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.