INTRODUCTION
Mercaptopurine is a prodrug of thioguanine, a purine analogue that
antagonizes endogenous purines and inhibits RNA and protein synthesis in
the S- phase of the cell cycle. The Food and Drug Administration (FDA)
has authorized the use of mercaptopurine (6MP) as a component of
combination therapy for acute lymphoblastic leukaemia (ALL) in both
children and adults [1]. With the introduction of 6MP, complete
remission to the tune of 90% has been reported in paediatric ALL, the
most prevalent childhood cancer worldwide [2] [3]. The Institute
for Safe Medication Practices (ISMP) has listed 6MP as a drug with
narrow therapeutic index and has classified it as having a heightened
risk of causing significant harm to the patient when used
inappropriately [4] [1].
Oral 6MP has low and variable bioavailability, less than 20% on
average, due to high first-pass metabolism in the intestinal mucosa and
liver. The plasma concentrations exhibit significant inter- and
intra-patient variability [5-8]. The oral formulation of 6MP is
currently available as 50 mg tablets in India, while liquid suspension
of 20 mg/mL is available in the United States and Europe. Dosing 6MP
using the tablet formulation poses several challenges, particularly in
children, owing to smaller body surface area. Splitting the tablet
and/or alternate day dosing are often practiced to achieve the
prescribed 6MP dose [9], although such manipulations are fraught
with the potential for medication errors. Besides, the National
Institute for Occupational Safety and Health (NIOSH), and the American
Society of Health-System Pharmacists (ASHP) clearly identify crushing as
an unsafe practice with a potential for increasing the risk of cytotoxic
drug exposure to the preparator [10]. Additionally, factors such as
the inability to swallow tablets, drug palatability, and giving crushed
tablets mixed with various foods may also alter 6MP disposition in
children [11]. To overcome these limitations, and to enable accurate
dosage adjustments with age, genetic polymorphisms, body weight, body
surface area, adverse outcomes, and so on, a powder for oral suspension
(PFOS) dosage form of 6MP was developed.
The pharmacokinetics and the extent of absorption must be comparable to
the tablet in order to consider the new formulation as an alternative
option. The purpose of this study was to evaluate the pharmacokinetic
equivalence between the PFOS of 6MP 10 mg/mL (Test) and Mercaptopurine
USP Tablets 50mg (Reference) in healthy adult male subjects. Based on
the pharmacokinetic profiles, the study also aimed to establish the
optimal dose of the new formulation which would match the 50 mg
reference tablet formulation in the extent of absorption within the BE
criteria using a model-based approach and intended to extrapolate the
exposure of the suggested dose in paediatric patients using an existing
model in the literature.