Effects of food on the pharmacokinetics of ponatinib in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: Ponatinib is a potent oral tyrosine kinase inhibitor with activity against BCR-ABL, the primary driver of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. This single-centre, single-dose, randomized, open-label, three-period crossover study evaluated the pharmacokinetics and bioavailability of a single oral dose of ponatinib (45-mg tablet) under fasting conditions and following consumption of high- and low-fat meals by healthy subjects. METHODS: Subjects were randomly assigned to one of the six possible treatment sequences, each evaluating three ponatinib 45-mg treatments: administered under fasting conditions; administered after a high-fat meal; or administered after a standardized low-fat meal. The high-fat meal derived approximately 50% of its total caloric content from fat, with approximately 150, 250 and 500-600 calories derived from protein, carbohydrates and fat, respectively (total of approximately 900-1000 calories). The standardized low-fat meal derived no more than 20% of total caloric content from fat, with approximately 56, 428 and 63 calories derived from protein, carbohydrates and fat, respectively (total of approximately 547 calories). During each of the three treatment periods, blood samples were collected predose and at 13 time points over the 96-h post-dose interval. Plasma concentrations of ponatinib were measured by liquid chromatography/tandem mass spectrometry. Mixed-model analyses of variance (anova) were performed on natural log-transformed PK parameters Cmax and AUC0-∞. RESULTS AND DISCUSSION: Geometric mean maximum plasma concentration (Cmax) values for the fasted, low-fat and high-fat regimens were 54·7, 51·6 and 51·5 ng/mL, respectively. Geometric mean area under the concentration-time curve from time zero to infinity (AUC0-∞) values for the fasted, low-fat and high-fat regimens were 1273, 1244 and 1392 h × ng/mL, respectively. All limits of the 90% CIs of the estimated geometric mean ratios for Cmax and all AUC comparisons fell within the 80%-125% margins. These results indicate that consumption of a high- or low-fat meal within 30 min prior to administration of ponatinib had no effect on the single-dose pharmacokinetics of ponatinib. WHAT IS NEW AND CONCLUSION: Food does not affect the single-dose pharmacokinetics of ponatinib. These data demonstrate that ponatinib may be administered with or without food.

Stereoselective metabolism and pharmacokinetics of tegafur.

OBJECTIVES: UFT is composed of racemic tegafur (FT), a prodrug of 5-fluorouracil (5-FU), and uracil in a fixed molar combination (1:4). FT contains a chiral center and has two stereoisomers, R-FT and S-FT. The objectives of this study were to assess the stereoselectivity in the metabolism of FT to 5-FU in vitro and to determine stereoselective differences in the disposition of FT in vivo. METHODOLOGY: R-FT, S-FT, and racemic FT were incubated with pooled human liver microsomes and S-9 fraction for a period of up to 30 min for in vitro studies. For pharmacokinetics, plasma samples were obtained from fasted cancer patients over a period of 24 h after oral administration of 200 mg UFT. Samples from in vitro studies and patient plasma samples were analyzed for FT using a validated achiral and a chiral assay, and for 5-FU using a validated GC/MS assay. RESULTS: R-FT was metabolized at a rate 5.6-times faster than S-FT by human liver microsomes. Similarly, stereoselective metabolism of R-FT was also seen in the S-9 incubations. In cancer patients, the peak plasma concentrations (C(max)) and the time to reach C(max) (T(max)) were similar for the two isomers after the administration of UFT suggesting no apparent differences in their absorption kinetics. However, the area under the curve from zero to infinity [AUC(INF)] and the terminal elimination half-life (T-HALF) values for R-FT were about 4.6- and 4.4-fold lower compared to S-FT, respectively, suggesting the preferential elimination of R-FT. The T-HALF of racemic FT (8.3 h) was comparable to the T-HALF of S-FT (10.3 h) which indicated that the kinetics of the racemate are governed by S-FT. The active cytotoxic moiety, 5-FU, exhibited formation rate limited kinetics from R-FT because the T-HALF of 5-FU (3.4 h) was similar to that of R-FT (2.4 h). CONCLUSIONS: The R-isomer of FT is preferentially metabolized to 5-FU compared to the S-isomer in vitro. The distinct kinetic profiles of the stereoisomers of FT following the administration of UFT is apparently due to the stereoselective disposition of the R-isomer relative to the S-isomer. These data suggest that the R-isomer of FT is worthy of further preclinical and clinical evaluation for safety, efficacy, and pharmacokinetics.