ABSTRACT TBAJ-587 is a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile than the first-generation bedaquiline. It is currently under development for the treatment of drug-susceptible and drug-resistant tuberculosis. A first-in-human trial of TBAJ-587, including single and multiple ascending oral doses and a dedicated food-effect cohort, was conducted in 92 healthy adults. Plasma exposures of TBAJ-587 were generally linear for AUCtau and slightly subproportional for Cmax, with the major circulating active metabolite, M3, remaining low relative to the parent. A high-fat meal increased the mean Cmax and AUClast 3.46- and 2.26-fold, respectively. TBAJ-587 accumulated with multiple dosing over the 28-day period, with mean accumulation ratios across the three tested doses ranging from 1.69 to 2.32 for Cmax and from 2.74 to 3.73 for AUCtau. However, steady-state conditions were not yet reached on day 28. Mean terminal half-lives after 28-day dosing of TBAJ-587 ranged from approximately 80 to 111 days. There were no deaths or serious adverse events, and TBAJ-587 was generally safe and well tolerated at single doses of 25–800 mg under fasting conditions and multiple doses of 50–200 mg once daily for 28 days after a standard breakfast. In addition, no dose- or time-dependent effects were noted for any of the other safety and tolerability parameters, including no clinically significant effects on the QTc interval. These results support further investigation of TBAJ-587 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04890535.

Pretomanid is a component of the World Health Organization-recommended treatment regimen for drug-resistant tuberculosis in patients aged ≥ 14 years. While preclinical rodent studies identified testicular toxicity as a potential clinical liability at elevated doses, no corresponding effects were observed in nonhuman primates nor clinical hormone assessments. This phase 2 clinical trial assessed testicular safety of therapy with bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in 26 adult males with drug-resistant tuberculosis recruited from South Africa and Georgia. The study included 26 weeks of treatment followed by 52 weeks of safety monitoring until study week 78. The primary endpoint measured change in total sperm count from baseline at week 26, with secondary endpoints evaluating sperm concentration, semen volume, and reproductive hormone concentrations. Results demonstrated favorable testicular safety outcomes. Mean total sperm count increased from 48.8 to 68.8 × 106 per ejaculate by week 26. Fifteen participants (68%) showed increased sperm counts, while 17 (77%) exhibited higher sperm concentrations from baseline to week-26 Thirteen participants (59%) experienced ≥ 50% improvement in both parameters. Two participants demonstrated > 50% decreases in total sperm count; however, sperm concentration reductions were < 50%, suggesting low semen volume as a factor. Testosterone levels increased from baseline, peaking at week 44, while inhibin B demonstrated steady increases, peaking at week 78. Follicle-stimulating hormone and luteinizing hormone remained stable throughout the study period. All assessable participants achieved sputum culture conversion by week 12. Pharmacokinetic analysis revealed no correlation between pretomanid plasma concentrations and sperm count changes. These findings provide reassurance that pretomanid does not impair human spermatogenesis nor disrupt reproductive hormone homeostasis.

TBI-223 is an oxazolidinone antibiotic under clinical development for the treatment of tuberculosis. Preclinical data indicate potent antituberculosis activity and a potentially improved safety profile over linezolid. In a single-ascending dose study and a multiple-ascending dose study in 114 healthy adults, TBI-223 was generally safe and well tolerated at single doses up to 2,600 mg and multiple doses up to 2,400 mg daily over 14 days. No deaths, serious or severe adverse events, or discontinuations resulting from adverse effects (other than COVID-19) occurred. Except for two instances of orthostatic tachycardia in the single-ascending dose (SAD) study that resolved, no clinically significant electrocardiogram changes were noted. Concentration-QTc modeling found significant relationships of QTc with concentrations of TBI-223 and its main metabolite. However, groups receiving TBI-223 experienced QTc > 450 ms at a similar rate to those receiving placebo. TBI-223 exposures were nearly dose proportional. In the SAD study, TBI-223 exhibited a terminal half-life of 1.9-3.8 hours. Sustained-release tablets achieved a mean AUC0-inf of 70%-80% relative to immediate-release tablets, with more than 50% lower mean Cmax. These results support further investigation of TBI-223 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03758612 and NCT04865536.

Rationale: Antibiotic-resistant mycobacterial infections are a major threat to health care. Telacebec is a novel, first-in-class agent targeting mycobacterial cellular energy production in a range of pathogenic mycobacteria, including Mycobacterium tuberculosis, M. leprae, and M. ulcerans. Objectives: To explore telacebec's early bactericidal activity, tolerability, safety, and pharmacokinetics in patients with pulmonary tuberculosis and to summarize its current state of development for other diseases. Methods: We randomly assigned 64 patients with smear-positive, drug-sensitive tuberculosis to daily telacebec 100, 200, or 300 mg, or standard four-drug treatment as control, for 14 days. Measurements and Main Results: Sputum collected overnight was cultured in liquid and on solid media to determine the change of viable mycobacteria over time. Safety and tolerability were assessed daily. A full pharmacokinetic profile was obtained on Day 14. We found a dose-dependent reduction of the sputum mycobacterial load with a mean ± SD daily change for telacebec 300 mg and control, respectively, of 0.097 ± 0.050 and 0.200 ± 0.073 log colony-forming units, and 3.738 ± 2.747 and 6.853 ± 1.194 hours to culture positivity over the first 14 days of treatment. Pharmacokinetics were dose proportional. Telacebec was well tolerated and safe, with low adverse event rates across all doses. Conclusions: These results confirm telacebec's clinical activity against M. tuberculosis. Longer trials, in combination with other agents, are required to validate these results and to investigate telacebec's full potential. These results encourage the exploration of telacebec for more effective, shorter treatment regimens for leprosy and Buruli ulcer. A clinical trial for Buruli ulcer is under way. Clinical trial registered with URL (NCT03563599).

TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin). TBAJ-876 was well-tolerated at single doses up to 800 mg and multiple doses up to 200 mg for 14 days. No deaths or serious adverse events occurred. No episodes of clinically significant prolongation of the QTc interval were observed. TBAJ-876 exposures were dose proportional in the SAD and MAD studies. TBAJ-876 exhibited multicompartmental pharmacokinetics (PK) with a long terminal half-life yielding quantifiable concentrations up to the longest follow-up of 10 weeks after a single dose and resulting in accumulation with multiple dosing. In the fed state, TBAJ-876 exposures approximately doubled with the tablet formulation, whereas M3 metabolite exposures decreased by approximately 20%. The relative bioavailability of TBAJ-876 was similar between tablets and the oral suspension at 100-mg doses. With co-administration of TBAJ-876, the AUC0-inf of midazolam was unchanged and the Cmax was reduced by 14%; the AUC0-last of digoxin was increased by 51%, and the Cmax was increased by 18%. These results support further investigation of TBAJ-876 for the treatment of tuberculosis.

Background Tuberculosis (TB) is the leading cause of mortality by an infectious disease worldwide. Despite national and international efforts, the world is not on track to end TB by 2030. Antibiotic treatment of TB is longer than for most infectious diseases and is complicated by frequent adverse events. To counter emerging Mycobacterium tuberculosis drug resistance and provide effective, safe drug treatments of shorter duration, novel anti-TB medicines, and treatment regimens are needed. Through a joint global effort, more candidate medicines are in the clinical phases of drug development than ever before. Objectives To review anti-TB medicines and treatment regimens under clinical evaluation for the future treatment of drug-susceptible and drug-resistant TB. Sources Pre-clinical and clinical studies on novel anti-TB drugs. Content Description of novel protein synthesis inhibitors (oxazolidinones and oxaboroles), respiratory chain inhibitors (diarylquinolines and cytochrome bc1 complex inhibitor), cell wall inhibitors (decaprenylphosphoryl-β-d-ribose 2′-epimerase, inhibitors, thioamides, and carbapenems), and cholesterol metabolism inhibitor currently evaluated in clinical trials and novel clinical trial platforms for the evaluation of treatment regimens, rather than single entities. Implications A large number of potential anti-TB candidate medicines and innovations in clinical trial design for the evaluation of regimens, rather than single medicines, provide hope for improvements in the treatment of TB.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.

BackgroundThe current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB.MethodsSimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed.FindingsBetween July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17–3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4–8) on 4 months of BPaMZ and 11 weeks (6–12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3–7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]).InterpretationFor DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments.FundingTB Alliance.

Bedaquiline (B), pretomanid (Pa) and linezolid (L) are key components of new regimens for treating rifampicin-resistant tuberculosis (TB). However, there is limited information on the global prevalence of resistance to these drugs and the impact of resistance on treatment outcomes. Mycobacterium tuberculosis (MTB) phenotypic drug susceptibility and whole-genome sequence (WGS) data, as well as patient profiles from 4 pretomanid-containing trials-STAND, Nix-TB, ZeNix and SimpliciTB-were used to investigate the rates of baseline resistance (BR) and acquired resistance (AR) to BPaL drugs, as well as their genetic basis, risk factors and impact on treatment outcomes. Data from >1,000 TB patients enrolled from 2015 to 2020 in 12 countries was assessed. We identified 2 (0.3%) participants with linezolid BR. Pretomanid BR was also rare, with similar rates across TB drug resistance types (0-2.1%). In contrast, bedaquiline BR was more prevalent among participants with highly resistant TB or longer prior treatment histories than those with newly diagnosed disease (5.2-6.3% vs. 0-0.3%). Bedaquiline BR was a risk factor for bacteriological failure or relapse in Nix-TB/ZeNix; 3/12 (25%, 95% CI 5-57%) participants with vs. 6/185 (3.2%, 1.2-6.9%) without bedaquiline BR. Across trials, we observed no linezolid AR, and only 3 cases of bedaquiline AR, including 2 participants with poor adherence. Overall, pretomanid AR was also rare, except in ZeNix patients with bedaquiline BR. WGS analyses revealed novel mutations in canonical resistant genes and, in 7 MTB isolates, the genetic determinants could not be identified. The overall low rates of BR to linezolid and pretomanid, and to a lesser extent to bedaquiline, observed in the pretomanid trials are in support of the worldwide implementation of BPaL-based regimens. Similarly, the overall low AR rates observed suggest BPaL drugs are better protected in the regimens trialed here than in other regimens combining bedaquiline with more, but less effective drugs.

Background The combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) provides the shortest duration of treatment required to sterilize mice in relapsing mouse models. SimpliciTB was an open-label study to evaluate the safety and efficacy of 4-months BPaMZ (4BPaMZ) compared to standard therapy (4HRZE/2HR) in DS-TB participants. The trial also included a cohort of DR-TB participants who received 6-months BPaMZ (6BPaMZ). The primary efficacy endpoint was time to culture negative status through 8 weeks; the key secondary endpoint was relapse-free cure at week 52. The proportions of patients with culture conversion by 8 weeks and of favorable outcome at week 52 (MITT analysis) for 4HRZE/2HR, 4BPaMZ and 6BPaMZ were 47.3%, 84.1%, 85.7% and 93.1%, 85.3%, 83.1%, respectively. The lower rates of favorable outcomes in BPaMZ arms were largely due to higher rates of hepatotoxicity-related trial discontinuations, in which PZA may have contributed. Methods Using Kaplan-Meier (KM) and Cox PH models adjusting for socio-demographic and clinical factors, we explored the effect on outcome of baseline resistance to pyrazinamide (BRZ) in the DR-TB group of participants. Results 55 of 152 (36.2%) participants in the DR-TB cohort had BRZ based on phenotypic and genotypic drug susceptibility testing. Time to negative sputum culture for patients with and without BRZ was not statistically significantly different (aHR=0.79, 95% CI (0.54,1.15) p= 0.22). Relapse-free cure was documented in 42/51 (82%) participants with and 68/79 (86%) participants without BRZ (unadjusted Chi-sq test p=0.57). Conclusion PZA resistance at baseline did not impact outcomes at week 8 or week 52 in DR-TB patients treated with BPaMZ. A regimen of pretomanid, moxifloxacin with a potent diarylquinoline could present an efficacious and better tolerated therapeutic alternative for DS- and DR-TB patients and should also be explored as a therapeutic option for DS-TB.

OBJECTIVES:To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. METHODS:The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. RESULTS:We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. CONCLUSIONS:In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.

BACKGROUND The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Purpose: The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability.Methods: The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 x 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined.Findings: Delafloxacin C-max and AUC(0-infinity), increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC(0-infinity) were dose proportional at doses of > 200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The C. of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin C-max and AUC(0-infinity), were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses >= 1200 mg.Implications: Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (>= 1200 mg). (C) 2016 The Authors. Published by Elsevier HS Journals, Inc.

INTRODUCTION RESULTS CONCLUSIONS Melinta Therapeutics 203-624-5606 info@melinta.com ID Week 2015 San Diego, CA, USA Oct. 7-11, 2015 Background: Delafloxacin (DLX) is an investigational broad spectrum fluoroquinolone with activity against methicillin-resistant S. aureus (MRSA) and susceptible gram-negative bacteria. DLX is in Phase 3 development for treatment of acute bacterial skin and skin structure infections (ABSSSI). Methods: This was a Phase 1 pharmacokinetic (PK) study in subjects with mild, moderate, or severe hepatic impairment (n=6 per category). Healthy subjects (n=18) were closely matched with the impaired subjects for age, weight, and sex. DLX was given as a 300 mg, 1-hour IV infusion, and plasma DLX concentrations were determined by LC-MS/MS. The effects of hepatic impairment were assessed by ANOVA of log-transformed values for AUC, Cmax, and systemic clearance, with hepatic group as a fixed effect. Each impairment group was compared with its matching healthy group, and also with pooled healthy subjects. Results: Mean AUCinf and Cmax in each impairment group were not significantly different from the pooled healthy subjects (P>.05). The 90% confidence interval (CI) of the ratios of least-squares means did not indicate significant differences between the impairment groups and pooled healthy subjects. No significant trend was observed for any PK parameter versus the ordered normal and impairment categories (P>.05). AUCinf and Cmax for the impairment groups were similar to historic values in Phase 1 studies with healthy subjects. Treatment-emergent adverse events (TEAEs) were mild or moderate (10 out of 39 subjects).