Optimal Dose Selection
The comparison of a range of doses that i.e., 25, 30, 35, 37.5, 40 and 50 mg that were simulated, clearly demonstrated the ability of the model to distinguish the PK profiles of each dose. The summary of pharmacokinetic profiles of various doses of Test product in comparison to Reference is presented in supplementary table 4. Figures 5 and 6 show the simulated Cmax and AUC for different doses. The BE assessment that was performed for pharmacokinetic simulation data for different test doses with simulated data for Reference product at 50 mg revealed that only 40 mg dose-based simulation qualified the BE criterion for the extent of absorption (AUC) while all other doses failed. The statistical summary of BE evaluation of 40 mg Test (suspension) vs. Reference (50 mg Tablet) is presented in Table 5.
Evaluation of the selected dose reduction in pediatrics with Acute lymphoblastic leukaemia.
Monte Carlo simulations were performed to confirm safe exposures of the 6MP PFOS formulation in children with ALL. The model that was deployed for simulations described the kinetic parameters of 6MP and 6TGN using the following equations where tvka, tvcl, tvvc, tvfm,tvclm and tvkme represent the population parameters and their inter-individual variability etas(η) for the respective individual parameters.
Ka = tvka * exp(η)
CL = tvcl*(WT/70) ^0.75*exp(η)
Vc = tvvc*(WT/70) *exp(η)
FM = tvfm*(2.56) ^TPMT
CLm = tvclm *(BSA)^1.16 * exp(η)
Kme = tvkme
The ODEs used to describe the drug and metabolite disposition in the gut and blood are as follows
Depot’   = -Ka*Depot
Central’ = Ka*Depot - CL/Vc*Central
Metabolite’ = FM*Kme*Central - CLm*Metabolite
The dose of the suspension was scaled down by 20% to 40mg/m2 from the standard dose of 50mg/m2 as suggested by the previous virtual bioequivalence study. The median simulated 6TGN concentration was 288.0 (pmol/8x108 RBCs) with a range between 114 and 703.6 pmol/8x108 RBCs. While there is no consensus on the reference range for the therapeutic levels of 6-TGN, variable ranges of 6TGN have been reported, In a research by Chrzanowska et al., 6-TGN concentrations ranged from 60 to 833 pmol/8 x 108 RBC in paediatric ALL patients receiving 6-MP dosed at 50 mg/m2 [14], while in a study Rosdiana et al., 6-TGN concentrations ranged from 6 to 234.04 pmol/8 x 108 RBC pmol/8 x 108RBC [15]. Patients in the research by Bhatia et al received a larger dose of 6-MP (75 mg/m2/day), but 6-TGN levels remained the same at 0.3-714.1 pmol/8 x 108 RBC [16]. A study by Zhou Y and colleagues reported a median 6TGN concentration of 217.13 pmol/8 x 108 RBC with a range from 89.38–674.77 in the paediatric population receiving a median dose of 42.3mg/day [17]. Thus, the simulations revealed relatively safe and effective levels of 6TGN that were comparable with the previous studies (Figure 7).