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M.tareq
Junior

2017-12-31 16:17

Posting: # 18130
Views: 985
 

 Non-compartmental analysis [Regulatives / Guidelines]

Dear all,

As per guidelines "Non-compartmental methods should be used for determination of pharmacokinetic parameters in
bioequivalence studies. The use of compartmental methods for the estimation of parameters is not
acceptable"

why the non-Compartmental analysis is preferred over compartmental ones ?

also use of PK/PD models to establish BE, as per my understanding BE is about detecting differences between formulations in healthy volunteers and from that, it can be extended to patients population.

PK/PD models can't be used to detect such differences? and conclude BE?



Also regarding use of pop/INDV BE, most FDA OGD drafts revolve around use of average BE in most cases and in case of HVDP, reference scaling and/or variability comparison -for FDA and SCABEL for EMA- is preferred due to number of subjects that would be needed.

when pop/indv BE is feasible or applicable? does the nature of the drug molecule determine such approach? also any published BE studies based on either of them.

Thanks in advance.
ElMaestro
Hero

Denmark,
2017-12-31 16:56

@ M.tareq
Posting: # 18131
Views: 853
 

 Non-compartmental analysis

Dear M.tareq,

» why the non-Compartmental analysis is preferred over compartmental ones ?

You have a point, certainly. When we want to know the PK-properties of a new drug we naturally use the compartmental methods to describe it.
But there are two good reasons to stick to noncompartmental:
1. There is not problem doing so. Experience has shown NCA to be a very useful and simply way of ascertaining that two products can be compared. Perhaps not in 100.0000% of cases but just in the vast majority. Hence that wording has found its way into guidance.
2. If we did compartmental analysis then we would open up the door to a plethora of settings, and results that would be package-dependent. Just think about the way the various constants are determined. It can be done in some many ways, and regulators would have difficulty in reproducing applicant's results in all cases.
In a way you can say NCA relies on fewer assumptions, making it more generally applicable.

» also use of PK/PD models to establish BE, as per my understanding BE is about detecting differences between formulations in healthy volunteers and from that, it can be extended to patients population.

BE in Europe is about detecting differences (or proving similarity) in rate and extent of absorption. BE in US is about rate and extent of the drug becoming available at the site of action. Thus in EU, BE is tightly linked to PK but not to PD. In US BE in contrast can be proven with PD.

» PK/PD models can't be used to detect such differences? and conclude BE?

See above.

» Also regarding use of pop/INDV BE, most FDA OGD drafts revolve around use of average BE in most cases and in case of HVDP, reference scaling and/or variability comparison -for FDA and SCABEL for EMA- is preferred due to number of subjects that would be needed.

Strictly speaking, EU agencies and FDA have no preference per se. They allow the use of scaling when the design and outcome within the study allows it.

» when pop/indv BE is feasible or applicable? does the nature of the drug molecule determine such approach? also any published BE studies based on either of them.

PopBE and IndivBE are today mainly relics from a bygone age. They were a complex solution to a problem that was never really existing in practice; it was essentially driven forward by theorist regulators with a poor understanding of real life, and possibly also by originator companies that wanted to out up obstacles to generics entry (try and check BE, alcohol and dose dumping for another example of how ugly this can get).
The absence of PopBE and IndivBE is simply not an issue. Products approved on basis of ABE, whether scaled or not will generally be safe and efficaceous as long as data is credible.

When I say generally, I mean "generally" which isn't quite the same as "always".

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
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