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Back to the forum  Query: 2017-08-24 06:41 CEST (UTC+2h)
 
mmw
Junior

India,
2017-05-06 11:07

Posting: # 17308
Views: 1,867
 

 Pharmacokinetic parameters CL, Vd and F [Regulatives / Guidelines]

Dear All,

As per the Guideline, for CFDA submissions, pharmacokinetic parameters CL, Vd and F needs to be submitted.

Can we calculate these parameters in Phoenix software?

Thank you in advance.

Regards

MMW


Edit: Category changed (was: software). [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-06 12:14

@ mmw
Posting: # 17309
Views: 1,683
 

 Pharmacokinetic metrics CL, Vd and F

Hi MMW,

» As per the Guideline, for CFDA submissions, …

This one (page 17)?

F = 100×AUCT/AUCR.

If the drug exhibits linear PK and different doses are administered a correction is suggested

F = 100×(AUCT×DR)/(AUCR×DT).


» … pharmacokinetic parameters CL, Vd and F needs to be submitted.

<nitpicking>

pharmacokinetic modeling → PK parameters
noncompartmental analysis → PK metrics

</nitpicking>

» Can we calculate these parameters in Phoenix software?

If you have a Phoenix/WinNonlin license, please RTFM. ;-)

To calculate ƒ (absolute bioavailability after an extravascular dose) you need a crossover study with EV vs. IV doses. Better is simultaneous administration of EV and stable isotope labeled IV – which requires cGMP of the IV dose (that’s a big obstacle). Then

ƒ = (AUC∞,EV×DIV)/(AUC∞,IV×DEV) and
F (%) = 100ƒ.

Note that ƒ calculated from a crossover study assumes constant inter-occasion clearances, which might not be correct (especially for highly variable drugs*).
CL and Vd are only accessible after an intravenous dose, where

CL = D/AUC and
Vd = D/C0.

Without ƒ (i.e., only EV dosing) you get just CL/ƒ and Vd/ƒ, which IMHO is of limited value since ƒ is unknown. Both are given in the standard output of Phoenix/WinNonlin. Report them to make the CFDA happy (irrelevant in BE) but please not as CL and V.


  • If the study is sufficiently large, ƒ might still be usable though the subjects show extreme variability in PK.

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

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Shuanghe
Regular

Spain,
2017-05-08 16:16

@ Helmut
Posting: # 17318
Views: 1,510
 

 Pharmacokinetic metrics CL, Vd and F

Hi,

» As per the Guideline, for CFDA submissions, pharmacokinetic parameters CL, Vd and F needs to be submitted
»
» This one (page 17)?

No longer true.

BE guideline linked by Helmut was from 2005 and it was updated by CFDA in 2015 (as an appendix in Chinese Pharmacopeia 2015 Edition) and it's basically a copy of EMA's BE guideline (with some missing information). However, in 2016, they also published another BE guideline (3rd attachment, in Chinese), which is basically a copy from FDA's BE guidance. So it's a bit of mess now as you can imagine. e.g., FDA and EMA has quite different opinion about fasting and/or fed study for solid oral immediate-release dosage forms (depending on SPC's recommended administration method), in addition to many other aspects. Which guideline should one follow?

I recently helped to review a BE protocol in China and they follow the newer guideline. So FDA beats EMA in China so to speak. :-D. e.g., for the IR oral dosage I reviewed, instead of fasting BE only they will do both fasting and fed.

There are many other things to consider. One thing I'm sure is that all those parameters, or metric as Helmut prefer ;-), mentioned above are no longer required.

So MMW, I'd suggest that you talk to some guys in China to have updated info. before you do anything.

All the best,
Shuanghe
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-09 13:52

@ Shuanghe
Posting: # 17334
Views: 1,457
 

 CFDA 2016 BE-GL

Hi Shuanghe,

» […] in 2016, they also published another BE guideline (3rd attachment, in Chinese), which is basically a copy from FDA's BE guidance.

THX for the update!

» So it's a bit of mess now as you can imagine. e.g., FDA and EMA has quite different opinion about fasting and/or fed study for solid oral immediate-release dosage forms (depending on SPC's recommended administration method), in addition to many other aspects.

If I trust in Google-translate:
AUC0–72 only for drugs with a long half-life. What does the last sentence mean?
Seemingly no reference-scaling.
Multiple strengths of drugs with nonlinear PK (grater than proportional increase in AUC)?

EMA: highest strength.
FDA: highest therapeutic dose.
CFDA?


» Which guideline should one follow?

The latest one (as you did)… :-D

[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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Shuanghe
Regular

Spain,
2017-05-10 13:03

@ Helmut
Posting: # 17342
Views: 1,408
 

 CFDA 2016 BE-GL

Hi Helmut,

» If I trust in Google-translate:

Lately it's getting better. I recently read quite a long piece of BE guideline in Russian to look for something specific. I can't imagine I'd be able to do that without it. :cool:

» AUC0–72 only for drugs with a long half-life. What does the last sentence mean?

Basically it's a translation from the FDA's guidance in the corresponding section:
"For drugs demonstrating high intrasubject variability in distribution and clearance, AUC truncation should not be used."

» Seemingly no reference-scaling.

It was mentioned in the section about general study design (page 4 of the word file) but there's no details. There's only one sentence about HVDP and I gave the rough translation as follows:

"With regard to high variable drug product, depending on the intra-subject variability of the reference product, the bioequivalence criteria can be adjusted appropriately; however, such adjustment should be based on adequate evidence."

There are more details about HVDP in the appendix of Chinese Pharmacopedeia 2015. It was mentioned that for Cmax the maximum criteria can be widened to 69.84% to 143.19% (ratio within 80–125%) but they didn't copy the rest information such as [U, L] = exp [±k·sWR], from EMA's guide (So if one doesn't know EMA's method, how can he/she obtain criteria for any particular CV%? :-D)

From a presentation in BE training course given by CFDA staff in 2017, it seems they are using EMA's approach for HVDP.

» Multiple strengths of drugs with nonlinear PK (grater than proportional increase in AUC)?
» EMA: highest strength.
» FDA: highest therapeutic dose.
» CFDA?

I think that FDA also recommend highest strength, same as EMA. See line 316–319 in the draft guidance. Where did it mention highest therapeutic dose? :confused:

For CFDA, highest strength.

To summarise, I think CFDA mixed EMA's and FDA's latest BE guides as their BE guide and took a stricter one when there's difference betweem EMA and FDA. e.g., fasting + fed for almost all drug as FDA does but there's cap of Cmax criteria for HVDP as EMA does.

All the best,
Shuanghe
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-10 15:17

@ Shuanghe
Posting: # 17344
Views: 1,389
 

 nonlinear PK: highest dose ⇔ strength

Hi Shuanghe,

THX for your explanations!

» » Multiple strengths of drugs with nonlinear PK (grater than proportional increase in AUC)?
» » EMA: highest strength.
» » FDA: highest therapeutic dose.
»
» I think that FDA also recommend highest strength, same as EMA. See line 316–319 in the draft guidance. Where did it mention highest therapeutic dose? :confused:

See lines 325–326 of the draft (and also the 2003 guidance). Applicable if linear PK is documented. I was referring to Davit et al.* (all authors of the FDA). Excerpt:

[…] generally the highest dose strength be used for in vivo BE studies, unless reasons of safety justify using a lower strength. In the case of drug substances that are characterized by nonlinear PK over the clinical dosing range, Canada, the EMA, USA, and WHO specify which dose strength should be used in these cases, depending on the type of nonlinearity and the underlying mechanism.

Dose strength used in the in vivo studies

  • Similarities
    All recommend that generally in vivo studies should be performed on the highest strength, unless reasons of safety justify use of a lower strength

  • Differences
    Some jurisdictions specify which strength should be used for drugs with nonlinear PK over the clinical dosing range, as follows
    EMA: the strength to be used depends upon the type of nonlinearity and the underlying causes
    If the nonlinearity is characterized by greater than proportional increases in AUC with increasing dose, conduct the BE studies on at least the highest strength
    USA: the strength to be used depends upon the type of nonlinearity
    If the nonlinearity is characterized by greater than proportional increases in AUC with increasing dose, conduct the BE studies on at least the highest therapeutic dose (38)

Highest dose vs. highest strength was a major issue at the 1st GBHI conference in Amsterdam 2015. No consensus reached…



[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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d_labes
Hero

Berlin, Germany,
2017-05-10 15:41

@ Helmut
Posting: # 17345
Views: 1,366
 

 highest dose ⇔ strength for dummies

Dear Helmut, dear all,

what I always wondering about and didn't dare to ask such silly question:
What is highest dose ⇔ strength?

Regards,

Detlew
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-10 15:45

@ d_labes
Posting: # 17346
Views: 1,356
 

 highest dose ⇔ strength for dummies

Dear Detlew,

» what I always wondering about and didn't dare to ask such silly question:

Dare To Be Stupid

» What is highest dose ⇔ strength?

Example phenytoin: Nonlinear PK (greater than proportional increase in AUC), NTID. Highest strength 100 mg (studies for the EMA). Highest approved therapeutic dose 3×100 mg (studies for the FDA).

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

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

Berlin, Germany,
2017-05-10 16:20

@ Helmut
Posting: # 17347
Views: 1,351
 

 highest dose ⇔ strength for dummies

Dear Helmut,

» Example phenytoin: Nonlinear PK (greater than proportional increase in AUC), NTID. Highest strength 100 mg (studies for the EMA). Highest approved therapeutic dose 3×100 mg (studies for the FDA).

If somebody creates a 300 mg tablet / capsule ... whatever, then highest strength is 300 mg :confused:. Or what?

Regards,

Detlew
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-10 16:28

@ d_labes
Posting: # 17348
Views: 1,347
 

 highest dose ⇔ strength for dummies

Dear Detlew,

» » Example phenytoin: Nonlinear PK (greater than proportional increase in AUC), NTID. Highest strength 100 mg (studies for the EMA). Highest approved therapeutic dose 3×100 mg (studies for the FDA).
»
» If somebody creates a 300 mg tablet / capsule ... whatever, then highest strength is 300 mg :confused:.

Not easy. First of all, what is the reference? For the EMA it is the product which was approved based on a complete dossier (acc. to article 8(3), 10a, 10b or 10c of 2001/83/EC). Say the highest strength was 100 mg and up to 300 mg were used in phase III. Hence, the innovator can develop a new 300 mg strength and get it approved in a line extension (only BE studies 300 mg vs. 3×100 mg).

Tricky for a 300 mg strength not developed by the originator:
  1. Highest strength of the innovator still 100 mg. Hybrid application (acc. to 8(3) of 2001/83/EC): Comparative BA 300 mg vs. 3×100 mg plus clinical studies.
  2. Highest strength of the innovator already 300 mg. Strictly speaking this product was not approved based on a complete dossier (but a line extension). IMHO, you cannot apply for a purely generic application (300 mg vs. 300 mg). Is case (a) applicable? Duno. Ask a lawyer and go for a scientific regulatory advice.
For the FDA at least the selection of the reference is somewhat easier: “RLD is what we decide to be the RLD. Full stop.” Look it up Drugs@FDA. If the originator gets a new 300 mg approved, the FDA might list this strength as the new RLD or decide to keep the 100 mg as the RLD…

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

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

Berlin, Germany,
2017-05-11 16:31

@ Helmut
Posting: # 17350
Views: 1,263
 

 highest dose ⇔ strength for dummies

Dear Helmut,

many thanks for enlighten me.

But I must confess I don't understand really.

Regards,

Detlew
mmw
Junior

India,
2017-05-15 06:53

@ Helmut
Posting: # 17354
Views: 1,078
 

 highest dose ⇔ strength for dummies

Dear All,

Thanks for your responses and updation.

MMW
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