Results
PBPK model and verification of TAC
The input parameters describing the PBPK model of TAC are listed in
Table 1. With the optimization of specific intestinal permeability, the
resulting TAC model was able to capture the PK profile of single 5mg TAC
dose in healthy volunteers (Supplement Figure 1). The simulated and
observed plasma concentration–time profiles of TAC are shown in Figure
1. There was a good match between predicted and observed data in both
adults and pediatrics. The predicted and observed PK parameters are all
summarised in Table 3. The accuracy of simulation was measured by
calculating the fold error between simulated and observed, described as
Eq. (1). Predicted PK parameters were reasonably consistent (0.5- to
2.0-fold) with observed clinical values which indicated that the
prediction accuracy of the developed PBPK models were acceptable and
could be used to simulate the different dosing regimens.
PBPK model and verification of VRCZ
The input parameters describing the PBPK model of TAC are listed in
Table 2. The simulated and observed plasma concentration–time profiles
of VRCZ are shown in Figure 2. Simulated plasma concentration–time
profiles of TAC in both adults and pediatrics corresponded well with the
observed profiles. The pharmacokinetic parameters of VRCZ were all
within 2.0-fold error (Table 3).
DDI simulations between TAC and VRCZ in adults and pediatrics
The plasma concentration–time curves of single oral TAC at baseline and
following both single IV and oral dose of VRCZ in adults and pediatrics
are shown in Figure 3. Model-predicted Cmax and AUC of TAC combined with
VRCZ (IV and oral) were obtained (supplement Table 1). These results
indicated that a higher IV dose
might lead to a great increase in Cmax and AUC of TAC in both adults and
pediatrics. Besides, compared
with IV administration, these two PK values of TAC increased more when
combined with VRCZ orally. The ratio of Cmax and AUC
in multidose simulation (IV and oral) was presented in Figure 4. The
ratio of two PK values increased with the age growthin the pediatrics.
And it increased progressively to adult values at the age group of 3-8.
Sensitivity Analysis
A sensitivity analysis was performed based on the simulation of the
therapeutic single oral dosing regimen (TAC oral 0.05mg/kg and VRCZ oral
400mg) to assess the impact of the parameters on the DDI between TAC and
VRCZ. Sensitivity analysis (Figure 5) revealed that the DDI between TAC
and VRCZ was sensitive to the values of TAC liposolubility, VRCZ
liposolubility, TAC fraction unbound in plasma, CYP2C19 kcat and
reference concentrition , CYP3A4 kcat and km, as well as intestinal
permeability. The most impactful drug parameters in the model were TAC
liposolubility.