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.