Discussion
This was the first study to explore the DDI between TAC and different
formulations of VRCZ in adults and pediatrics with different age groups
using PBPK models. The results
indicated that IV and oral VRCZ both had a significant effect on PK of
TAC in two population. However, for pediatrics at the age of 0-1, VRCZ
presented a relatively unremarkable effect on the PK of TAC compared
with adults, and DDI was more pronounced when VRCZ was administered
orally. Besides, TAC liposolubility was the most significant parameter
on the DDI between TAC and VRCZ.
Predicted values of the PBPK model established in this study were highly
close to the clinical observed values, indicating that the results
predicted by DDI model were credible. Firstly, it has shown that in
pediatrics at the age of 0-1, the
DDI between TAC and VRCZ was inapparent compared with adults. Besides,
the DDI progressed gradually as
the age advanced and was finally equal to adults. That might be due to
enzyme inhibition of VRCZ was dose dependent[23]. Our study also
showed the same result that 6mg IV
single dose showed more obvious interaction compared with 4mg IV single
dose. Pediatrics had faster metabolism of VRCZ and lower accumulation of
VRCZ than adults, and thus the interaction in pediatrics was less
pronounced than that in adults[24]. Besides, many studies
illustrated that compounds which were mainly metabolized by CYP3A4 were
likely to be mainly metabolized by CYP3A7 in neonates and young
infants[25-27]. The activity of CYP3A4 was extremely weak or absent
in the fetus and began to rise after birth to reach 30–40% of the
adult activity after 1 month[28]. There are also studies that show
that CYP3A4 levels from the 5–15 year age-group that were only 25% of
the average CYP3A4 value obtained from the adult samples[29]. In our
study, for the age dependent hepatic clearance, default CYP3A4 ontogeny
information was described in the online PK-Sim Ontogeny Database Open
Systems Pharmacology (2018). The activity of CYP3A4 increased after
birth and reached the adult level over approximately 4 years. Therefore,
the DDI in pediatrics at the age of 3-8 years was basically at the same
level compared with adults.
In the present study, it also illustrated that compared with IV
administration, both Cmax and AUC of TAC increased more when combined
with VRCZ orally. Previous research has also shown that the AUC of oral
midazolam increases by 885 %, and the AUC of intravenous midazolam
increases by 261 % on administration of 400 mg of oral VRCZ [30].
The metabolism of TAC was known to be mainly mediated by CYP3A family,
which was most relevant in the intestinal and liver[31, 32]. In the
gut wall, members of the CYP3A sub-family are the predominant enzymes,
accounting for 82 % of total intestinal CYP[23, 33]. Since VRCZ was
known to strongly inhibit CYP3A activity [34, 35], oral VRCZ might
not only inhibit the metabolism of TAC in liver, but also inhibit the
absorption and transport of TAC in intestinal which could explain the
more prominent interaction when orally VRCZ[36]. Besides, there had
been some study illustrated that oral administration of VRCZ had a
stronger impact on CYP3A activity than intravenous administration. This
was expected because CYP-containing enterocytes would be exposed to
higher drug concentrations during duodenal and jejunal passage of orally
administered VRCZ compared with the lower concentrations reaching
enterocytes from the blood compartment[23].
Finally, our study showed that TAC liposolubility was likely a most
contributing factor to the DDI between TAC and VRCZ. We also attempted
to simulate the DDI between TAC and VRCZ in different levels
liposolubility of TAC, and found that increasing the liposolubility of
TAC significantly reduced the degree of interaction with VRCZ. A rapid
initial distribution phase was followed by a plasma clearance phase
whose t1/2 depended on the physical chemistry characteristics of
drugs[37]. Lipid-soluble agents had lower plasma
concentrations[38-40], perhaps because a more lipid soluble drug
might result in more-extensive tissue uptake, a larger volume of
distribution, lower plasma clearance values and a longer terminal
half-life[41]. This then could lead to a relatively less significant
interaction.
There were actually some limitations in our present study. Because of
the insufficient information of our existing population data, the object
of this study is only a virtual healthy population. The physiological
complications of transplant patients and changes during post-operative
period might affect the PK of TAC and VRCZ and influence their
interaction. In addition, previous researchers found that CYP2C19
polymorphism as a major metabolizing pathway of VRCZ might influence the
extent of drug interaction in healthy volunteers [42, 43]. Since
VRCZ blood concentrations in slow metabolizers of CYP2C19 may be higher
than fast metabolizers, which might result in more significant drug
interaction. The specific changes in CYP2C19 activity were not
considered in our models. The effects of CYP450 polymorphism on the
interaction and the specific changes in CYP2C19 activity would be
considered in our further researches.