Data analysis and statistical analysis
The sample size was calculated using the coefficient of variations (AUC:
43.7% and Cmax: 46.8%) derived from the
Cmax and AUC of carotegrast after oral administration of
carotegrast methyl.17 The correlation coefficient was
assumed to be 0.7. When the point estimate of the geometric mean ratio
of the PK parameters of carotegrast methyl obtained in the absence and
presence of rifampicin was set to 1, indicating no drug interaction, the
number of subjects required to have a 90% confidence interval (CI) of
0.8 – 1.25 was calculated to be 19 for AUC and 21 for
Cmax with 80% power. Considering the feasibility of
conducting the trial at the study site, the number of subjects was set
to 20.
The PK parameters were assessed in all subjects who received carotegrast
methyl and whose PK data were adequate for the calculation of ≥ 1
primary PK parameter (the PK analysis set). Safety was assessed in all
subjects who received the study drug (the safety analysis set). Levels
of analyte below the level of quantification were entered as 0 for
calculations. Descriptive statistics were used to summarize demographics
and safety parameters. The PK parameters of carotegrast methyl,
carotegrast, M-I, M-II, and carotegrast-gluc were calculated based on
the plasma drug concentration data from subjects who received
carotegrast methyl alone or in combination with rifampicin using
non-compartmental analysis. For plasma drug concentration and PK
parameters, descriptive statistics and the two-sided 95% CIs were
calculated. A natural logarithmic transformation of PK parameters except
for Tmax was applied for all statistical inference. The
90% CI for ratios of geometric means of logarithmic PK parameters was
calculated by the following mixed effects model;
Loge (PK Parameter) = μ + group + sequence + time point
+ subject + ε
μ: population mean, time point: duration of administration, subject:
interindividual variation, ε: error
The geometric mean ratios and their 90% CI for the
AUC0-t and Cmax of carotegrast methyl
and carotegrast when carotegrast methyl was administered in combination
with rifampicin versus when carotegrast methyl was administered alone
were calculated. When the 90% CI of the geometric mean ratio of both
parameters fell within the range of 0.80 – 1.25, it was determined that
there was no PK interaction. The same analysis was performed for the
other metabolites including M-I, M-II and carotegrast-gluc and for other
PK parameters including Tmax, t1/2, and
MRT0-t as a reference. For Tmax, a
nonparametric test was performed. PK parameters were calculated using
noncompartmental analysis with WinNonlin Professional Version 6.3
(Phoenix Corporation, Mountain View, California, USA). AEs were coded
using the Medical Dictionary for Regulatory Activities (MedDRA) version
20.0. All data processing, summarization, and analyses were conducted
using SAS software ver. 9.3 for Windows (SAS Institute Inc., Cary, NC,
USA).