Population Model Development
The population model fitting in the observed healthy volunteer study
data revealed that a two-compartment pharmacokinetic model adequately
described the pharmacokinetics of 6MP after numerous iterative steps.
The compartment-based pharmacokinetic model fit indicated significantly
different absorption rates for the Test and the Reference product.
Therefore, the cumulative fraction dissolved from the in-vitro
dissolution study was fitted to a first-order exponential function to
assess the rate of dissolution specific to the products which were then
incorporated as fixed parameters specific to the formulation in the
model. The final PK model
described the pharmacokinetics of Mercaptopurine PFOS 10mg/mL after oral
dosing with a dissolution and transit compartment followed by two
compartmental pharmacokinetics. The PK model parameterized the volume of
distribution of central and peripheral compartments (denoted as V1 and
V2 respectively), clearance parameters from the central as well as
inter-compartment (cl and Q respectively), and a first-order absorption
rate (ka). Figure 3 describes the schematic representation of the PK
model
The final model parameters for the PK model fit into the 51 subject
clinical data for Test and Reference products along with their
inter-individual variabilities are illustrated in Table 3. Diagnostic
plots for the population PK fit for Reference and test product indicate
an acceptable fit of the model. The diagnostic plots of the model fit
for the reference and test products are presented in supplementary
figures 2 and 3 respectively.
Replication of BE results
for Test and Reference product
The model fitted population parameters were used to simulate the PK of
the Test and Reference products in 51 virtual subjects. The model
simulation results matched the observed clinical data closely. Figure 4
shows the observed vs simulated concentration-time profiles for the test
and reference. The Cmax and AUC values calculated from the actual data
and simulated data were comparable with a ratio ranging from 0.78 to
1.02 (Table 4). The BE assessment results for the model simulated data
matched the results observed using clinical data. The 90 % CI of the
geometric means were comparable
(Supplementary table 3).