Beholder
★    

Russia,
2019-11-08 07:51
(edited by Beholder on 2019-11-08 11:27)

Posting: # 20764
Views: 183
 

 Clarification from Russian expert organization regarding telmisartan BE studies [Regulatives / Guidelines]

Hi to all!

An article which might serve as "guideline" for conducting telmisartan BE studies in Russia written by expert organization representative. Open access and abstract in English is available.

Main points represented in the article:
  1. 7 BE studies performed in Russia were assessed.
  2. Not only males should be enrolled but females as well (50/50).
  3. HPLC FLD is, in some cases, more sensitive than HPLC MS/MS (see study 3) ;-).

Best regards
Beholder
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2019-11-08 15:35

@ Beholder
Posting: # 20768
Views: 146
 

 Clarification from Russian expert organization…

Hi Beholder,

» An article which might serve as "guideline" for conducting telmisartan BE studies in Russia written by expert organization representative. Open access and abstract in English is available.

THX; interesting. In Table 3 three studies are give twice each. Could reproduce the pooled CV of Cmax (43.57%). The upper limit 44.84% is based on a 75% CI. I would use a 80% CL. Given.

library(PowerTOST)
design <- "2x2x2"
n      <- c(85, 36, 40, 59, 60, 50, 40)
CV     <- c(43.27, 32.72, 33.67, 48.35, 49.45, 34.12, 55.34)/100
df     <- n - 2
study <- data.frame(design = "2x2x2", n = n,
                    df = df, CV = CV, CV.CL = NA,
                    stringsAsFactors = FALSE)
for (j in seq_along(CV)) {
  study$CV.CL[j] <- signif(CVCL(CV = study$CV[j], df = study$df[j],
                                side = "upper", alpha = 0.25)[["upper CL"]], 4)
}
print(study); print(CVpooled(study, alpha = 0.25), verbose = TRUE)

#   design  n df     CV  CV.CL
# 1  2x2x2 85 83 0.4327 0.4677
# 2  2x2x2 36 34 0.3272 0.3701
# 3  2x2x2 40 38 0.3367 0.3781
# 4  2x2x2 59 57 0.4835 0.5331
# 5  2x2x2 60 58 0.4945 0.5449
# 6  2x2x2 50 48 0.3412 0.3778
# 7  2x2x2 40 38 0.5534 0.6280
# Pooled CV = 0.4357 with 356 degrees of freedom
# Upper 75% confidence limit of CV = 0.4485


The recommended sample of 20 subjects is for a 2×2×4 design and ABEL based on a GMR of 0.95 and CV 0.45). I would not be that optimistic and suggest a GMR of not better than 0.90 (42 subjects).
Not sure whether it makes sense to work with the pooled CV at all (different sampling schedules and bioanalytical methods).

I like that the experts recommend 2-sequence 4- (TRTR|RTRT) and 3-period (TRT|RTR) full replicate designs and not the lousy partial replicate. Kudos!

Cheers,
Helmut Schütz
[image]

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

Russia,
2019-11-08 22:00

@ Helmut
Posting: # 20772
Views: 114
 

 Questions

Hi Helmut,

» In Table 3 three studies are give twice each. Could reproduce the pooled CV of Cmax (43.57%). The upper limit 44.84% is based on a 75% CI. I would use a 80% CL. Given.

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

Questions:
  • 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'
  • what do you think about FLU results (study 3)? 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

Kind regards,
Mittyri
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2019-11-09 11:36

@ mittyri
Posting: # 20776
Views: 85
 

 Guesses & answers

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
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Activity
 Thread view
Bioequivalence and Bioavailability Forum |  Admin contact
19,975 posts in 4,227 threads, 1,373 registered users;
online 6 (0 registered, 6 guests [including 4 identified bots]).
Forum time (Europe/Vienna): 00:40 CET

The fundamental cause of trouble in the world today is
that the stupid are cocksure
while the intelligent are full of doubt.    Bertrand Russell

The BIOEQUIVALENCE / BIOAVAILABILITY FORUM is hosted by
BEBAC Ing. Helmut Schütz
HTML5