In vitro metabolic profile and drug-drug interaction assessment of secnidazole, a high-dose 5-nitroimidazole antibiotic for the treatment of bacterial vaginosis.

A single-dose oral granule formulation of secnidazole 2 g (SOLOSEC™ ) has been approved in the US as a treatment for bacterial vaginosis. Available data on the likelihood of in vitro drug-drug and alcohol-drug interactions are limited. Secnidazole was incubated with cultured human hepatocytes over a range of concentrations (0-10 000 µmol/L) to assess metabolic profiling. Cytochrome P450 (CYP) and aldehyde dehydrogenase inhibition over a similar concentration range were evaluated in human liver microsomes (HLMs) or recombinant enzymes using competition or time-dependent inactivation assays. Secnidazole exhibited very low metabolism in HLMs at concentrations up to 6400 µmol/L. Secnidazole was found to be metabolized to a limited extent predominantly by CYP3A4 and CYP3A5 among a panel of cDNA-expressed enzymes. Secnidazole inhibited CYP2C19 and CYP3A4, with IC50 values of 3873 and 3722 µmol/L, respectively. Secnidazole did not exhibit time-dependent inhibition. There was no inhibition (IC50 value >5000 µmol/L) observed for any other CYP enzyme or with human recombinant aldehyde dehydrogenase 2 (ALDH2). These results are the first reported observation of the metabolism and drug-drug interaction profile for secnidazole and demonstrate that the agent has minimal to no potential drug interactions of concern.

An Integrated Efficacy and Safety Analysis of Single-Dose Secnidazole 2 g in the Treatment of Bacterial Vaginosis.

Bacterial vaginosis (BV) is the most common gynecologic infection in women aged 14 to 49 years. Currently recommended treatments require extended dosing and are thus associated with poor adherence. A single-dose oral granule formulation of secnidazole 2 g (SOLOSEC™ [secnidazole], Symbiomix Therapeutics, a Lupin company, Baltimore, MD), a 5-nitroimidazole antibiotic with antimicrobial activity, has been approved by the US Food and Drug Administration for the treatment of BV in adult women. As part of the US registration package, two randomized, double-blind, placebo-controlled clinical studies were conducted to confirm the efficacy and safety of a novel single-dose oral formulation of secnidazole 2 g. This is an integrated analysis of efficacy and safety results from these studies, pivotal study 1 and pivotal study 2. By combining the results of the two studies, relevant information is presented especially when considering the effect of secnidazole on patients with recurrent episodes of BV and the difference in effect on patients of black race. Single-dose secnidazole 2 g was statistically superior to placebo on all primary and secondary efficacy outcomes in both trials, including clinical outcome responder rate (P < 0.001), achievement of Nugent scores in the normal range of 0 to 3 (P < 0.001), greater numbers of patients as therapeutic outcome responders at the test of cure/end of study visit on days 21-30 (P < 0.001), and fewer patients requiring additional treatment at the test of cure/end of study visit (P < 0.001), supporting the role for single oral dose secnidazole 2 g granules as treatment for women with BV.

Two Phase 1, Open-Label, Single-Dose, Randomized, Crossover Studies to Assess the Pharmacokinetics, Safety, and Tolerability of Orally Administered Granules of Secnidazole (2 g) in Healthy Female Volunteers Under Different Administration Conditions.

Bacterial vaginosis (BV) is the most common vaginal infection in reproductive-age women and a significant risk factor for sexually transmitted diseases and pregnancy complications. Standard 5- to 7-day antimicrobial treatments for BV are associated with high rates of recurrence and adverse events. SYM-1219 is a novel granule formulation containing 2 g of secnidazole, developed as an oral, single-dose BV treatment. Two phase 1, open-label, single-center, randomized, crossover trials (studies 102 and 103) assessed the pharmacokinetics and safety of SYM-1219 single doses (≥7-day washout between doses) in healthy, nonpregnant women aged 18 to 65 years inclusive. Study 102 compared SYM-1219 in applesauce in fasted vs fed states. Study 103 compared SYM-1219 (fasted) in pudding and yogurt vs applesauce. Studies 102 and 103 each dosed 24 subjects (mean [standard deviation] ages, 36 [1.8] and 40 [11.6] years, respectively). In both studies the 90% confidence intervals for all treatment comparisons of maximum plasma concentration, area under the concentration-time curve from 0 to last measurable concentration and to infinity, geometric mean ratios were within 80% to 125%, demonstrating bioequivalence. In both studies median fasted time to maximum plasma concentration was 4 hours (6 hours fed in study 102), and mean half-life ranged from 17 to 19 hours. Treatment-emergent adverse events occurred in 70.8% and 83.3% subjects in studies 102 and 103, respectively, most commonly headache (41.7% and 50.0%) and gastrointestinal treatment-emergent adverse events. The pharmacokinetics of SYM-1219 were similar in fed and fasted states and when administered in different foods.

Thorough QT/QTc Evaluation of the Cardiac Safety of Secnidazole at Therapeutic and Supratherapeutic Doses in Healthy Individuals.

SYM-1219, a novel oral granule formulation of secnidazole, is under development as single-dose treatment for bacterial vaginosis. This 4-way, randomized, crossover study evaluated the effects of SYM-1219 on electrocardiographic (ECG) parameters in 52 healthy subjects. Subjects were administered single doses of SYM-1219, 2 g (proposed therapeutic dose), 6 g (supratherapeutic dose), placebo, and moxifloxacin (positive control). Serial digital 12-lead ECGs were recorded pre- and postdose; blood samples were taken to determine plasma secnidazole concentrations. A high-precision QT technique measured ECGs. The primary end point was change from baseline QTcF (∆QTcF); data were analyzed with the objective of excluding QT effects >10 milliseconds at postdosing time points and with exposure-response analysis. Safety and tolerability were assessed. Single doses of 2 g and 6 g SYM-1219 did not have a clinically relevant effect on the QTcF interval; an effect >10 milliseconds could be excluded at all postdosing time points. A shallow slope of the exposure-response relationship was seen (0.058 millisecond per µg/mL; 90%CI 0.042, 0.073); in this model, the effect on QTc can be predicted to be <10 milliseconds up to a secnidazole plasma concentration of ∼125 µg/mL, approximately 3.4-fold higher than anticipated peak therapeutic plasma levels. The moxifloxacin QT response demonstrated assay sensitivity. The most frequently reported treatment-emergent adverse events with SYM-1219 were headache, dizziness, and nausea. This thorough QT study demonstrated that SYM-1219 in doses and plasma concentrations up to 3-fold above therapeutically relevant levels does not have a clinically concerning effect on ECG parameters, including the QT interval.

Secnidazole Treatment of Bacterial Vaginosis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate secnidazole as a single oral dose treatment for bacterial vaginosis in a phase 2 randomized, double-blind, placebo-controlled study. METHODS: In a phase 2, randomized, double-blind, dose-ranging, placebo-controlled study, women with bacterial vaginosis who met all Amsel criteria (discharge; pH 4.7 or greater; 20% or greater clue cells; positive whiff test) were randomized one to one to one at 24 U.S. centers to 1 or 2 g secnidazole compared with placebo. The primary endpoint was clinical cure (normalization of discharge, amine odor, and clue cells) 21-30 days after treatment. Secondary endpoints included microbiologic cure, defined as a Nugent score of 0-3, and therapeutic cure, defined as meeting criteria for both clinical and microbiologic cure. The modified intent to treat was used for efficacy analyses and included all randomized patients who met the enrollment criteria. Assuming a clinical cure rate of 40% in the active groups and 15% in the placebo group, a sample size of 52 patients per group provided approximately 80% power to detect a significant difference between groups (.05 level [two-sided]) using a Cochran-Mantel-Haenszel test. RESULTS: Between May and September 2014, 215 patients were enrolled. In the intent-to-treat population, the clinical cure rate was 65.3% for the 2-g group, 49.3% for the 1-g group, and 19.4% for the placebo group. The modified intent-to-treat population included 188 women (median age 33 years; 32% with four or more bacterial vaginosis episodes in the previous year; 54% black) with baseline Nugent scores 4 or greater. Clinical, microbiologic, and therapeutic cure rates were 67.7%, 40.3%, and 40.3% for 2 g secnidazole and 51.6%, 23.4%, and 21.9% for 1 g secnidazole compared with 17.7%, 6.5%, and 6.5% for placebo, respectively (P<.05 for secnidazole compared with placebo; all endpoints). Both doses were well-tolerated. CONCLUSION: Oral granules containing 1 and 2 g secnidazole were superior to placebo in bacterial vaginosis treatment (P<.001 for both groups). These data support the development of secnidazole for bacterial vaginosis treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147899.

Lack of a Pharmacokinetic Interaction Between SYM-1219 Granules Containing 2 Grams of Secnidazole and a Combined Oral Contraceptive in a Phase 1, Randomized, Open-Label Study in Healthy Female Volunteers.

INTRODUCTION: Bacterial vaginosis (BV) is a serious infection that is the most common vaginal infection in women of childbearing potential. SYM-1219 is a novel, granule formulation containing 2 g of secnidazole that is being developed as a single, oral dose to treat women with BV. Because many of the women diagnosed with BV use hormonal contraception, the effect of SYM-1219 on the pharmacokinetics (PK) of commonly prescribed oral contraceptive drugs, ethinyl estradiol (EE2), and norethindrone (NET) was evaluated. METHODS: This two-period, randomized, open-label study examined effects in 54 healthy female subjects. During the first period of the study, each subject received EE2 0.035-mg/NET 1-mg tablets. During the second period of the study, subjects were randomized to receive either EE2 0.035-mg/NET 1-mg tablets with concomitant 2-g SYM-1219 or 2-g SYM-1219 followed by EE2 0.035-mg/NET 1-mg tablets 1 day later. The PK of EE2 and NET were analyzed for 24 h following administration. RESULTS: Coadministration of SYM-1219 and EE2/NET, either on the same day or 1 day apart, had no clinically relevant effects on the bioavailability of EE2 or NET. The combined use of SYM-1219 with EE2/NET was well tolerated. Taken together, these results indicate that contraceptive efficacy should be maintained during coadministration of SYM-1219 and EE2/NET. CONCLUSION: SYM-1219 is a valuable single-dose treatment option for women with BV that will not interfere with combined oral contraceptive methods. FUNDING: Symbiomix Therapeutics.