Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented; a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free base roller compacted (RC) tablets, free base high shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.80 to 1.25 confidence bounds; however, the HSWG tablet maximum observed concentration (C max ) was higher compared to the reference (ratio: 1.15; 90% CIs: 1.0113, 1.3047). In the healthy adult (n=16) and adolescent (n=17) study, a gepotidacin mesylate salt tablet was evaluated as a 1,500-mg single dose, 2 doses administered 6 or 12 h apart (6,000 mg total), or placebo. Single-dose mean C max was ∼27% higher in adolescents versus adults and area under the concentration-time curve (AUC) was comparable in both populations. After 2 doses were administered, mean C max was similar for both ages and mean AUC was ∼35% higher in adolescents versus adults. Concentrations increased proportionally with dose. Safety-risk profiles were similar in both ages. Across studies, the most common adverse events were gastrointestinal. Overall, the pharmacokinetics of the final gepotidacin mesylate salt tablet have been well-characterized, enrollment of adolescents into the pivotal trials is supported, and dosing intervals were determined that should provide adequate exposures for microbiological efficacy.

Comparative Pharmaceutical Standardization and Oral Bioavailability Study on Praval Pishti and Praval Bhasma

Background: Praval (coral) is a very usually occurring calcium form. It is rich source of calcium & minerals. As per text it can be converted into two formulas which are bhasma (calcinated ash) and pishti(powdered form without agni).These forms may have different rate of immersion. This needs to be studied. Aim: Pharmaceutical Standardization study of Praval Pishti & Praval Bhasma and comparative evaluation of their relative oral bioavailability. Materials and methods: The two formulations will be prepared from Praval (coral). By triturating with Gulab jala Praval Pishti will be prepared and by traditional Puta method Praval Bhasma will be prepared. The prepared formulations will be assessed for Bhasma Pariksha mentioned in Ayurveda. Organoleptic characters, Physicochemical parameters and Particle size distribution analysis, SEM –EDX (Scanning Electron Microscopy, Energy Dispersive X-Ray Analysis), FTIR (Fourier-transform infrared spectroscopy), XRD (X-Ray Diffraction), and GCMS (Gas Chromatography Mass Spectroscope) will be evaluated. To assess the relative oral bioavailability of Praval Pishti & Praval Bhasma study will be conducted in healthy volunteers and will be compared with the standard calcium supplement. Observation and results: The study will be assessed for its relative oral bioavailability in healthy Volunteers by using unpaired “t” Test, One-way ANOVA. Conclusion: The pharmaceutical study of Praval Bhasma and Praval Pishti will provide the standard parameters and comparative evaluation with standard will generate evidence for better bioavailability.

Association Between Dietary Intake of Magnesium With Blood Biomarkers

Objectives The purpose of this study was to investigate the relationship between dietary Mg intake and concentrations of ionized magnesium (iMg+2) in whole blood and total Mg in serum. Methods We evaluated blood iMg+2 concentration, the physiological active measure of Mg, as well as serum Mg concentration which is a more commonly used measure of body's status. The data study population were healthy participants (18–52 years; n = 23) who participated in three clinical visits in a magnesium supplement bioavailability study. All study participants were not taking Mg supplements within two weeks of study screening. Dietary Mg intake obtained from 3-day food records was compared with iMg+2 in whole blood and total Mg in serum concentrations using Pearson's correlations. Ionized magnesium was measured with NOVA 8 (NOVA Biochemical, Waltham, MA), serum Mg was measured with atomic absorption spectroscopy, and dietary intake of Mg was assessed using the Nutrition Data System for Research (NDSR; University of Minnesota, MN). Results were reported as means (standard deviations) and percentages for continuous and categorical data, respectively. Results Mean iMg+2 and serum Mg concentrations, and dietary Mg intake were 1.27 (0.07) mg/dL, 2.20 (5.0) mg/dL and 304.05 (128.77) mg/day, respectively. Results from the Pearson's correlation coefficient showed no significant association between dietary Mg intake vs. and serum Mg (r = −0.30, p = 0.23), nor was there a significant association between dietary Mg intake and iMg+2 (r = −0.08, p = 0.74). Conclusions Our findings suggest that iMg+2 and serum Mg concentrations may not reflect dietary Mg intake in a significant manner. Further research is needed to identify objective and accurate biomarkers that reflect dietary Mg intake, which will enable a better understanding of Mg deficiency and its association with conditions such as cardiovascular diseases, hypertension, diabetes, and chronic kidney disease. Funding Sources An unrestricted educational grant from New Capstone Inc., the manufacturer of ReMag®.

Quantitative determination of Cpd118, A novel FBPase inhibitor, in dog plasma by HPLC–MS/MS

Aim: A HPLC–MS/MS method was first developed and validated for the quantification of Cpd118, a novel fructose-1, 6-bisphosphatase inhibitor for controlling gluconeogenesis in Type 2 diabetes mellitus. Materials & methods: Cpd118 was extracted from dog plasma following acetonitrile protein precipitation, separated by HPLC on a CAPCELL PAK ADME column (3.5 μm, 2.1 mm × 100 mm) and quantified using negative heated electrospray ion source-MS/MS. Results: Cpd118 was quantified from plasma using the method described above over a linear range of 10–20,000 ng/ml, with interday and intraday assay accuracy from -11.78 to 4.01% and the precision was ≤11.15%. Conclusion: The method was sensitive and selective for the quantification of Cpd118 and was successfully used to the pharmacokinetic and bioavailability study of Cpd118 in dogs.