Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-03-06 16:23
(4289 d 07:44 ago)

Posting: # 8221
Views: 23,303
 

 EMA: Q&A on biphasic MR products [BE/BA News]

Dear all,

as a first augury of the new MR guideline (draft expected QIV 2012), the Q&A document was updated (Section 12). Excerpt:

Biphasic modified release formulations are characterised by two phases of drug release: a first phase determined by the immediate release dose fraction to provide a therapeutic drug level shortly after administration, and a second extended release phase to provide the dose fraction required to maintain an effective therapeutic level for a prolonged period. The clinical rationale behind their development is that a rapid onset of action is required in addition to subsequent prolonged release characteristics.

For the pharmacokinetic evaluation, these two phases should be separated through a cut-off time point, which needs to be pre-specified and universally applied to all subjects and for both test product and reference product. The identification of this cut-off time point should aim to describe the plasma concentrations in the first phase driven by the immediate release dose fraction whilst avoiding bias through an increasing contribution of the extended release phase.

Equivalence needs to be shown for both extent and rate of absorption (reflecting AUC and Cmax for conventional bioequivalence criteria), separately for both phases:

  • For the first phase, the assessment of equivalence should be based on the truncated AUC from t=0 until the cut-off time describing the immediate release dose fraction, and on Cmax during the first phase.
  • For the second phase, the assessment of equivalence should be based on the AUC from the cut-off time until the end of observation period, and on Cmax during the second phase.

These considerations are in principle valid for studies in fed state and in fasting state. If no significantly different pharmacokinetic profile between fasting and fed state is expected then the cut-off time point should be identical.


These recommendations are inline with recent product-specific guidances of the FDA (methylphenidate ER capsules: fasting 3 h, fed 4 h, zolpidem ER tablet: fasting 1.5 h, fed no cut-off).

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
ElMaestro
★★★

Denmark,
2012-03-06 20:09
(4289 d 03:58 ago)

@ Helmut
Posting: # 8222
Views: 20,713
 

 EMA: Q&A on biphasic MR products

Hi HS,

I can follow the logic, although I could be a little afraid that the innovator industry as a means of brand protection could start building IP protection around the cut-offs (or other). It would be tremendously effective if granted.

What's your own take on this?

Pass or fail!
ElMaestro
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-03-07 04:52
(4288 d 19:15 ago)

@ ElMaestro
Posting: # 8223
Views: 21,002
 

 EMA: Q&A on biphasic MR products

Dear ElMaestro!

❝ I can follow the logic, …


Me too. Like it.

❝ … although I could be a little afraid that the innovator industry as a means of brand protection could start building IP protection around the cut-offs (or other). It would be tremendously effective if granted.


Can be very tough. Early partial AUCs are always highly variable. No scaling for EMA… See this one (slides 51–56). Besides the CV, have a look at the PEs of the two studies of slide 54. All formulations got approval as hybrids (MR vs. IR + clinical studies). Interchangeability: ¡nada!

❝ What's your own take on this?


I make my living from it. :-D
Joking aside I like that some clinical reasoning seems to come back. Or I’m just getting old (1980s-style: steady state to reduce variability, active metabolite if longer half-live than parent, music of the Talking Heads, Laurie Anderson’s performances, etc.).


Meeting of the Pharmaceutical Science and Clinical Pharmacology Advisory Committee,
April 13, 2010
Midha KK and G McKay
Use of Partial Area Under the Curve for BE Assessment of Products with Complex PK Profiles; a View Point
slides 1–58
RA Lionberger
PK Profile Comparison for Modified Release Products
slides 59-85
BM Davit
Use of Partial AUC: Case Studies and BE Approaches
slides 86-177

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
ElMaestro
★★★

Denmark,
2012-03-07 20:20
(4288 d 03:47 ago)

@ Helmut
Posting: # 8227
Views: 20,677
 

 EMA: Q&A on biphasic MR products

Dear HS,

❝ Can be very tough. Early partial AUCs are always highly variable. No scaling for EMA… See this one (slides 51–56). Besides the CV, have a look at the PEs of the two studies of slide 54. All formulations got approval as hybrids (MR vs. IR + clinical studies). Interchangeability: ¡nada!


Patents are not assessed to any degree resembling the assessment at NCAs. I meant to say that in spite of all the trouble with variability and SPC's and food and all the other fancy stuff that matters in the PK-approval-agency-world, originator companies could try and patent the cuttoff or profile. If they were successful it would be game over for the generic industry for any MR covered by the patent regardless of other patent expiry:
First approval of one MR or other, then a year or two before generic competition is possible do a line extension (which does not necessarily require equivalence) to a formulation principle which is patented and which entails a cutoff or other such thingy, then cancel the MA for the original formulation and enjoy another x effective years of protection.

Best regards,
EM.
d_labes
★★★

Berlin, Germany,
2012-03-07 11:26
(4288 d 12:41 ago)

@ Helmut
Posting: # 8224
Views: 20,740
 

 EMA vs. FDA

Dear Helmut,

❝ These recommendations are inline with recent product-specific guidances of the FDA (methylphenidate ER capsules: fasting 3 h, fed 4 h, zolpidem ER tablet: fasting 1.5 h, fed no cut-off).


with the exception that the FDA recommends (T = cut-off time)

Cmax,                     AUC(0-T), AUC(T-tlast) and AUC(0-inf)

whereas the EMA demands

Cmax(0-T), Cmax(T-tlast), AUC(0-T), AUC(T-tlast)

if I interpret the Q&A and the product specific guidances right.
As always "International harmonisation" :no:. But 50% accordance is better then nothing.

Can we expect an additional burden by the two Cmax values?

What to do in cases where there are no distinct Cmax in both phases like the concentration-time curves of Methylphenidate ER products shown on slide 43 (bottom left) of the presentation you have linked?

BTW: I can't see any return of clinical reasoning in the EMA Q&A.

"The identification of this cut-off time point should aim to describe the plasma concentrations in the first phase ... :blahblah:".


Regards,

Detlew
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-03-07 15:22
(4288 d 08:45 ago)

@ d_labes
Posting: # 8225
Views: 21,103
 

 MPH examples

Dear Detlew!

❝ ❝ These recommendations are inline with recent product-specific guidances of the FDA …

❝ with the exception that the FDA recommends (T = cut-off time)

    Cmax,                     AUC(0-T), AUC(T-tlast) and AUC(0-inf)

❝ whereas the EMA demands

    Cmax(0-T), Cmax(T-tlast), AUC(0-T), AUC(T-tlast)

❝ if I interpret the Q&A and the product specific guidances right.


Absolutely correct. Eagle eye! Tougher to pass.

❝ Can we expect an additional burden by the two Cmax values?


Yes. Not so much by the CV, but – at least for MPH formulations – the PE. Examples (PE, CI, CV%):
                      Cmax                   Cmax0-4                 Cmax0-t
Markowitz et al.1 67.6 62.2  73.3 15     53.3  48.9  58.9 17
Wang et al.2                             97    85   111   22.7   91   84    99   13.9
Fischer et al.3  103.0 96.5 110.0  8.9  103.8  96.4 111.7 10.0  102.7 95.9 109.9  9.2
Tuerck et al.4    86   81    91   12    106   100   113   12.4   82   77    88    14
Haessler et al.5  68.6 63.3  74.3 17.0   73.3  66.6 80.7  20.4   70.2 64.5  76.4  18.0
Schütz et al.6    76.6 66.7  87.8  9.2   79.1  69.6 90.0  18.3   74.9 63.8  88.0  23.0

In the 2nd study two development formulations (slow, fast) of Ritalin LA were tested. In the 3rd study the same formulation was tested (intact capsule vs. sprinkled). In these studies all metrics passed, slightly higher CVs for ‘partial Cmax’ (hey – a new term!). In the 4th study almost all metrics passed. In all studies where different formulations were compared1,5,6 the global Cmax failed as well; wouldn’t say that partial Cmax is more discriminatory.

❝ What to do in cases where there are no distinct Cmax in both phases like the concentration-time curves of Methylphenidate ER products shown on slide 43 (bottom left) of the presentation you have linked?


These curves are typical for MPH MR formulations. You have to deal with profiles of similar shape but different lag-times and the zero-order input of the osmotic pump (OROS ‘Concerta’). Everybody went with a pragmatic approach and uses the maximum concentration (C≤4 and C>4) ignoring the actual shape (also Q&A: “… cut-off time point, which needs to be pre-specified and universally applied to all subjects …”). See this goody from a 60 mg MD study:

[image]

It might well be that a couple of subjects show a Cmax,0-4 at 4 h despite there was a decrease from an earlier peak or there is no clearly defined peak in one of the two sections at all. BTW, would be nice to know how these guys deal with it. :-D

❝ BTW: I can't see any return of clinical reasoning in the EMA Q&A.

❝ ❝ "The identification of this cut-off time point should aim to describe the plasma concentrations in the first phase ... :blahblah:".


Hhm. I don’t get your point here. Can you elaborate?


  1. Markowitz JS, Straughn AB, Patrick KS, DeVane CL, Pestreich L, Lee J, Wang Y, Muniz R. Pharmacokinetics of Methlphenidate After Oral Administration of Two Modified-Release Formulations in Healthy Adults. Clin Pharmacokinet. 2003;42(4):393–401. doi:10.2165/00003088-200342040-00007.
  2. Wang Y, Lee L, Somma R, Thompson G, Bakthiar R, Lee J, Rekhi GS, Lau H, Sedeck G, Hossain M. In Vitro Dissolution and In Vivo Oral Absorption of Methlphenidate from a Bimodal Release Formulation in Healthy Volunteers. Biopharm Drug Dispos. 2004;25:91–8. doi:10.1002/bdd.390.
  3. Fischer R, Schütz H, Grossmann M, Leis HJ, Ammer R. Bioequivalence of a methylphenidate hydrochloride extended-release preparation: comparison of an intact capsule and an opened capsule sprinkled on applesauce. Int J Clin Pharmacol Ther. 2006;44(3):135–41. doi:10.5414/CPP44135.
  4. Tuerck D, Wang Y, Maboudian M, Wang Y, Sedek G, Pommier GF, Appel-Dingemanse S. Similar bioavailability of dexmethylphenidate extended (bimodal) release, dexmethylphenidate immediate release and racemic methylphenidate extended (bimodal) release formulations in man. Int J Clin Pharmacol Ther. 2007;45(2):662–8.
  5. Haessler F, Tracik F, Dietrich H, Stammer H, Klatt J. A pharmacokinetic study of two modified-release methylphenidate formulations under different food conditions in healthy volunteers. Int J Clin Pharmacol Ther. 2008;46(9):466–76.
  6. Schütz H, Fischer R, Großmann M, Mazur D, Leis HJ, Ammer R. Lack of bioequivalence between two methylphenidate extended modified release formulations in healthy volunteers.
    Int J Clin Pharmacol Ther. 2009;47(12):761–9. doi:10.5414/CPP47761.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
d_labes
★★★

Berlin, Germany,
2012-03-07 17:18
(4288 d 06:49 ago)

@ Helmut
Posting: # 8226
Views: 20,690
 

 MPH examples

Dear Helmut!

Thanx for that answer. Elaborate and concise as always.

❝ ... ‘partial Cmax’ (hey – a new term!)

:clap: Excerpt from my next report: "We have evaluated the partial Cmax according to Schütz ..." :-D

❝ It might well be that a couple of subjects show a tmax,0-4 at 4 h despite there was a decrease from an earlier peak or there is no clearly defined peak in one of the two sections at all.


In the extremal case this would mean that the Cmax values are the same in both phases! See the red curve of your example picture.

❝ would be nice to know how these guys deal with it. :-D


Me too.

❝ ❝ BTW: I can't see any return of clinical reasoning in the EMA Q&A.

❝ ❝ "The identification of this cut-off time point should aim to describe the plasma concentrations in the first phase ... :blahblah:".


❝ Hhm. I don’t get your point here. Can you elaborate?


Your cut-off point T=4 h is driven by clinical reasoning I think, like the arguments in the linked presentation?

I worry that the sentence in the Q&A calls for a cut point that is solely driven by the separation of the two phases in the concentration time courses. This would lead in the example courses you have given to T somewhere between 2-3h.

But eventually I'm too anxiety psychotic regarding taking guidances literally :surprised: (me sitting in front of a snake).

Regards,

Detlew
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-03-08 02:07
(4287 d 22:00 ago)

@ d_labes
Posting: # 8230
Views: 20,734
 

 MPH examples

Dear Detlew!

❝ ❝ ... ‘partial Cmax’ (hey – a new term!)

:clap: Excerpt from my next report: "We have evaluated the partial Cmax according to Schütz ..." :-D


Well I think it’s a stupid term. Maybe roman indices would work better (Cmax,I and Cmax,II).

❝ ❝ It might well be that a couple of subjects show a tmax,0-4 at 4 h despite there was a decrease from an earlier peak or there is no clearly defined peak in one of the two sections at all.

❝ In the extremal case this would mean that the Cmax values are the same in both phases! See the red curve of your example picture.


That’s why I said:

❝ ❝ […] the maximum concentration (C4 and C>4) ignoring the actual shape


In my example (red line) the first one is at 4 h and the second one at 4.5 h. :cool: But it’s counterintuitive to call a concentration in the decreasing part of a profile Cmax.

❝ Your cut-off point T=4 h is driven by clinical reasoning I think, like the arguments in the linked presentation?


Exactly. All references above show data in fed state.

❝ I worry that the sentence in the Q&A calls for a cut point that is solely driven by the separation of the two phases in the concentration time courses. This would lead in the example courses you have given to T somewhere between 2-3h.


MR MPH is a nice model because variability is very low (both intrinsic and analytical). Formulations contain IR and SR parts (50/50 or 30/70). Due to variability in gastric emptying the second peak is more or less pronounced. Sometimes the first peak is missing (gradual increase – just a ‘shoulder’), the second peak is ± shifted, etc. I did a lot of PK modeling as well (both classical and PopPK), but finding a data-driven cut-off is simply impossible (+ against the Q&A). Even eyeballing fails in many cases (does the blue curve have three peaks or just two – the peak at 1.5 h being only noise?)…

❝ But eventually I'm too anxiety psychotic regarding taking guidances literally :surprised: (me sitting in front of a snake).


Yeah. Though I’m evaluating both Cmax-values since 1999 – only as a descriptive metric. The initial ramp (rapid onset) was shown to be important for efficacy, so AUC0-4 makes sense. Some authors discussed a potential development of acute tolerance (tachyphylaxis) – but this was never proven in a clinical study. These authors advocated the second peak to be higher than the first one, which also mimics IR MPH given 4 hours apart. But receptors don’t give a damn on single concentrations. AUC4-t is therefore suitable as well. BTW, AFAIK the hybrid authorisations were granted in clinical studies: MR vs. 2×IR (BE of AUC) vs. placebo (superiority of MR and IR). All of them were shown to be safe and efficacious despite differences in profiles. Of course they are not interchangeable and a generic application is not that easy.

Zolpidem is even more tricky. You get an idea looking at the mean curves in Kam’s slides. I once saw some spaghetti plots – there’s never a ‘first peak’. Requiring Cmax,1.5 is very strange.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
d_labes
★★★

Berlin, Germany,
2012-03-08 09:29
(4287 d 14:38 ago)

@ Helmut
Posting: # 8232
Views: 20,644
 

 FDA more straight?

Dear Helmut!

From all what you have explained to me I have the impression that two so-called 'Cmax' values are not so very sound. I have the impression that the authors of the Q&A have had some ideal time courses with distinct bi-phases in their mind.

The FDA approach seems here more straight I think, taking the partial AUC as measure of 'early exposure' (as they have suggested already since times) and the one Cmax as measure of 'peak exposure'.

It suffers at least not from the inconsistencies in defining some 'Cmax,I' or 'Cmax,II' where no maximum is seen.

I think the discriminatory value of the partial AUC is well enough seen from the examples in the presentation.
Thus the additional metrics only raise the burden.

Regards,

Detlew
ElMaestro
★★★

Denmark,
2012-03-08 12:37
(4287 d 11:30 ago)

@ d_labes
Posting: # 8233
Views: 20,576
 

 and what about power?

Dear d_labes,

❝ I think the discriminatory value of the partial AUC is well enough seen from the examples in the presentation.

❝ Thus the additional metrics only raise the burden.


I agree.
Another practical issue for the sponsor will be power. In a normal BE study with a tablet having just one Cmax, the power is typiclly based on the expected T/R and the expected CV, the latter typically for Cmax as this is oftentimes slightly more variable than AUC.
In simple cases we might write something like P(Success) = P(BE AUC and Cmax) = P(BE AUC) * P(BE Cmax), but in reality Cmax and AUC are correlated and therefore the two components are not independent. It is implicitly assumed anyway when companies just ignore the less variable component and power the study for Cmax and assume that if Cmax is BE then AUC will be as well. This is a proven successful strategy as long as we don't talk inhalation products or other nasty things.
Now for the bi-phasic formulations. Here I am not sure what to do. I imagine a bunch of problems in practice. We will have four parameters that need to be BE, all of them are correlated. One could of course try and ID the most variable of them (Cmax,II?) and power on basis of that but I would certainly not feel comfortable to relay the message to management that the chancee of success is 80% if the dimensioning is based on power consideration for just one of the three/four parameters.

Finally, linear kinetics: How to assess it? What if something appears linear based on phase I but not really linear based on phase II?

Pass or fail!
ElMaestro
d_labes
★★★

Berlin, Germany,
2012-03-08 14:26
(4287 d 09:41 ago)

@ ElMaestro
Posting: # 8235
Views: 20,561
 

 and what about power?

Dear ElMaestro!

Very good points! I must confess I have not the slightest idea.

There is a publication out there which may be helpful:

Kem F. Phillips (!)
"Power for Testing Multiple Instances of the Two One-Sided Tests Procedure"
The International Journal of Biostatistics.
Volume 5, Issue 1, Pages 1–12.

I must further confess that I had not understood a lot of this paper.
Things like Wishart matrices are definitely beyond me.
Unfortunately Kem has only given R code for the case of two comparisions (2 TOST's).

Eventually you can make sense of it.
Thus expect some "mehl in der mehlkiste" :-).

Regards,

Detlew
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-03-08 14:36
(4287 d 09:31 ago)

@ ElMaestro
Posting: # 8236
Views: 20,619
 

 and what about power?

Dear ElMaestro!

❝ In simple cases we might write something like P(Success) = P(BE AUC and Cmax)= P(BE AUC) * P(BE Cmax), but in reality Cmax and AUC are correlated and therefore the two components are not independent. It is implicitly assumed anyway when companies just ignore the less variable component and power the study for Cmax and assume that if Cmax is BE then AUC will be as well.


Yessir! If you want to step into murky waters:

KF Phillips
Power for Testing Multiple Instances of the Two One-sided Tests Procedure
Int J Biostat 5(1), 1–12 (2009)


❝ Now for the bi-phasic formulations. Here I am not sure what to do. […] One could of course try and ID the most variable of them (Cmax,II?) …


I would say more likely Cmax,I.

❝ … and power on basis of that but I would certainly not feel comfortable to relay the message to management that the chancee of success is 80% if the dimensioning is based on power consideration for just one of the three/four parameters.


:-D

❝ Finally, linear kinetics: How to assess it? What if something appears linear based on phase I but not really linear based on phase II?


Oh dear! Yes, that’s theoretically possible if partial AUCs are very different (e.g. saturation of enzymes). Do you want me to check my MPH-data? Linear PK within 10–60 mg based on AUC0-t.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-03-08 13:51
(4287 d 10:16 ago)

@ d_labes
Posting: # 8234
Views: 20,958
 

 FDA more straight?

Dear Detlew!

❝ From all what you have explained to me I have the impression that two so-called 'Cmax' values are not so very sound. I have the impression that the authors of the Q&A have had some ideal time courses with distinct bi-phases in their mind.


First of all let me thank you again for your eagle eye. When I (rather too quickly) read the Q&A I was happy with the change because I think it’s a scientific valid approach. The term “biphasic MR formulations” is correct but does not imply that the profiles will exhibit some kind of “trough” between two distinct peaks. In other words: “biphasic” is related to pharmaceutical technology which may or may not translate into PK.

In presentations of the PK-working party about the MR guideline two different types of “multiphasic MR products” were distinguished:
  • Biphasic release (loading dose + maintenance dose)
  • Pulsatile release (delivers a burst of drug release at one or more predetermined time intervals)
Whilst the former consist of an IR part and a controlled release part the latter consists of one or more delayed relase part(s). Personally I don’t understand the difference between a “single-pulse system” and a conventional delayed release formulation, but I’m no specialist in pharmaceutical technology.
An interesting slide about metrics:[1]


Multiphasic modified release products
(e.g. biphasic- or pulsatile-release)

  • Partial AUC at different times after dosing
    e.g. AUC truncated at the population median of tmax values for reference formulation
  • Similarity factor for comparison of shape of concentration vs. time profiles
  • Clinical equivalence studies
  • Special relevance of tmax (pulsatile peak 4h vs 6h)
Now let’s see:
  • Truncation at population median: Though used by the FDA for many years (as a measure of early exposure) maybe EMA didn’t like it (data-driven?). OK, fixed cut-off instead.
  • Similarity factor f2: Not a statistic.[2] Relevance? Not a single publication. Led to serious grumbling sounds in the audience at the EUFEPS workshop (Barcelona, February 2011).
    Difference factor f1[3] proposed a while ago; BE if f1 ≤ 20.[4] α, β? Throw away your sample size tables!
  • Sure. Be prepared to setup nonparametric CIs of rating-scales according to Duchateau… :-D
  • Ha! Here we are. tmax for pulsatiles may be interesting. But: Even for simple DR formulations it’s a nightmare (different lag-times due to variable gastric emptying). Although I haven’t seen a two-pulse formulation myself I can imagine that it’s possible to have two distinguished peaks at e.g 3 and 5 hours in one case and at 7 and 10 hours in another. Fixed cut-off impossible (what if set to 6 h?). BTW, tmax leads to an anaphylactic shock of assessors. Maybe this is where the Cmax,I and Cmax,II come from?
For a comparison of some exotic metrics (together with two examples) see here (slides 24–32).

❝ The FDA approach seems here more straight I think, taking the partial AUC as measure of 'early exposure' (as they have suggested already since times) and the one Cmax as measure of 'peak exposure'.


Right, that’s clinical relevant thinking. Partial AUCs for efficacy and (global!) Cmax for safety.

❝ It suffers at least not from the inconsistencies in defining some 'Cmax,I' or 'Cmax,II' where no maximum is seen.


Exactly. See zolpidem and all osmotic pump systems.

❝ I think the discriminatory value of the partial AUC is well enough seen from the examples in the presentation.

❝ Thus the additional metrics only raise the burden.


Right again. I’m afraid we will have to wait until the draft is published and flood the PK group with comments. In the meantime we have to work according to the Q&A. If your formulation does not contain MPH or zolpidem – where a consensus about the cut-off seems to exist – invest a good deal of time in search not only the literature about PK but also about PD.


  1. Neuhauser J, Baumgärtel C. (AGES PharmMed, LCM)
    Understanding the proposed guideline for modified release. Presentation at “Innovations in Modified Release“, Berlin, 8 November 2011.
  2. Liu J-p, Ma M-C, Chow S-C. Statistical Evaluation of Similarity Factor f2 as a Criterion for Assessment of Similarity Between Dissolution Profiles. Drug Information Journal. 1997;31:1255–71.
  3. Moore JW, Flanner HH. Mathematical Comparison of curves with an emphasis on in vitro dissolution profiles. Pharm Tech. 1996;20(6):64–74.
  4. Bayoud HA, Awad AM. Performance of Several Bioequivalence Metrics for Assessing the Rate and Extent of Absorption. J Bioequiv Availab. 2011;3(7):174–7.
    doi:10.4172/jbb.1000080.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
luvblooms
★★  

India,
2012-03-09 07:55
(4286 d 16:12 ago)

@ Helmut
Posting: # 8240
Views: 20,534
 

 FDA more straight?

Dear HS/D_labes/El

Does that mean that the same would be applicable to Dexlansoprazole DR capsules as well???

What about varying rate of gastric emptying??

We have done a few studies on the said molecule and the first peak comes at 3 hr (range 30 min to 5 hrs) and second at 6 hrs (3-8 hrs) and the main reason was varying gastric emptying??

Then what should be the cut off time???? ;-)

You fix any cut off time and you will surely fail for partial AUC!!!!

Life of a generic scientist is getting tougher day by day!!!!!

Regards

Luv

~A happy Soul~
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-03-09 13:18
(4286 d 10:49 ago)

@ luvblooms
Posting: # 8241
Views: 20,657
 

 Multiphasic MR ≠ DR

Dear Luv!

❝ Does that mean that the same would be applicable to Dexlansoprazole DR capsules as well???


No. This is a delayed release formulation.

❝ What about varying rate of gastric emptying??

❝ We have done a few studies on the said molecule and the first peak comes at 3 hr (range 30 min to 5 hrs and second at 6 hrs (3-8 hrs) and the main reason was varying gastric emptying??


Not uncommon for PPIs. Sometimes physiology plays havoc with formulations.

❝ Then what should be the cut off time????

❝ You fix any cut off time and you will surely fail for partial AUC!!!!


No cut-off, no pAUCs. See the guidance – only conventional FDA's metrics: AUC0-t, AUC0-∞, Cmax. If you are able to show high variability in a replicate design study you are allowed to scale (both AUCs and Cmax).
AFAIK FDA has issued only two product specific guidances for “pAUC BE Metrics for Multiphasic MR Formulations”: zolpidem ER tablets and methylphenidate ER capsules.

❝ Life of a generic scientist is getting tougher day by day!!!!!


Well, I consider myself an ‘original scientist’. ;-)

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
jag009
★★★

NJ,
2012-03-28 17:29
(4267 d 07:38 ago)

@ Helmut
Posting: # 8341
Views: 20,193
 

 Multiphasic MR ≠ DR

Dear Helmut,

Do you think eventually FDA will impose the "biphasic" BE requirement for other methylphendiate MRs as well, like Metadate CD?

Thanks

John
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-03-28 17:45
(4267 d 07:22 ago)

@ jag009
Posting: # 8342
Views: 22,168
 

 Metadate CD (30/70)

Dear John!

❝ Do you think eventually FDA will impose the "biphasic" BE requirement for other methylphendiate MRs as well, like Metadate CD?


Definitely. The guidance deals with ER capsules. Metadate CD contains 30% of the dose as IR beads and 70% as ER beads. BTW, not bioequivalent to Concerta if partial AUC is considered.*


  • González MA, Pentikis HS, Anderl N, Benedict MF, DeCory HH, Dirksen SJ, Hatch SJ. Methylphenidate bioavailability from two extended-release formulations. Int J Clin Pharmacol Ther. 2002;40(4):175–8.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
UA Flag
Activity
 Admin contact
22,811 posts in 4,783 threads, 1,636 registered users;
26 visitors (0 registered, 26 guests [including 7 identified bots]).
Forum time: 00:07 CET (Europe/Vienna)

Believe those who are seeking the truth.
Doubt those who find it.    André Gide

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5