## Interpreting results of a DDI study [Design Issues]

you confirmed in registration that you have read and will comply with the forum’s policy. Please read the relevant section again. You managed it to full quote in

*all*of your replies. That’s an amazing percentage.

Hence, this is the first warning.

You shouldn’t expect to learn the

*basics*from an internet forum. Suggested reading:

- Hauschke D, Steinijans V, Pigeot I.
*Bioequivalence Studies in Drug Development. Methods and Applications.*Chichester; Wiley: 2007.

Chapter 8:*Analysis of pharmacokinetic interactions.*

- Chow S-C, Liu J-p.
*Design and Analysis of Bioavailability and Bioequivalence Studies.*Boca Raton; Chapman & Hall / CRC Press: 3^{rd}ed. 2009.

Chapter 18.2:*Drug Interaction Studies.*

- Patterson S, Jones B.
*Bioequivalence and Statistics in Clinical Pharmacology.*Boca Raton; Chapman & Hall / CRC Press: 2^{nd}ed. 2017.

Chapter 8.4:*Food Effect Assessment and Drug-Drug Interactions (DDIs).*

- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.
*Drug Interaction Studies. M12.*08 June 2022. Online.

*clinically relevant*interaction is found, there’s no reason to panic. It only has to be stated as such in the label / prescribing information.

❝ […] concluded there is no clinically relevant drug–drug interaction between CHF 5993 and result of cimetidine co-administration, with total exposure increased by 16 %, and peak concentration by 26 %.

❝ I need to know how they concluded.

What do you fail to understand?

Methods

This two-period, open-label, crossover study examined the drug–drug interaction of CHF 5993 and cimetidine. In one period, subjects received cimetidine 800 mg twice daily for 6 days; on the fourth day they also received CHF 5993 (BDP/FF/GB 400/24/100 µg). In the other, they received CHF 5993 alone. Primary objective was to compare the area under the plasma concentration–time curve from time 0 to last quantifiable concentration (AUC_{0–t}) of GB, with and without cimetidine. Secondary endpoints included GB AUC_{0–12h}, maximum concentration (C_{max}) […]

Results

Twenty-six subjects were randomised; 25 completed. Co-administration of CHF 5993 and cimetidine resulted in small, statistically significant increases in GB AUC_{0–t}, AUC_{0–12h} and C_{max} vs CHF 5993 (ratios 1.16, 1.21 and 1.26, respectively) […]

Conclusions

Overall, this study indicates that there is no clinically relevant drug–drug interaction between GB and the other components of the triple combination of GB/FF/BDP that comprise extrafine CHF 5993, and cimetidine […]

Statistically significant = 90% confidence interval of the ratio of adjusted geometric means does not include 1. Unfortunately only three significant digits are given in Table 3: AUC

_{0–t}1.16 (1.07, 1.27), AUC

_{0–12h}1.21 (1.08, 1.36), C

_{max}1.26 (1.00, 1.58). Perhaps the lower confidence limit of C

_{max}in full precision was >1.

Contrary to bioequivalence, where the clinically relevant difference \(\small{\Delta}\) is commonly set to 20%, leading to the limits \(\small{\{\theta_1,\theta_2\}=\{1-\Delta,\,(1-\Delta)^{-1}\}=\{0.8,\,1.25\}}\), in DDI-studies a different (while still

*pre-specified*) \(\small{\Delta}\) can be chosen. The paper does not give \(\small{\Delta}\). From the sample size section (page 272) one can assume that \(\small{\Delta=0.15}\), which would be pretty strict. Since the authors claimed that the increase was not clinically relevant, one could recalculate \(\small{\widehat{\Delta}_\text{r}}\) from the upper confidence limit by \(\small{\widehat{\Delta}_\text{r}=\left|CL_\text{upper}^{-1}-1\right|}\). For the ‘worst’ PK metric C

_{max}, we get \(\small{\widehat{\Delta}_\text{r}\approx\left|1.58^{-1}-1\right|\approx0.367}\). IMHO, that’s a lot. If we consider only the primary PK metric AUC

_{0–t}, \(\small{\widehat{\Delta}_\text{r}\approx0.213}\). The study was extremely underpowered (≈55%) for this PK metric. Interesting that the within-subject

*CV*of C

_{max}was smaller than the one of AUC

_{0–t}. Not impossible but rare.

-script below.

`library(PowerTOST)`

design <- "2x2x2"

n <- 25

metrics <- c("AUC0-t", "AUC0-12", "Cmax")

ratio <- c(1.16, 1.12, 1.26)

CL.lower <- c(1.07, 1.08, 1.36)

CL.upper <- c(1.27, 1.36, 1.58)

res <- data.frame(metric = metrics, ratio = ratio,

CL.lower = CL.lower, CL.upper = CL.upper,

Delta.r = NA_real_, CV = NA_real_,

power = NA_real_)

for (j in seq_along(metrics)) {

res$Delta.r[j] <- abs(CL.upper[j]^-1 - 1)

res$CV[j] <- suppressMessages(

CI2CV(lower = CL.lower[j],

upper = CL.upper[j],

design = design, n = n))

res$power[j] <- suppressMessages(

power.TOST(CV = res$CV[j], theta0 = ratio[j],

theta1 = 1 - res$Delta.r[j],

design = design, n = n))

}

res[, 5:7] <- signif(res[, 5:7], 4)

print(res, row.names = FALSE, right = FALSE)

`metric ratio CL.lower CL.upper Delta.r CV power `

AUC0-t 1.16 1.07 1.27 0.2126 0.1780 0.5453

AUC0-12 1.12 1.08 1.36 0.2647 0.2410 0.8761

Cmax 1.26 1.36 1.58 0.3671 0.1555 0.9996

*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:

- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-13 13:51 [Design Issues]
- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-14 09:05
- Drug-drug interaction with two different route of administration dshah 2022-07-20 10:27
- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-21 11:24
- Drug-drug interaction with two different route of administration dshah 2022-07-21 18:51
- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-22 07:23
- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-27 08:31
- Interpreting results of a DDI studyHelmut 2022-07-27 09:52

- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-27 08:31

- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-22 07:23

- Drug-drug interaction with two different route of administration dshah 2022-07-21 18:51

- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-21 11:24

- Drug-drug interaction with two different route of administration dshah 2022-07-20 10:27

- Drug-drug interaction with two different route of administration Mr.Rao 2022-07-14 09:05