Case details of enrolled victim drugs
A total of 33 drugs, approved by the FDA between 2011 and 2020, were
enrolled for evaluation of predictive performance after meeting specific
screening criteria. To be eligible, these drugs were required to have
available pharmacokinetic profiles when administered alone or
co-administered with ketoconazole, as well as available ADME properties.
The structure of these 33 compounds is presented in Figure S3, and their
characteristics and statistics are listed in Table 1. The DDI potentials
of the drugs were divided into two categories based on the 90%
confidence interval of AUCR, where 15 out of the 33 compounds had
AUCR<2, accounting for 45% of the total. Table 1 shows that
there were no significant differences between the two categories in
terms of logP, Peff, BP, Vss,fu , and ClR. However, compounds
with AUCR>2 tended to have higher Clliver(ClCYP3A4 + Clother) and in vivofm . A correlation analysis of
Clliver, in vitro fm , and
AUCR was performed using a 3-D plot as showed in the Figure 1, which
indicated that compounds with higher Clliver andin vitro fm had higher AUCRs. Out of 33
compounds co-administered with ketoconazole, six victim drugs
experienced an increase in exposure of more than three times. All six of
these victim drugs have a high Clliver (>15
L h-1) and a high fm(>75%). Conversely, the 18 drugs with lower clearance
rates (<15 L h-1) among the 33 compounds
showed an increase in exposure of less than three times after being
co-administered with ketoconazole, regardless offm .