Effect of food on the pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and assessment of dose proportionality in healthy volunteers.

OBJECTIVES: Empagliflozin is an orally available, potent and highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2). This study was undertaken to investigate the effect of food on the pharmacokinetics of 25 mg empagliflozin and to assess dose proportionality between 10 mg and 25 mg empagliflozin under fasted conditions. MATERIALS AND METHODS: In this open-label, 3-way, cross-over study, 18 healthy volunteers received 3 single doses of empagliflozin in a randomized sequence (25 mg empagliflozin under fasted conditions, 25 mg empagliflozin after a high-fat, high-calorie breakfast and 10 mg empagliflozin under fasted conditions), each separated by a washout period of at least 7 days. Serial plasma samples were collected at selected time points over a period of 72 hours. RESULTS: Administration with food had no clinically relevant effect on the area under the plasma concentration-time curve (AUC0-∞) of empagliflozin (geometric mean ratio (GMR): 84.04, 90% confidence interval (CI): 80.86 - 87.34). The decrease observed in the maximum plasma concentrations (Cmax) of empagliflozin (GMR: 63.22, 90% CI: 56.74 - 70.44) when administered with food was not considered clinically meaningful. The increases in AUC0-∞ and Cmax for 10 mg vs. 25 mg empagliflozin administered under fasting conditions were roughly dose-proportional, as demonstrated by the slope ß of the regression lines being slightly less than 1 (slope ß for AUC0-∞: 0.94, 95% CI: 0.90 - 0.97; slope ß for Cmax: 0.91, 95% CI: 0.80 - 1.01). Empagliflozin was well tolerated under fed and fasting conditions. CONCLUSIONS: The results support administration of empagliflozin tablets independently of food. Increases in empagliflozin exposure under fasting conditions were roughly dose-proportional between 10 mg and 25 mg empagliflozin.

Alanine scanning of MS2 coat protein reveals protein-phosphate contacts involved in thermodynamic hot spots.

The co-crystal structure of the MS2 coat protein dimer with its RNA operator reveals eight amino acid side-chains contacting seven of the RNA phosphates. These eight amino acids and five nearby control positions were individually changed to an alanine residue and the binding affinities of the mutant proteins to the RNA were determined. In general, the data agreed well with the crystal structure and previous RNA modification data. Interestingly, amino acid residues that are energetically most important for complex formation cluster in the middle of the RNA binding interface, forming thermodynamic hot spots, and are surrounded by energetically less relevant amino acids. In order to evaluate whether or not a given alanine mutation causes a global change in the RNA-protein interface, the affinities of the mutant proteins to RNAs containing one of 14 backbone modifications spanning the entire interface were determined. In three of six protein mutations tested, thermodynamic coupling between the site of the mutation and RNA groups that can be even more than 16 A away was detected. This suggests that, in some cases, the mutation may subtly alter the entire protein-RNA interface.