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Back to the forum  Query: 2017-06-27 02:08 CEST (UTC+2h)
 
Dr_Dan
Senior

2017-06-08 16:57

Posting: # 17461
Views: 850
 

 increased solubility = different PK profile? [Dissolution / BCS / IVIVC]

Dear all
there are tons of literature describing how the bioavailability of certain drugs can be improved but AFAIK this seldom leads to new products. My question in this regard is: if I have a reference product with a low soluble drug substance and developed a test product with an increased solubility of the same drug would it then be possible to achieve bioequivalence even if the dose of the new product can be adjusted?
I guess not, but I would like to learn your opinions.
IMHO in case dissolution is the time determining step you are confronted with the following dilemma: either you can reach the same Cmax but you would have a lower AUC and vice versa you can reach the same AUC but Cmax will be increased. The shorter t1/2 the more pronounced is this effect, right?
And if you can not demonstrate bioequivalence you are forced to conduct phase III studies for the registration of your new product and this makes the new product unattractive from a commercial point of view.
Do you have any experience in this field?

Kind regards and have a nice day
Dr_Dan
nobody
Senior

2017-06-08 17:16

@ Dr_Dan
Posting: # 17462
Views: 759
 

 increased solubility = different PK profile?

Hi Dr!

To me: That's not how it works with generics. Go for equivalent dissolution and therefore Cmax/AUC. End of story.

Why go for "better" solubility and end up non-BE? ;-) Don't see the point at all.

You could go for some hybrid application in Europe (regulatory is not my piece of cake), but good luck with explaining the "advantage" of your product to the authority(ies) :-D

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2017-06-08 17:18

@ Dr_Dan
Posting: # 17463
Views: 758
 

 increased solubility = different PK profile?

Dear Dan,

do I get you right: BCS Class 2?

» IMHO in case dissolution is the time determining step you are confronted with the following dilemma: either you can reach the same Cmax but you would have a lower AUC and vice versa you can reach the same AUC but Cmax will be increased.

Cmax is a lously PK metric. It is pretty insensitive to changes in the rate of absorption (papers by the two Lászlós two decades ago). Let’s say you will get the same AUC. Then the true rate of absorption (ka) can increase a lot until you will fall out of the BE-limits for Cmax.

» The shorter t1/2 the more pronounced is this effect, right?

No idea.

» And if you can not demonstrate bioequivalence you are forced to conduct phase III studies for the registration of your new product and this makes the new product unattractive from a commercial point of view.

Yes.

» Do you have any experience in this field?

No.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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nobody
Senior

2017-06-08 17:22

@ Helmut
Posting: # 17464
Views: 761
 

 increased solubility = different PK profile?

» Cmax is a lously PK metric. It is pretty insensitive to changes in the rate of absorption (papers by the two Lászlós two decades ago). Let’s say you will get the same AUC. Then the true rate of absorption (ka) can increase a lot until you will fall out of the BE-limits for Cmax.

Hmmm, did anybody try to establish ka as an alternative in BE? Would be fun to see some 100s of old BE-trials re-evaluated based on ka, I guess...

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2017-06-09 14:35

@ nobody
Posting: # 17477
Views: 649
 

 ka vs. Cmax

Hi nobody,

» Hmmm, did anybody try to establish ka as an alternative in BE?

IIRC, it was the other way ’round. Theoretically we are interested in ka, and Cmax (better together with tmax) is only a better accessible surrogate for it. In the early days of BE people tried to estimate ka indeed. For a one-com­partment model Wagner-Nelson or the residual method works. But: Due to error propagation, the estimate is not very robust. For more than one compartment we have only Loo-Riegelman and deconvolution (both requiring IV data and six to ten samples up to ~2×tmax). Difficult. So, people gave up and since then Cmax is the established surrogate metric for the rate of absorption.

» Would be fun to see some 100s of old BE-trials re-evaluated based on ka, I guess...

AFAIK, in those ol’ days BE-limits for ka were never defined. Given that Cmax is less sensitive (influenced by AUC) – even if one has data to reliably estimate ka – I guess it would be rather difficult to show BE with the common limits.

[image]All the best,
Helmut Schütz 
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The quality of responses received is directly proportional to the quality of the question asked. ☼
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nobody
Senior

2017-06-09 16:27

@ Helmut
Posting: # 17478
Views: 630
 

 ka vs. Cmax

...deconvolution YEAH! That rocked... :-D

BE for ka would be (much) harder, was my first opinion, too. Would be nice to see some data. I think we need some data slaves (aka Diplomanden, Ph.D. students...) here to do all the funny calculations we come up with ;-)

Sorry for OT, but it's Friday:

https://xkcd.com/1847/

Kindest regards, nobody
mittyri
Senior

Russia,
2017-06-10 14:59

@ Helmut
Posting: # 17483
Views: 579
 

 ka vs. Cmax

Hi Helmut & nobody,

Just got a chance to listen Laszlo Tothfalusi regarding this one

I'm not Nick H. and not Mats K. ever, but for me the problem is oversimplified there (Linked PKPD model with Concentration dependent hazard).

Since Ka is a key parameter (OK,ok, bioavailability) for bioequivalence, we need to get more suitable model for absorption of each drug (taking into account different rates for different parts of intestine, first-pass metabolism, distributed delay of absorption and so on)
PBPK guys are trying hard but it is still just endless investigations...

Even if all things are done, we got some tricky distribution of Ka among the population depending on formulation and many other things. Then we need to compare the distributions in some given populations...
Oh, sorry, looks like I was overdosed by popPK people :-D

Kind regards,
Mittyri
ElMaestro
Hero

Denmark,
2017-06-08 17:24

@ Dr_Dan
Posting: # 17465
Views: 753
 

 increased solubility = different PK profile?

Dear Dr_Dan,


» (...) low soluble drug substance and developed a test product with an increased solubility of the same drug would it then be possible to achieve bioequivalence even if the dose of the new product can be adjusted?

Not understood.
You mean an injectable in two different solvents for T and R?
Usually formulations do not increase solubility. It is intrinsic. I probably got your basic message a bit wrong here?


» (...) same AUC but Cmax will be increased.
» Do you have any experience in this field?

It is common in the intra-nasal and inaled field to see matching AUCt and non-matching Cmax or vice versa. Sometimes -quite often even- this can be negotiated with an agency. But it requires dialogue and most important of all the right agency and the right attitude from the guys in the Armani suits who otherwise want to decide which countries to include in the first wave of DCPs.

There are no rules. Case by case, weight of evidence, yada yada yada :-):-)

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
Dr_Dan
Senior

2017-06-08 17:36

@ ElMaestro
Posting: # 17466
Views: 754
 

 increased solubility = different PK profile?

O.k., I see I need to add some more information. The idea behind this question is to develop an oral formulation with a less drug load than the reference product but with the same bioavailability in order to decrease non-systemic adverse events.

Kind regards and have a nice day
Dr_Dan
nobody
Senior

2017-06-08 17:43

@ Dr_Dan
Posting: # 17467
Views: 750
 

 increased solubility = different PK profile?

» O.k., I see I need to add some more information. The idea behind this question is to develop an oral formulation with a less drug load than the reference product but with the same bioavailability in order to decrease non-systemic adverse events.

If you claim less AEs, you will have to proof it. In my opinion. So: Clinical trials ahead, I guess.

Kindest regards, nobody
Ohlbe
Hero

France,
2017-06-08 18:23

@ Dr_Dan
Posting: # 17469
Views: 749
 

 increased solubility = different PK profile?

Dear Dr Dan,

» The idea behind this question is to develop an oral formulation with a less drug load than the reference product but with the same bioavailability in order to decrease non-systemic adverse events.

There is one (old) example I can think of: fenofibrate. Very low solubility. Started with a 300 mg capsule formulation. Decreased to 200 mg with an improved formulation (if I remember correctly, co-micronisation with sodium laurylsulfate). Decreased further with new formulation improvements: 160 mg and now 145 mg tablets.

I don't know through which type of procedure they were approved, whether BE was demonstrated on both Cmax and AUC, and whether they did any clinical trials in addition to BE. But it may be worth having a look at public assessment reports, if available.

Regards
Ohlbe
nobody
Senior

2017-06-08 18:58

@ Ohlbe
Posting: # 17472
Views: 750
 

 increased solubility = different PK profile?

...had a quick look for Lipanthyl at the French authority, could find anything meaningful...

Kindest regards, nobody
ElMaestro
Hero

Denmark,
2017-06-08 18:45

@ Dr_Dan
Posting: # 17470
Views: 743
 

 increased solubility = different PK profile?

Hi Dr_Dan,


» O.k., I see I need to add some more information. The idea behind this question is to develop an oral formulation with a less drug load than the reference product but with the same bioavailability in order to decrease non-systemic adverse events.

"To support safety, it should be demonstrated that the systemic exposure is not higher for the test product than for the reference product, i.e. the upper limit of the 90% confidence interval should not exceed the upper bioequivalence acceptance limit 125.00."

Taken from section 3.4 here.

In my experience it is enforced the way it is written and even though 3.4 deals with OIP&scaling the sentence is enforced verbatim even in situations where scaling is not a topic when a 10.3 submission is foreseen even if it isn't an OIP.
Pick the right agency. I can't emphasize it enough. :ok::pirate:

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
nobody
Senior

2017-06-08 18:57

@ ElMaestro
Posting: # 17471
Views: 744
 

 increased solubility = different PK profile?

Hmmm, but with lower than REF systemic exposure you should not be able to proof efficacy, I guess?

Kindest regards, nobody
nobody
Senior

2017-06-09 09:38

@ nobody
Posting: # 17474
Views: 676
 

 increased solubility = different PK profile?

...and btw. 1.2 from ElMaestros link would be relevant, in my opinion...

Kindest regards, nobody
Kiran
Junior

2017-06-24 11:02

@ Dr_Dan
Posting: # 17499
Views: 102
 

 increased solubility = different PK profile?

Hello everyone,

I am new to the group, found this topic interested, can we decrease the extent of release of test product containing highly soluble polymorphic form by varying formulation changes in order to match the dissolution profile with that of reference product containing low soluble polymorphic form ??.

I am asking thus because inorder to match the dissolution profile of low soluble polymorphic form of generic product with that of highly soluble polymorphic form of reference products we generally adopt methods such as micronisation, adding solubility enhancers, solid dispersion technology .

Any opinions???


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut]
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