Pharmacokinetics and Safety of Rifamycin SV after Single and Multiple Doses of MMX® Modified Release Tablets in Healthy Male and Female Volunteers.

The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV's pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, Cmax,0-24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration at the corresponding times. On Day 1, the total amount excreted in urine was 0.0013%, and was 0.0029% on Day 7. The study results confirmed those of the previous Phase I study: the systemic absorption of rifamycin SV was also proved negligible after 7 days of the 600 mg t.i.d. dose regimen of the newly formulated tablets, currently under development for the treatment of several small and large intestinal pathologies, including diarrhea-predominant irritable bowel syndrome, hepatic encephalopathy, and others. Registered at ClinicalTrials.gov with the identifier NCT02969252, last updated on 26JAN18.

Pressor response to oral tyramine during co-administration with safinamide in healthy volunteers.

The aim of this study was to evaluate the pressor response to oral tyramine during repeated administration of oral safinamide in healthy volunteers. Twelve females and eight males aged 52.7 ± 4.9 years entered the study. An oral tyramine screening test was conducted to select subjects sensitive to the tyramine pressor effect on systolic blood pressure (SBP) in the dose range of 200-400 mg. Safinamide 300 mg was then administered once daily under fasting conditions. Starting on day 5 (safinamide pharmacokinetic steady state), single ascending doses of tyramine were co-administered daily: 50, 100 and 200 mg were administered on days 5, 6 and 7, respectively. Vital parameters were monitored by telemetry. No SBP increase ≥30 mmHg over baseline was observed when tyramine was co-administered with safinamide. Less than one third of the 400 mg responders reported SBP increases between 22 and 27 mmHg, which were below the threshold of 30 mmHg over baseline. SBP increases, as well as time interval to pressor response measured after co-treatment with safinamide and tyramine 200 mg, were not significantly different from those measured after administration of oral tyramine 200 mg alone. Safinamide 300 mg, administered o.d. under fasting conditions, does not change the tyramine pressor response as evaluated at steady state after 6-7 days of treatment as compared with the effect of tyramine administered alone. Safinamide, which inhibits monoamine oxidase (MAO)-B, does not affect oral tyramine metabolism mediated mostly by the intestinal MAO-A.

Relative bioavailability and pharmacokinetics of two oral formulations of docosahexaenoic acid/eicosapentaenoic acid after multiple-dose administration in healthy volunteers.

OBJECTIVES: To assess the comparative pharmacokinetic profile and bioavailability of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) after multiple-dose administration of a new oral formulation (test formulation) and a commercially available reference formulation in healthy subjects. METHODS: Forty-eight healthy subjects received a 28-day oral treatment with DHA/EPA in the form of either the test or the reference product according to an open-label, randomized, parallel-group design. Both formulations were given t.i.d. at 8-h intervals at a dose of 3.0 g/day. Steady-state DHA and EPA concentrations in plasma and lysed whole blood were measured by gas-liquid chromatography at baseline and after 7, 14, 21 and 28 days of treatment. Kinetic parameters were compared both after subtraction of baseline concentrations and by using baseline concentrations as a covariate. RESULTS: For both DHA and EPA, plasma and RBC concentrations measured from day 7 to day 28 were significantly higher than at baseline and did not differ significantly between the two products. On day 28 the plasma DHA concentration on average doubled the baseline level after administration of test and reference product, while there was a 10-fold increase in EPA plasma concentration. When the assessment was performed using baseline values as covariate, test-to-reference ratios for area under the curve (AUCss(0-8)) and for peak concentration (Css(max)) after the last administration on day 28 met bioequivalence criteria (i.e., 90% confidence intervals within 0.80-1.25 for AUCss(0-8) ratios, and within 0.75-1.33 for Css(max) ratios). When the assessment was conducted after subtraction of baseline values, the 90% confidence intervals for Css(max) ratios were within the bioequivalence range, whereas the intervals for AUCss(0-8) ratio were borderline for bioequivalence. CONCLUSION: The two formulations tested were similarly effective in increasing DHA and EPA concentrations in plasma and lysed whole blood, and showed comparable bioavailability for both active components.