explain drug toxicity then??? what about specifically those drugs that accumulate on steady state dosing? I believe that is a major function of "therapeutic drug monitoring". OK, about DKMA I think i misunderstood the date as 2007 instead of 2006. But my focus was not on the date but on the contents of the directive. I was merely commenting on how people would like to interpret guidelines in a crooked manner. Regards Shabana N. -- Edit: Full quote removed. [HS] |
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Helmut ★★★ Vienna, Austria, 2007-02-12 16:09 (6275 d 20:20 ago) @ shabana Posting: # 512 Views: 7,951 |
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Dear Shabana, thanks for for your fruitful contribution. ❝ As i understand washout periods are meant to "wash out" the drug from the body, completely remove it, or as nearly completely as possible (correct me here if I am wrong). Yes, you’re right – in order to apply a cross-over design, we must consider not only PK, but all pharmacological effects (with may appear as a residual effect) as well. Therefore PK is just a part of successful study planning! ❝ Most PK scientists would tell us that the consensus on five half lives for washout period came from the fact that 96.9 % of the drug has been removed from the body by the time five half lives are over. […] By three half-lives, 87.5% of the drug is lost, by four half-lives 93.5% of the drug is removed. 96.9% are cleared after 5 half lives for a 1-compartment open model, or to be precise 1-½i applies (i is a multiple of the half life): i % of steady stateI would not call this a consensus, but rather a convention. For anything more complicated – and even a 2-compartment model is ‘complicated’ in this respect, total clearance can become a pretty nasty function depending on all rate constants and volumes of distribution involved (not even thinking about drugs with nonlinear PK of the MM-type). ❝ Of course some regulatory bodies give you the option of applying at least three half-lives that emcompasses both washout and run-up. By three half-lives, 87.5% of the drug is lost, by four half-lives 93.5% of the drug is removed. So i guess if you are happy with 87.5% (=three half-lives) of the drug lost from the body, no problems in accommodating with the design they suggest. Don’t get me wrong. Personally I think three half lives are too short either! I was only arguing against your initial statement… ❝ no regulatory body recommends a washout less than at least 7-10 half-lives in steady state studies. … and was referring to some regulatory examples ❝ Whether you call it "washout period" or "build-up", they are meant to remove the drug from the body. The former, yes; the latter no! “Build-up” is just synonymous to the saturation phase you have to apply in the beginning of each treatment period. ❝ I think the operative word here is "at least"; the regulatory recommends a lower margin, and puts no tabs on the upper margin. Its up to the sponsor to arrive on a judicious upper margin,balancing the effects of subject dropout and unacceptable results. Full ACK ❝ When you say ❝ ❝ Forget about washouts in steady-state; they are just a waste of time, increasing the chance of subjects dropping out from the study ❝ do you mean you are totally againt washout periods in biostudies involving steady state??? IMHO (at least for drugs with linear PK) they don’t make any sense. Again, for a fixed dosage level given at the same dosage interval we will obtain exactly the same steady state level, irrespectively which level we are starting the “build up” from (=‘zero’ for subjects in period 1, 12.5% residual after 3 half lives, 3.1% residual after 5 half lives, etc). In order to apply the superposition principle (SD AUC0–∞ = MD AUC0–τ), we must demonstrate achievement of steady state anyhow (e.g., three pre-dose concentrations with slope≈0). I will be happy if anyone would come up with a simulation where the profile in steady state is substantially different if an additional wash-out is applied. ❝ I wonder how this statement would go down with Ethics Committees??? Which problems do you expect from IECs? You have a shorter duration of the study, the number of samples per subject is reduced by one (since the last sample of the profile in period 1 is the first pre-dose sample in the build up). ❝ And you have to agree that the regulatory bodies, in general, recommend a longer washout in steady-state studies as compared to single dose studies. Yes, but that does not disqualify a switch-over design ❝ ❝ you would get the same plasma concentrations no matter what initial concentration you start with. ❝ I am afraid i don't think this can be treated as a blanket statement, though it may be true in most cases. Consequently, you have to know the PK of your drug. But at least for drugs with ‘uncomplicated PK’ the statement holds true. ❝ How will you explain drug toxicity then??? Simple: the concentration is above the toxicity level… But the discussion started with – and should be confined within – steady state designs for bioequivalence assessment. ❝ what about specifically those drugs that accumulate on steady state dosing? I don’t see the problem. Actually my example (t½ 10 h, τ 24 h) shows an accumulation index $$R=\frac{1}{1-\exp (-k_\textrm{10}\cdot \tau)}$$ of 1.23 (i.e., Css,max is 23% higher than Cmax). ❝ I believe that is a major function of "therapeutic drug monitoring". No, that’s a different cup of tea. In TDM you must have
❝ OK, about DKMA […] I was merely commenting on how people would like to interpret guidelines in a crooked manner. Yes, but this ‘people’ are belonging to a European Regulatory Body.  — 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 |
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shabana ● 2007-02-13 06:33 (6275 d 05:56 ago) (edited by HS on 2007-02-13 11:18) @ Helmut Posting: # 513 Views: 7,876 |
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Dear HS Let me see if I get this right. For successful planning of BE studies, both PK and PD have to be taken into account. Right, that's ok. This is good. so washout will serve two purposes here - assure you that both PK and PD effects have worn off. So the IECs are not going to be happy only if you can show a reduction in "n", you also need to assure them that subjects will not be exposed to unnecessary risks, that their welfare is well taken care of, among other things. so when you say ❝ ❝ How will you explain drug toxicity then??? ❝ Simple: the concentration is above the toxicity level… a CONCENTRATION above toxicity level is responsible for the observed toxicity. you have to assure them that the concentration does not go above toxicity. that is the trouble you may anticipate from IECs. Nor do I advocate "additional washouts", as you put it. I say "judicious", one that will keep everyone involved happy. As for "uncomplicated drugs", as mentioned you have to demonstrate and justify that the effects are as you expect. Regards Shabana -- Edit: Full quote removed. [HS] |
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Helmut ★★★ Vienna, Austria, 2007-02-13 12:34 (6274 d 23:56 ago) @ shabana Posting: # 514 Views: 7,966 |
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Dear Shabana! ❝ […] so washout will serve two purposes here - assure you that both PK and PD effects have worn off. So the IECs are not going to be happy only if you can show a reduction in "n", you also need to assure them that subjects will not be exposed to unnecessary risks, that their welfare is well taken care of, among other things. so when you say ❝ ❝ ❝ ❝ How will you explain drug toxicity then??? ❝ ❝ Simple: the concentration is above the toxicity level… ❝ ❝ a CONCENTRATION above toxicity level is responsible for the observed toxicity. you have to assure them that the concentration does not go above toxicity. that is the trouble you may anticipate from IECs. Again: Since we are talking about bioequivalence, highest concentrations are to be expected in the steady state profiles. It simply does not matter whether we apply a washout phase between treatment phases or not. So still I’m not getting your point about IECs. ❝ Nor do I advocate "additional washouts", as you put it. I say "judicious", one that will keep everyone involved happy. As for "uncomplicated drugs", as mentioned you have to demonstrate and justify that the effects are as you expect. Full ACK! P.S. Please avoid “TOFU” (see the Forum’s Policy) — 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 |
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Helmut ★★★ Vienna, Austria, 2007-08-23 23:10 (6083 d 14:20 ago) @ shabana Posting: # 1015 Views: 7,850 |
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Dear Shabana, following our conversation earlier this year I want to quote a guideline issued by the FDA (Erlotinib HCl; recommended Jan 2006, updated Aug 2007) which may help sorting things out. ❝ no regulatory body recommends a washout less than at least 7-10 half-lives in steady state studies. Quoting the guideline (my emphases): Dosing on each treatment should continue for a sufficient time to allow equilibration on the test and reference treatments, hence for four to five half-lives prior to bioequivalence study plasma sampling. ❝ of course, if the drug has accumulated and not completely removed from body in the washout period, it will show up as significant pre-dose concentration in the next period,and there you are caught!!! then the second period will never be considered for PK and statistical analysis at all. Again the Guideline: Similarly, sufficient time for re-equilibration should be allowed for the crossover treatment. Washout between treatment periods is not recommended. — 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 |
Ing. Helmut Schütz