DISCUSSION
In this study, an enhanced bioavailability of the 10mg/ml liquid formulation was observed. The presence of a robust clinical data along with in-vitro dissolution profile of the drug enabled the development of a model that accurately matched the clinical profiles. This model facilitated the identification of a corrected dose of PFOS which is 20% lower than the conventional tablet. Additionally, exposures in children were simulated using an existing model from literature and the allometrically scaled parameter values from the adult data and were found to be acceptable. PFOS can facilitate flexible and precise dosage adjustment based on the patient’s demographics and response to therapy which are crucial in establishing treatment success.
Maintenance of remission is a challenge in the context of high variability in the disposition of 6MP and consequently, the duration and depth of neutropenia between individuals. It is observed that the dose of 6MP in the maintenance therapy varies 5-fold among patients [18]. Interestingly, the PFOS had a lower pharmacokinetic variability compared to the tablet (55.87% versus 63.21%), although the bioavailability was higher. The increased bioavailability of the 10mg/ml liquid formulation can be attributed to various factors such as the type of formulation, constituents in the formulation, concentration, and viscosity of the suspension. An earlier study reported increased bioavailability with extemporaneously prepared 6MP liquid formulations compared to the tablet and notably, 6MP exposure in 5mg/ml solution was significantly higher compared to 50mg/ml solution in paediatrics with ALL [20]. Two other studies carried out with 6MP 20mg/ml liquid formulation either found comparable or lower oral bioavailability of the suspension compared to the tablet [21, 22]. In fact, our formulation has a 47% higher relative bioavailability compared to the 20 mg/ml liquid suspension, clearly demonstrating the effect of concentration and viscosity thereof on bioavailability. The relatively small body sizes of children in India and other LMICs compared to their Western European or North American counterparts prompted us to develop a more dilute suspension.
The applications of model-informed drug development have been significantly increasing and virtual bioequivalence studies can assess the similarity and potential differences of pharmacokinetic and clinical performance between test and reference formulations based on the translational link between in-vitro, in-vivo, as well as physicochemical properties of the molecule to its clinical pharmacokinetic property [23]. The simulation results are encouraging and allometry is still considered as a reasonable choice that extrapolates adult estimates and predicts paediatric clearance within 25% - 50% for most drugs [24]. Of course, the 6MP exposure with the test formulation needs to be validated in paediatric ALL patients to confirm safe and effective exposures. A major limitation of the study is that the paediatric dosage simulation was based on only one population pharmacokinetic study in paediatric ALL patients conducted in a small cohort of 19 children [12]. Nevertheless, we believe that it is a reasonable pointer to the starting dose which could be further optimized based on routine blood cell count monitoring to compensate for the variable bioavailability and response. The palatability of the liquid formulations is a huge advantage as it can significantly improve adherence rates in pediatrics as shown by a survey on the acceptability of 6MP liquid formulation [25]. Importantly, the developed 6MP formulation will make it easier to choose an appropriate and constant treatment intensity of 6MP with precise dosing aided by lower pharmacokinetic variability of the PFOS compared to the tablets.