## Guesses & answers [Regulatives / Guidelines]

Hi mittyri,

» They stated above regarding 90% CI. Don't know what kind of distribution was used for CI calculation.

I think that’s wrong. The upper 90% confidence limit of the pooled CV (0.4357) with 356 degrees of freedom is 0.4601.

library(PowerTOST) alpha <- c(0.25, 0.20, 0.10) CV    <- 0.4357 df    <- 356 res <- data.frame(alpha = alpha, df = df, CV = CV, upper.CL = NA) for (j in seq_along(alpha)) {   res\$upper.CL[j] <- signif(CVCL(CV = CV, df = df, side = "upper",                                  alpha = alpha[j])[["upper CL"]], 4) } print(res, row.names = FALSE) # alpha  df     CV upper.CL #  0.25 356 0.4357   0.4485 #  0.20 356 0.4357   0.4516 #  0.10 356 0.4357   0.4601

»   – what do you think about statement that males and females (50/50) should be enrolled, since RLD says regarding sex differences in PK? 'Otherwise the marketed formulation could be not BE for other gender'

From the EPAR:

Plasma concentrations were higher in females than in males, without relevant influence on efficacy.
Differences in plasma concentrations were observed, with Cmax and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males.

That confirms the observation that highly variable drugs have a flat dose-response curve (no relevant influence on efficacy despite significantly higher concentrations). Since the experts recommended males and females, go for it. Bioanalysts will like it.

»   – what do you think about FLU results (study 3)?

I don’t believe it. Look at Figure 1 and Table 1.

» There's a comment in the text stated that LC-MSMS should be recommended since higher (!) concentrations were achieved with that method and LLOQ 0.5-3.0

Agree. The concentration in study 3 are way lower than what is not only seen in the other studies but also in the originator’s. Furthermore, the LLOQ is 14% of the (mean!) Cmax. That’s insufficient.

Cheers,
Helmut Schütz

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