A novel 5 mg mini-tablet formulation of mercaptopurine (6-MP) was developed to provide flexible and accurate doses to treat children with acute lymphoblastic leukemia. We conducted two open-label, randomized, single-dose, four-period, two-sequence, full-replicate, crossover trials to characterize the pharmacokinetics and relative bioavailability of the novel 6-MP mini-tablet (N) compared to the reference 6-MP tablet (R) under both fasted and fed conditions. The 6-MP plasma concentrations were measured using ultra performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS). The Cmax, AUC0-t, and AUC0-inf were used to evaluate the relative bioavailability. The results showed that the 6-MP mini-tablet was bioequivalent to the reference formulation under fasting condition. Under the fasted condition, the geometric least-squares mean ratios (GLSMR) (90% CI) of Cmax, AUC0-t, and AUC0-inf of N over R were 91.71% (81.31%-103.44%), 97.53% (92.57%-102.76%), and 97.91% (93.17%-102.90%), respectively. The mean CL/F (238.4 vs 219.3 L/h), the mean Vd/F (523.4 vs 451.8 L), the median Tmax (1.50 vs 1.25 h), and the mean t1/2 (1.55 vs 1.44 h) of N and R showed similarity. Under fed condition, the GLSMR (90% CI) of Cmax, AUC0-t, and AUC0-inf of N over R were 68.16% (59.62%-77.93%), 86.22% (81.37%-91.37%), and 86.59% (81.88%-91.57%), respectively. Furthermore, a high-fat diet increased both CL/F and Vd/F of 6-MP and decreased exposure of 6-MP, with all changes exceeding two-fold. Both products exhibited a favorable safety profile without any SAE being observed. These results supported the marketing of 6-MP mini-tablets.
Chen et al. (Wed,) studied this question.