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.