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sciguy ☆ Canada, 2011-11-02 17:52 (4932 d 03:13 ago) Posting: # 7586 Views: 8,879 |
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Hi all, I'm new to the forum and just wanted to get opinions from the group on the following issue: The sponsor wants to compare two different formulations of a drug with 2 different strengths, say 5 mg vs 10 mg. Dose normalization on the relevant PK parameters is performed and the assessment of equivalence using standard BE criteria is applied. If BE is met, we can only conclude dose proportionality but not bioequivalence since 2 different strengths are being compared. True bioequivalence must be evaluated on non dose-normalized data. Agree/disagree? Thanks a lot! sciguy |
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Helmut ★★★   Vienna, Austria, 2011-11-02 22:11 (4931 d 22:55 ago) @ sciguy Posting: # 7587 Views: 8,262 |
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Dear sciguy! ❝ The sponsor wants to compare two different formulations of a drug with 2 different strengths, say 5 mg vs 10 mg. Dose normalization on the relevant PK parameters is performed and the assessment of equivalence using standard BE criteria is applied. If BE is met, we can only conclude dose proportionality but not bioequivalence since 2 different strengths are being compared. True bioequivalence must be evaluated on non dose-normalized data. Agree/disagree? An often overlooked trap. Let’s consider the basic BA equations:
If we assume (!) DT ≈ DT and CLT ≈ CLR these terms cancel out and we obtain
If we dose-adjust and want to assess for BE we try to kill two birds with one stone. In your example comparing twice the AUC after the 5 mg dose to the AUC after the 10 mg requires strict linear PK: Both Clearance and fraction absorption independent from dose (a straight line through the origin). Whereas the former is drug-specific the latter might be (also) formulation specific. Imagine a hypothetical scenario (of course nonlinear PK): capacity limited absorption and Clearance. At 5 mg F = 0.9, CL = 12.5 and at 10 mg F = 0.8, CL = 10. AUCs are 0.360 and 0.800. Dose normalisation will lead to BA = (0.360 × 2) / 0.800 = 90.0 %. So far so good – but is this ‘true’? What we want to compare in BE is FT/FR. Only because Fs are not accessible we use AUCT/AUCR instead. FT/FR from above would be 112.5 %. Even if I have strong evidence of linear PK (where dose-normalisation would definitely work) I would opt to dose the same amount if BE is to be assessed. P.S.: There’s another thread dealing with dose-proportionality. I will elaborate on it later on over there. Just a first glimpse: We once had a study where an MR formulation (20 mg oad) was compared to an IR formulation (2 ×10 mg, τ 4 h). AUC was BE. Since no data on dose-proportionality were available we dosed the MR formulation also at 10 mg and 40 mg (4-way crossover). We showed BE after dose-normalisation (strict linear PK) after applying a Bonferroni-correction (αadj 0.0167 ≡ 96.67 % confidence intervals). It was a hybrid application and we had two clinical studies showing safety/efficacy at these levels (compared to reference and superiority to placebo). European regulators accepted the study (= approval for all three strengths) but told us that they didn’t like our approach.  They would have preferred to get three studies instead: 2×10 mg MR vs. (10+10) mg IR, 1×20 mg MR vs. (10+10) mg IR, 1×40 mg MR vs. (2×10+2×10) mg IR… (only the 10 mg IR acting as reference).— 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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sciguy ☆ Canada, 2011-11-03 21:30 (4930 d 23:35 ago) @ Helmut Posting: # 7596 Views: 7,932 |
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Thanks Helmut, So you're saying that theoretically, BE can be concluded even after dose normalization on different dosage strengths - so long as the requirement for linear PK is fulfilled. In your experience though, it sounds like reg. agencies don't like this and would rather you match up the strengths with 2x, 3x etc doses. The problem I have is that I have different strengths that are not whole number multiples of each other, for example 10 mg vs 8 mg. In this case, maybe it is acceptable to dose normalize and declare BE (assuming linear PK of course). If, however, the 10 mg vs 8 mg are different formulations, then we can't dose normalize and assess BE since we don't know what impact the formulation differences can have on f (and linear PK may no longer hold). In this case, would we have to assess BE on non dose-normalized data? Thanks again, sciguy |
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Helmut ★★★ Vienna, Austria, 2011-11-03 22:06 (4930 d 22:59 ago) @ sciguy Posting: # 7597 Views: 7,959 |
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Hi sciguy! ❝ So you're saying that theoretically, BE can be concluded even after dose normalization on different dosage strengths - so long as the requirement for linear PK is fulfilled. Yes, but it must be clear that here BE is based on a more tough assumption. Genrally (well, outside of Canada) we are not allowed to perform a dose-correction at the same strengths even if we know that actual contents differ. Imagine a CI of 77-118% and actual contents of 100% (test) and 104.91% (reference). After dose correction the formulation would pass (81.91–122.91%). We have to assume DT=DR despite better knowledge. Regulator’s paranoia think that you performed the study, know the outcome and afterwards falsify the CoAs. ❝ In your experience though, it sounds like reg. agencies don't like this and would rather you match up the strengths with 2x, 3x etc doses. Yes. I keep trying; but in the light of the above I’m not very optimistic. See also there. ❝ The problem I have is that I have different strengths that are not whole number multiples of each other, for example 10 mg vs 8 mg. In this case, maybe it is acceptable to dose normalize and declare BE (assuming linear PK of course). If, however, the 10 mg vs 8 mg are different formulations, then we can't dose normalize and assess BE since we don't know what impact the formulation differences can have on f (and linear PK may no longer hold). Yes, one example are MR methylphenidate·HCl formulations. Most MR formulations come in strengths of 5-60 mg, and Concerta in 18, 27, 36, 54, 72 mg. BE (?) studies are published with dose normalization. But: there’s a lot of data available that MPH has really linear PK. ❝ In this case, would we have to assess BE on non dose-normalized data? Hhm, but how? If we dose-normalize your example we get e.g. 90.00-111.11%. If we don’t normalize, we get 112.50–138.89%. That's an Ouroboros: ![[image]](https://upload.wikimedia.org/wikipedia/commons/7/71/Serpiente_alquimica.jpg) — 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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Ohlbe ★★★ France, 2011-11-04 11:19 (4930 d 09:47 ago) @ Helmut Posting: # 7604 Views: 7,885 |
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Dear Helmut and Sciguy, I just noted this in a Q&A on the CMDh web site. See question 8a, on the situation when the relevant strength of the reference product is no longer marketed: In general the cumulative strength of the reference product should be the same as the strength that the applicant has applied for, thus maintaining the direct link with the reference product. However it may be justified to use different strengths when pharmacokinetics are linear and a potency correction is performed. This would apply if the different strengths or pharmaceutical forms of the reference product are part of the same Global Marketing Authorisation and the general biowaiver criteria as outlined in section 4.1.6 of the Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev.1/Corr**) should be met for the test product when relevant. The acceptability of using a different strength or pharmaceutical form of the reference medicinal product should also be discussed with the competent authority of the country where the reference product is authorised. To summarise: it may be acceptable, but ask for scientific advice first  Regards Ohlbe — Regards Ohlbe |
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sciguy ☆ Canada, 2011-11-04 16:34 (4930 d 04:32 ago) @ Helmut Posting: # 7605 Views: 7,867 |
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Hi Helmut and Ohlbe, ❝ Yes, but it must be clear that here BE is based on a more tough assumption. Genrally (well, outside of Canada) we are not allowed to perform a dose-correction at the same strengths even if we know that actual contents differ. Actually, the latest Canadian draft guidance (Jan 2010, line 84) implies removal of the dose correction and the inclusion of the 5% similarity requirement (like the rest of the world!) - not sure when the final will be released. ❝ Hhm, but how? If we dose-normalize your example we get e.g. 90.00-111.11%. If we don’t normalize, we get 112.50–138.89%. I was thinking of the case where the sponsor wants to show their formulation (eg: 10 mg capsule) is bioequivalent to another formulation of different strength (eg: 8 mg tablet). Here, dose normalization would not be necessary because we actually want to show the capsule of this strength is BE to the tablet. Moreover, it would not be appropriate since different formulations = potentially diff f. sciguy |
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Helmut ★★★ Vienna, Austria, 2011-11-04 17:25 (4930 d 03:40 ago) @ sciguy Posting: # 7611 Views: 7,907 |
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Hi sciguy, ❝ ❝ Hhm, but how? If we dose-normalize your example we get e.g. 90.00-111.11%. If we don’t normalize, we get 112.50–138.89%. ❝ ❝ I was thinking of the case where the sponsor wants to show their formulation (eg: 10 mg capsule) is bioequivalent to another formulation of different strength (eg: 8 mg tablet). Here, dose normalization would not be necessary because we actually want to show the capsule of this strength is BE to the tablet. Moreover, it would not be appropriate since different formulations = potentially diff f. If you get a CI within 80–125% after 10 mg compare to 8 mg without dose-correction f is lower, right? It might be possible that (e.g. with an MR compared to an IR) you partly miss the absorption window of the drug. f will be lower. Guidelines are tricky: US CFR 21/5 320.1: (d) Pharmaceutical alternatives means drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. — 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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sciguy ☆ Canada, 2011-11-04 20:18 (4930 d 00:47 ago) @ Helmut Posting: # 7612 Views: 7,830 |
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Hi Helmut, ❝ If you get a CI within 80–125% after 10 mg compare to 8 mg without dose-correction f is lower, right? It might be possible that (e.g. with an MR compared to an IR) you partly miss the absorption window of the drug. f will be lower. You're right - I meant if f and clearance are different than it wouldn't be appropriate to dose normalize. In a properly designed study, it would seem unlikely clearance would be much different though since the strengths are similar. Thanks for your input! sciguy |
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Helmut ★★★ Vienna, Austria, 2011-11-04 20:55 (4930 d 00:11 ago) @ sciguy Posting: # 7613 Views: 7,876 |
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Hi sciguy! ❝ You're right - I meant if f and clearance are different than it wouldn't be appropriate to dose normalize. In a properly designed study, it would seem unlikely clearance would be much different though since the strengths are similar. Yes, that’s the second assumption in BE-testing: identical clearances. In the good ol’ days this assumption seemed to be justified. But we have learned from Les Benet that this must not necessarily always be the case. Different excipients may play havoc with transporters. But how do we calculate clearance? CL=D×F/AUC. Back to the unknows. The only way out of this dilemma would be simultaneous administration of a stable isotope-labeled API. As a nice side effect HVDs would disappear, leaving only HVDPs for scaling. — 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