The Oral ß-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies.

SYN-004 (ribaxamase) is a ß-lactamase designed to be orally administered concurrently with intravenous ß-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess ß-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of ß-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated, and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of ß-lactam antibiotics in the human intestine (registered at ClinicalTrials.gov under NCT02419001 and NCT02473640).

Vilazodone lacks proarrhythmogenic potential in healthy participants: a thorough ECG study.

OBJECTIVE: Vilazodone is a potent serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder (MDD) in adults. The effect of clinical and supratherapeutic doses of vilazodone on cardiac repolarization was determined in healthy volunteers. METHODS: In this Phase 1, randomized, doubleblind, placebo- and active-controlled, 3-arm, parallel, single-center study, healthy subjects received placebo; moxifloxacin 400 mg; or vilazodone (sequentially escalated every 3 days) 10, 20, 40, 60, and 80 mg/day. The primary endpoint was the time-matched change from baseline in the QT interval corrected for heart rate (QTc) using an individual correction method (QTcI). RESULTS: Placebo-corrected time-matched analysis of the QTcI duration for the vilazodone treatment effect indicated that no vilazodone dose had an upper bound that approached or exceeded 10 ms, demonstrating no signal for a significant vilazodone effect on cardiac repolarization. Vilazodone had no significant effect on heart rate, PR, or QRS interval duration. The pharmacokinetic/pharmacodynamic model showed that the QTcI slope for vilazodone was not different from 0.0 and that the predicted increase from baseline in the QTc at Cmax for the highest therapeutic dose (156 ng/ml after 40 mg/day) was < 1 ms. The incidence of adverse events (AEs) was higher in the vilazodone group (57.6%) than in the moxifloxacin (37.0%) and placebo (35.6%) groups, though AEs were generally mild to moderate in severity and resulted in few discontinuations. CONCLUSIONS: Vilazodone had no significant effect on cardiac repolarization, heart rate, PR or QRS interval duration, or ECG morphology in healthy adult participants.

Pharmacokinetics of vilazodone in patients with mild or moderate renal impairment.

BACKGROUND AND OBJECTIVE: In patients with impaired renal function, the pharmacokinetics of a drug may be altered, resulting in decreased renal excretion or metabolism, and altered absorption, plasma protein binding or distribution. Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder. Vilazodone is extensively hepatically metabolized with minimal renal excretion. The primary objective of this study was to assess the pharmacokinetics of a single 20-mg dose of vilazodone in subjects with mild or moderate renal impairment. METHODS: This was a Phase 1, open-label, single-dose study of vilazodone in community-dwelling subjects with renal impairment and in healthy subjects to evaluate the pharmacokinetics of vilazodone in the presence of renal impairment. Thirty-two subjects were enrolled: eight subjects with mild (estimated glomerular filtration rate [est GFR] >50-80 mL/min) renal impairment matched individually by age, sex and body mass index to eight control subjects with normal renal function (est GFR >80 mL/min), and eight subjects with moderate (est GFR ≥30-50 mL/min) renal impairment matched with eight control subjects with normal renal function. Subjects received a single, 20-mg dose of vilazodone and pharmacokinetics, safety and plasma protein binding were assessed for 14 days. The pharmacokinetic parameters calculated were maximum plasma concentration (Cmax), time to maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time zero to 24 h, AUC from time zero to the last measurable concentration, AUC from time zero to infinity estimated by linear trapezoidal rule and extrapolation, oral clearance, terminal elimination rate constant, elimination half-life (t½), free fraction in plasma, apparent free drug clearance, amount of vilazodone recovered in urine 0-96 h following drug administration, percent of dose recovered in urine over 96 h following drug administration, renal clearance and volume of distribution. Safety assessments were adverse events, clinical laboratory test results, 12-lead electrocardiograms and vital signs. RESULTS: Vilazodone pharmacokinetic parameters in renally impaired subjects were variable but not substantially different from healthy controls. Mean values for vilazodone Cmax and AUC were similar among groups. Mean t½ (35.7 and 34.8 h mild and moderate vs. 37.0 and 34.8 h matched controls), total drug clearance (19.9 and 25.1 L/h vs. 26.4 and 26.9 L/h), and mean vilazodone recovery in urine (1.21 % and 0.58 % vs. 0.95 % and 0.81 %) were similar for mild and moderate renally impaired subjects and matched controls with normal renal function. There were no apparent systematic trends in vilazodone pharmacokinetic parameters associated with decreasing renal function. Protein binding was variable (coefficient of variation, 29-65 %) but not substantially different among the three groups, and total drug clearance was not affected. Safety and tolerability of vilazodone were comparable in all groups of subjects. CONCLUSION: This study suggests that systemic exposure of vilazodone is not affected by mild or moderate renal impairment. No dose adjustments are recommended in patients with mild or moderate renal impairment.

Effect of the rate of niacin administration on the plasma and urine pharmacokinetics of niacin and its metabolites.

The metabolic profile of niacin is influenced by the rate of niacin administration. This study characterizes the effect of administration rate on the pharmacokinetics of niacin and its metabolites. Twelve healthy males were enrolled in an open-label, dose-rate escalation study and received 2000 mg niacin at 3 different dosing rates. Plasma was analyzed for niacin, nicotinuric acid, nicotinamide, and nicotinamide-N-oxide. Urine was analyzed for niacin and the metabolites nicotinuric acid, nicotinamide, nicotinamide-N-oxide, N-methylnicotinamide, and N-methyl-2-pyridone-5-carboxamide. C(max) and AUC(0-t) for niacin and nicotinuric acid increased with an increase in dosing rate. The changes observed in plasma nicotinamide and nicotinamide-N-oxide parameters, however, did not correlate to dosing rate. The total amount of niacin and metabolites excreted in urine was comparable for all 3 treatments. However, with the increase in dosing rate, urine recovery of niacin and nicotinuric acid showed a significant increase, whereas N-methyl-2-pyridone-5-carboxamide and N-methylnicotinamide showed a significant decrease.