## Changing the regulations: Hope dies last. [NCA / SHAM]

❝ I don't think that our regulators will be able to understand this, …

Well, the majority of regulators is not stupid.

That’s

*basic*PK and \(\small{CL=\textrm{const}}\) is a pretty

*strong*assumption, which might be outright

*false*. Then the entire concept is built on sand: Studies are substantially larger than necessary, exposing innocent subjects to nasty drugs.

❝ … or there will be a desire and dare to change the foundations.

Correct. However, the FDA

^{1}gives in its regulatory definitions of BE ‘rate and extent of absorption’ without mentioning any PK metrics, the EMA

^{2}‘BE with the reference medicinal product […] demonstrated by appropriate bioavailability studies’. Only the WHO

^{3}gives specifically

*AUC*for the extent of absorption. Too lazy to check other jurisdictions.

Somehow it reminds me on the comparison of \(\small{AUC_{t_\textrm{last}}}\), which is

*known*to be biased if \(\small{t_\textrm{last,T}\neq t_\textrm{last,R}}\). Nobody gives a shit. Remember the endless story of the inflated Type I Error in SABE? For HVDs (not HVDPs) probably we could counteract the high variability, use ABE with

*fixed*limits, and all is good.

Of course, it would mean changing the guidelines.

Abdallah (FDA/CDER):

It is recommended that area correction be attempted in bioequivalence studies of drugs where high intrasubject variability in clearance is known or suspected. […] The value of this approach in regulatory decision making remains to be determined.

Lucas*et al.*:

Performance of the AUC·k ratio test […] indicate that the regulators should consider the method for its potential utility in assessing HVDs and lessening unnecessary drug exposure in BE trials.

❝ Also, I think NLME modeling can be applied.

Hhm, can you elaborate?

- CFR 21–320.23(b)(1). 2021.

- Directive 2001/83/EC, Article 10(2)(b). 2001.

- TRS 992, Annex 6. 2017.

P.S.: \(\small{C_\textrm{max}}\) is a lousy metric for comparing rates of absorption, since it is

*composite*of \(\small{k_\textrm{a}}\) and \(\small{AUC_{0-\infty}}\). Lots of publications… What about: $$\small{\frac{F_\textrm{T}}{F_\textrm{R}}\sim \frac{C_\textrm{max,T}\big{/}\left(AUC_{0-\infty,\textrm{T}}\cdot k_\textrm{T} \right)}{C_\textrm{max,R}\big{/}\left(AUC_{0-\infty,\textrm{R}}\cdot k_\textrm{R} \right)}}$$ Deserves a paper.

*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

### Complete thread:

- AUC · k for variable inter-occasion CL Helmut 2021-09-30 23:31 [NCA / SHAM]
- AUC · k for variable inter-occasion CL PharmCat 2021-10-01 00:15
- Changing the regulations: Hope dies last.Helmut 2021-10-01 11:18
- AUC * k d_labes 2021-10-01 13:52
- AUC * k Helmut 2021-10-01 17:01
- AUC * k d_labes 2021-10-02 10:55
- Ratio/product of two lognormals Helmut 2021-10-03 20:29
- Not for HVDPs? Helmut 2021-10-04 12:05
- what about recyclers? mittyri 2021-10-04 14:22
- Oh dear! Helmut 2021-10-04 16:10

- what about recyclers? mittyri 2021-10-04 14:22

- AUC * k d_labes 2021-10-02 10:55

- AUC * k Helmut 2021-10-01 17:01
- Changing the regulations: Hope dies last. PharmCat 2021-10-01 18:48

- AUC * k d_labes 2021-10-01 13:52

- Changing the regulations: Hope dies last.Helmut 2021-10-01 11:18

- AUC · k for variable inter-occasion CL PharmCat 2021-10-01 00:15