| Popis: |
AIMS 6 mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukaemia (ALL) and is conventionally available as 50 mg tablets. This study aimed to evaluate the bioequivalence of a new 6MP Powder for Oral Suspension (PFOS) intended for paediatric use. Additionally, a virtual study with the obtained data was planned for determining a dose of the PFOS that matches tablet exposures and to confirm optimal drug levels in pediatrics. METHODS An open-label, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy subjects. A population pharmacokinetic (PopPK) model was developed using the data to perform simulations with various PFOS doses and select a bioequivalent dose. To simulate 6MP and 6 thioguanine (6TGN) exposures in pediatrics, a literature model for paediatric ALL patients, and allometrically scaled PK parameters were utilised. RESULTS The 6MP PFOS had 47% higher bioavailability compared to the reference product. Simulations using a two-compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to the 50mg tablets. The simulated 6TGN concentrations in virtual paediatric patients were between 114 and 703.6 pmol/8x108 RBCs, which was within the range of values reported in paediatric ALL studies. CONCLUSION The study demonstrates that 40 mg dose of 6MP PFOS 10 mg/mL has the same extent of absorption as the 50 mg tablet which can be precisely administered in pediatrics. The study also demonstrates the role of modelling and simulation to perform virtual bioequivalence and paediatric studies. |
