PRMT4 inhibitor TP-064 inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo and induces peritonitis-associated neutrophilia in vivo.

Previous in vitro studies have shown that protein arginine N-methyltransferase 4 (PRMT4) is a co-activator for an array of cellular activities, including NF-κB-regulated pro-inflammatory responses. Here we investigated the effect of PRMT4 inhibitor TP-064 treatment on macrophage inflammation in vitro and in vivo. Exposure of RAW 264.7 monocyte/macrophages to TP-064 was associated with a significant decrease in the production of pro-inflammatory cytokines upon a lipopolysaccharide challenge. Similarly, thioglycollate-elicited peritoneal cells isolated from wildtype mice treated with TP-064 showed lowered mRNA expression levels and cytokine production of pro-inflammatory mediators interleukin (IL)-1ß, IL-6, IL-12p40, and tumor necrosis factor-α in response to lipopolysaccharide exposure. However, TP-064-treated mice exhibited an ongoing pro-inflammatory peritonitis after 5 days of thioglycollate exposure, as evident from a shift in the peritoneal macrophage polarization state from an anti-inflammatory LY6ClowCD206hi to a pro-inflammatory LY6ChiCD206low phenotype. In addition, TP-064-treated mice accumulated (activated) neutrophils within the peritoneum as well as in the blood (7-fold higher; P < 0.001) and major organs such as kidney and liver, without apparent tissue toxicity. TP-064 treatment downregulated hepatic mRNA expression levels of the PRMT4 target genes glucose-6-phosphatase catalytic subunit (-50%, P < 0.05) and the cyclin-dependent kinases 2 (-50%, P < 0.05) and 4 (-30%, P < 0.05), suggesting a direct transcriptional effect of PRMT4 also in hepatocytes. In conclusion, we have shown that the PRMT4 inhibitor TP-064 induces peritonitis-associated neutrophilia in vivo and inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo. Our findings suggest that TP-064 can possibly be applied as therapy in NF-κB-based inflammatory diseases.

Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities.

BACKGROUND: Lefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management. METHODS: In LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin. RESULTS: Lefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference - 1.1%; 95% CI - 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified. CONCLUSIONS: Lefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

Pharmacokinetics and safety of lefamulin after single intravenous dose administration in subjects with impaired renal function and those requiring hemodialysis.

STUDY OBJECTIVE: Lefamulin is a novel IV and oral pleuromutilin recently approved for the treatment of community-acquired bacterial pneumonia (CABP). Given that renal comorbidities are common in patients admitted for CABP, understanding the pharmacokinetics of lefamulin in the face of severe renal impairment, including those requiring hemodialysis, is needed. DESIGN: Open-label, Phase-1 pharmacokinetic study. SETTING: Research Study Center. PATIENTS: Twenty-three matched subjects were included, seven with "Normal" renal function (creatinine clearance >90 ml/min), eight with "Severe" renal impairment (glomerular filtration rate <30 ml/min/1.73 m2 ), and eight subjects requiring hemodialysis. MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of lefamulin IV 150 mg as a 1-h infusion. Subjects in the hemodialysis group started hemodialysis within 1 h after lefamulin infusion (On dialysis), as well as, on a non-dialysis day (Off dialysis). Plasma, urine, and dialysate fluid were collected for 36 h and analyzed for lefamulin and its major metabolite, BC-8041. Lefamulin was primarily excreted non-renally across groups. Statistical analyses revealed lefamulin and BC-8041 pharmacokinetics were similar between Normal and Severe groups, except for renal clearance, which decreased in Severe subjects (mean 1.3 L/h Normal vs. 0.4 L/h Severe). Likewise, lefamulin pharmacokinetics during on and off dialysis were unchanged, with lefamulin not measurably filtered in dialysate fluid. Two, three, and three subjects reported drug-related treatment-emergent adverse events (TEAE) in Normal, Severe, and Hemodialysis groups, respectively. All TEAEs were mild, except one (infusion-site reaction) that was classified as moderate. CONCLUSION: No dosage adjustment is required for patients with renal impairment, and lefamulin can be administered without regard to hemodialysis timing.

Pharmacokinetics and safety of lefamulin after single intravenous dose administration in subjects with impaired-hepatic function.

STUDY OBJECTIVE: Lefamulin is a novel pleuromutilin recently approved by the FDA for the treatment of community-acquired bacterial pneumonia. Given that, lefamulin is primarily metabolized by CYP450 Phase-1 reactions, this study evaluated the pharmacokinetics of IV lefamulin in subjects with various degrees of hepatic impairment as compared with matched healthy subjects. DESIGN: Open-label, Phase-1 clinical pharmacokinetic study. SETTING: Research Study Center. PATIENTS: Twenty-seven subjects; comprised of 11 individuals with normal hepatic function and eight each with moderate or severe hepatic impairment were included, as classified by Child-Pugh scores. MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of IV lefamulin 150 mg over 1 h. Plasma was collected for 48 h and analyzed for lefamulin and its major metabolite, BC-8041, concentrations in addition to assessing lefamulin plasma protein binding. Pharmacokinetics were evaluated by noncompartmental analysis. Pharmacokinetic parameters were compared using least square geometric mean ratios. Lefamulin was well tolerated in all hepatic function groups. Statistical analyses revealed reductions in Cmax and increases in renal clearance for Moderate and Severe groups, as well as, the increased volume of distribution for the Severe group. Lefamulin plasma AUC mean (SD) was similar across groups at 7615 (1554), 8233 (2286), and 8938 (1640) h.ng/mL for Normal, Moderate, and Severe groups, respectively, despite decreased clearance observed primarily during terminal elimination phases. Decreased plasma-protein binding was seen in hepatically-impaired versus normal subjects. CONCLUSION: Lefamulin was generally well tolerated. Differences in lefamulin and BC-8041 pharmacokinetics were small, relative to the overall variability, and any changes appear to be compensated by increases in renal clearance and decreased protein binding.

Lefamulin: A Novel Oral and Intravenous Pleuromutilin for the Treatment of Community-Acquired Bacterial Pneumonia.

Lefamulin is a novel oral and intravenous (IV) pleuromutilin developed as a twice-daily treatment for community-acquired bacterial pneumonia (CABP). It is a semi-synthetic pleuromutilin with a chemical structure that contains a tricyclic core of five-, six-, and eight-membered rings and a 2-(4-amino-2-hydroxycyclohexyl)sulfanylacetate side chain extending from C14 of the tricyclic core. Lefamulin inhibits bacterial protein synthesis by binding to the 50S bacterial ribosomal subunit in the peptidyl transferase center (PTC). The pleuromutilin tricyclic core binds to a pocket close to the A site, while the C14 side chain extends to the P site causing a tightening of the rotational movement in the binding pocket referred to as an induced-fit mechanism. Lefamulin displays broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria as well as against atypical bacteria that commonly cause CABP. Pleuromutilin antibiotics exhibit low rates of resistance development and lack cross-resistance to other antimicrobial classes due to their unique mechanism of action. However, pleuromutilin activity is affected by mutations in 23S rRNA, 50S ribosomal subunit proteins rplC and rplD, ATP-binding cassette (ABC)-F transporter proteins such as vga(A), and the methyltransferase cfr. The pharmacokinetic properties of lefamulin include: volume of distribution (Vd) ranging from 82.9 to 202.8 L, total clearance (CLT) of 19.5 to 21.4 L/h, and terminal elimination half-life (t1/2) of 6.9-13.2 h; protein binding of lefamulin is high and non-linear. The oral bioavailability of lefamulin has been estimated as 24% in fasted subjects and 19% in fed subjects. A single oral dose of lefamulin 600 mg administered in fasted patients achieved a maximum plasma concentration (Cmax) of 1.2-1.5 mg/L with a time of maximum concentration (Tmax) ranging from 0.8 to 1.8 h, and an area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of 8.5-8.8 mg h/L. The pharmacodynamic parameter predictive of lefamulin efficacy is the free plasma area under the concentration-time curve divided by the minimum inhibitory concentration (fAUC24h/MIC). Lefamulin efficacy has been demonstrated using various animal models including neutropenic murine thigh infection, pneumonia, lung infection, and bacteremia. Lefamulin clinical safety and efficacy was investigated through a Phase II clinical trial of acute bacterial skin and skin structure infection (ABSSSI), as well as two Phase III clinical trials of CABP. The Phase III trials, LEAP 1 and LEAP 2 established non-inferiority of lefamulin to moxifloxacin in both oral and IV formulations in the treatment of CABP. The United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Health Canada have each approved lefamulin for the treatment of CABP. A Phase II clinical trial has been completed for the treatment of ABSSSI, while the pediatric program is in Phase I. The most common adverse effects of lefamulin include mild-to-moderate gastrointestinal-related events such as nausea and diarrhea. Lefamulin represents a safe and effective option for treating CABP in cases of antimicrobial resistance to first-line therapies, clinical failure, or intolerance/adverse effects to currently used agents. Clinical experience and ongoing clinical investigation will allow clinicians and antimicrobial stewardship programs to optimally use lefamulin in the treatment of CABP.

Erdosteine salvages cardiac necrosis: Novel effect through modulation of MAPK and Nrf-2/HO-1 pathway.

Isoproterenol (ISO) induced oxidative stress and inflammation is involved in the pathogenesis of myocardial necrosis. To optimize the effect of erdosteine against myocardial necrosis, male albino Wistar rats were divided into eight groups (n = 6), that is, normal, ISO-control, erdosteine pretreatment with ISO. Rats were administered erdosteine orally for 28 days. Two doses of ISO (85 mg/kg), s.c. were given to ISO-C and erdosteine treatment groups on the 27th and 28th day. On the 29th day, hemodynamic parameters were recorded and the heart was excised for further parameters. In ISO-C rats, significantly increased levels of inflammatory markers, pro-oxidants, and structural damage were observed as compared with normal group. Furthermore, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed an increased expression of apoptotic proteins. Erdosteine at 80 mg/kg reversed the deleterious effects of ISO and normalized myocardium. Erdosteine showed anti-inflammatory, antiapoptotic, and antioxidant activities through inhibition of MAPK and Nrf-2/HO-1 pathways. To conclude, erdosteine was found protective in ISO-induced myocardial necrosis through MAPK and Nrf-2/HO-1 pathway.

Use of mucolytics in COPD: A Delphi consensus study.

BACKGROUND: International guidelines recommend mucolytic agents as add-on therapy in selected patients with COPD because they may reduce exacerbations and improve health status. As the evidence varies among mucolytic agents, we used the Delphi method to assess consensus amongst an international panel of COPD experts on mucolytics use in COPD. METHODS: 53 COPD experts from 12 countries were asked to complete an online questionnaire and rate their agreement with 15 statements using a 5-point scale. The mucolytic agents evaluated were carbocysteine, erdosteine and N-acetylcysteine (NAC). Data were collected anonymously and consensus presented using descriptive statistics. RESULTS: The 47 respondents reached consensus on the statements. They agreed that regular treatment with mucolytic agents effectively reduces the frequency of exacerbations, reduces the duration of mild-to-moderate exacerbations, and can increase the time to first exacerbation and symptom-free time in COPD patients. Consensus was consistently highest for erdosteine. The experts agreed that all three mucolytics display antioxidant and anti-inflammatory activity. Erdosteine and NAC were thought to improve the efficacy of some classes of antibacterial drugs. All three mucolytics were considered effective for the short-term treatment of symptoms of acute exacerbations when added to other drugs. The panel agreed that approved doses of mucolytic agents have favorable side-effect profiles and can be recommended for regular use in patients with a bronchitic phenotype. CONCLUSIONS: Consensus findings support the wider use of mucolytic agents as add-on therapy for COPD. However, the differences in pharmacological actions and clinical effectiveness must be considered when deciding which mucolytic to use.

Lefamulin vs moxifloxacin for community-acquired bacterial pneumonia.

Lefamulin is a novel pleuromutilin antibiotic with potent in vitro activity against key community-acquired bacterial pneumonia (CABP) pathogens. However, the clinical efficacy and safety of lefamulin for treating CABP remains unclear.An integrated analysis of 2 phase III trials investigating the clinical efficacy and safety of lefamulin vs moxifloxacin in the treatment of CABP was conducted.A total of 1289 patients (lefamulin group: 646 and moxifloxacin group: 643) were included in this analysis. The early clinical response rate was 89.3% and 90.5% among lefamulin and moxifloxacin group, respectively. Lefamulin was noninferior to moxifloxacin (89.3% vs 90.5%, RR: 0.99, 95% CI: 0.95-1.02, I = 0%). In terms of clinical response at test of cure, no significant difference was observed between the lefamulin and moxifloxacin groups (for modified intention to treat population, RR: 0.98, 95% CI: 0.94-1.02, I = 0%; for clinically evaluable population, RR: 0.96, 95% CI: 0.93-1.00, I = 0%). In the subgroup analysis, the early clinical response rate at early clinical assessment and clinical response rate at test of cure of lefamulin was similar to that of moxifloxacin across different subgpopulations and all baseline CABP pathogens. Lefamulin was associated with a similar risk of adverse events as moxifloxacin.Clinical efficacy and tolerability for lefamulin in the treatment of CABP were similar to those for moxifloxacin.

Ultrafast liquid chromatographic analysis of erdosteine in human plasma based on fluorimetric detection and precolumn derivatization with 4-bromomethyl-7-methoxycoumarin: Application to pharmacokinetic studies.

In this study, a new analytical method for erdosteine (ERD) in plasma based on high-performance liquid chromatography and a fluorimetric detector, is presented. Precolumn derivatization of ERD with 4-bromomethyl-7-methoxy coumarin (BrMmC) and dibenzo-18-crown-6-ether as a reaction catalyst led to the production of a fluorescent compound. ERD was monitored by fluorescence with an excitation wavelength λext. = 325 nm and emission wavelength λem. = 390 nm. Optimum reaction conditions were carefully studied and optimized. A chromatographic procedure was performed using a C18 column of 150 × 4.6 mm and 3 µm particle size and a mobile phase consisting of methanol:acetonitrile:water (30:30:40, v/v/v) under a flow rate of 0.5 ml min-1 . A calibration plot was established covering analyte concentration range 0.2-3.0 µg ml-1 ; the detection limit was 0.015 µg ml-1 and quantification limit was 0.05 µg ml-1 . Mean recovery was 87.33% and relative standard deviation was calculated to be less than 4.4%. The developed method was successfully used to determine pharmacokinetic preparations of ERD subsequent to administration of a 900 mg dose capsule to a healthy 40-year-old woman volunteer.

Protective effects of Erdosteine on interleukin-1ß-stimulated inflammation via inhibiting the activation of MAPK, NF-κB, and Wnt/ß-catenin signaling pathways in rat osteoarthritis.

Osteoarthritis (OA), a degenerative arthropathy, is featured with progressive degradation of cartilage and a chondrocyte inflammatory response. Erdosteine (ER) showed the anti-oxidant properties and various anti-inflammatory effects in various diseases. However, whether it protects against OA remains unknown. In this study, we explore the potential therapeutic properties of ER on IL-1ß-stimulated rat chondrocytes and its underlying mechanism in vitro and vivo. Cell viability, pro-inflammatory cytokines and the degradation of ECM biomarkers were tested to determine the effects of ER at 10, 20, and 40 µM doses on IL-1ß-induced rat chondrocytes for 24 h in virto. In vivo, intra-articular injections of 50 µl of 100 mg/ml ER twice a week for 8 weeks. The results showed ER significantly suppressed the expressions of IL-1ß-induced the production of inflammatory factors in a dose-dependent pattern (4.30-fold decrease in COX-2, p < 0.05; 4.77-fold decrease in iNOS, p < 0.05 at 40 µM in protein levels). Moreover, ER could attenuate the degradation of ECM in IL-1ß-induced rat chondrocytes by repressing the expression of OA-related factors (2.40-fold decrease in ADAMTS-5, p < 0.05; 3.12-fold decrease in MMP1, p < 0.05; 3.97-fold decrease in MMP3, p < 0.05; and 2.62-fold decrease in MMP-13, p < 0.05 at 40 µM in protein levels). Furthermore, our study revealed that ER could inhibit the activations of IL-1ß-induced MAPK and Wnt/ß-catenin. Besides, ER could suppress the process of IL-1ß-induced P65 from the cytoplasm into the nucleus. In vivo, ER delaied the osteoarthritis progression in rat OA models. Collectively, ER might become a new therapeutic agent for OA.

Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia.

OBJECTIVES: Lefamulin is a semi-synthetic intravenous (iv) and oral pleuromutilin antibiotic active against community-acquired bacterial pneumonia (CABP) pathogens. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses were carried out to evaluate lefamulin 150 mg iv q12h and 600 mg orally q12h under fed and fasted conditions for the treatment of patients with CABP. METHODS: The analyses undertaken used a population PK model based on Phase 1 PK data, non-clinical PK/PD targets for efficacy and in vitro surveillance data for Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), and Monte Carlo simulation. Percentage probabilities of PK/PD target attainment by MIC on day 1 were determined using median total-drug epithelial lining fluid (ELF) and free-drug plasma AUC:MIC ratio targets associated with 1 and 2 log10 cfu reductions from baseline. RESULTS: Percentage probabilities of attaining the total-drug ELF AUC:MIC ratio target for a 1 log10 cfu reduction from baseline for SP were ≥99.2% at the MIC90 of 0.12 mg/L and 96.7%, 82.1% and 96.3% for iv and oral dosing regimens under fed and fasted conditions, respectively, at the MIC99 of 0.25 mg/L. Percentage probabilities of attaining the free-drug plasma AUC:MIC target for the same endpoint at the SP MIC99 were 100% for each regimen. For the SA MIC90 of 0.12 mg/L and AUC:MIC ratio targets for the same endpoint, percentage probabilities were 92.7%-100% for iv and oral dosing regimens. CONCLUSIONS: These data provide support for lefamulin 150 mg iv q12h and 600 mg orally q12h for the treatment of patients with CABP and suggest that doses may not need to be taken under fasted conditions.

Pharmacokinetics and tolerability of lefamulin following intravenous and oral dosing.

OBJECTIVES: To explore the pharmacokinetics (PK) of oral and intravenous (iv) lefamulin after single and multiple doses, and the effect of food on bioavailability. METHODS: Lefamulin PK was examined in four studies. In Study 1, PK was assessed in patients with acute bacterial skin and skin structure infections who received repeated iv lefamulin q12h (150 mg). In Study 2, a four-period crossover study, healthy subjects received a single dose of oral lefamulin [immediate-release (IR) tablet, 1 × 600 mg] in a fasted and fed state, oral lefamulin (capsule, 3 × 200 mg) in a fasted state, and iv lefamulin in a fasted state. In Study 3, a three-period crossover study, healthy males received a single oral lefamulin dose (IR) in the following states: fasted, fasted followed by a high-calorie meal 1 h post-dose, and fed. Study 4 had two parts; in part A, healthy males received a single lefamulin dose (IR) in a fasted and fed state; in part B, subjects received repeated doses of lefamulin (IR, q12h) or placebo. Adverse events (AEs) were recorded in each study. RESULTS: Single and repeated dosing of iv and oral lefamulin resulted in comparable exposure. Intravenous and oral lefamulin (given fasted or with a meal 1 h post-dose) resulted in bioequivalence. Bioequivalence was not established between oral lefamulin in the fed state and iv or oral administration in the fasted state. All AEs were mild or moderate in severity, no serious AEs were reported, and no participant discontinued because of an AE. CONCLUSIONS: The PK of lefamulin supports successful switch from iv to oral therapy; lefamulin was generally well tolerated.

Prediction of lefamulin epithelial lining fluid penetration after intravenous and oral administration using Phase 1 data and population pharmacokinetics methods.

OBJECTIVES: Lefamulin is a semi-synthetic intravenous and oral pleuromutilin antibiotic with activity against pathogens commonly associated with community-acquired bacterial pneumonia. Using data from two Phase 1 studies, a population pharmacokinetics (PPK) model for lefamulin in plasma and epithelial lining fluid (ELF) was constructed. METHODS: Plasma pharmacokinetic (PK) data from a crossover, bioavailability, food-effect study and plasma and ELF PK data from a tissue penetration study in normal healthy volunteers were used to construct a PPK model for lefamulin. Model development involved refinement of a previous PPK model for intravenous and oral administration, followed by application of the model to plasma and ELF data from the tissue penetration study. The ELF penetration ratio of lefamulin was determined using model-based simulations. RESULTS: The PPK analysis data set contained 1103 plasma and 12 ELF lefamulin concentrations from 32 subjects. A three-compartment model with non-linear protein binding and two parallel absorption processes provided precise and unbiased estimated plasma concentration-time profiles. The absorption rate was slower and bioavailability was decreased after a high-fat/high-calorie meal. ELF data were well described using first-order rate constants into and out of the ELF compartment. The median predicted lefamulin total-drug ELF AUC0-24/free-drug plasma AUC0-24 ratio was ∼5:1 after intravenous or oral administration. CONCLUSIONS: The final PPK model allowed precise characterization of plasma and ELF exposures after intravenous and oral administration. The high ELF penetration ratio suggests that the penetration of lefamulin into the effect site is rapid and extensive, irrespective of route of administration.

Introduction: lefamulin and pharmacokinetic/pharmacodynamic rationale to support the dose selection of lefamulin.

Lefamulin is the first semisynthetic pleuromutilin being developed for oral and intravenous administration. The drug selectively inhibits prokaryotic ribosomal protein synthesis by binding to the peptidyl transferase centre via four H-bonds and other interactions, resulting in an 'induced fit' that tightens the binding pocket around lefamulin. This unique mechanism of action has been associated with a low probability of cross-resistance to other antimicrobial classes commonly used to treat community-acquired bacterial pneumonia (CABP). This Supplement, entitled 'Pharmacokinetic and pharmacodynamic analyses and dose rationale for lefamulin, a novel pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia', is intended to be a valuable resource for both clinicians and researchers. It provides the essential pharmacokinetic and pharmacodynamic data on lefamulin that were used to support the optimal dose selection of lefamulin for the safe and effective treatment of CABP in adults.

Comparative efficacy and safety of lesinurad 200 mg and 400 mg combined with a xanthine oxidase inhibitor in hyperuricemic patients with gout: A Bayesian network meta-analysis of randomized controlled trials
.

OBJECTIVES: We aimed to assess the relative efficacy and safety of once-daily administration of lesinurad in combination with xanthine oxidase inhibitor (XOI) in hyperuricemic patients with gout. MATERIALS AND METHODS: A Bayesian random-effects network meta-analysis was performed to combine the direct and indirect evidence from randomized controlled trials (RCTs) for evaluating the efficacy and safety of lesinurad 200 mg + XOI, lesinurad 400 mg + XOI, and XOI monotherapy in hyperuricemic patients with gout. RESULTS: Three RCTs including a total of 1,537 patients fulfilled the inclusion criteria. The number of patients who had achieved a target serum uric acid (sUA) level was significantly higher in the lesinurad 40 mg + XOI and lesinurad 200 mg + XOI groups than in the XOI monotherapy group (R 4.55, 95% credible interval (CrI) 2.13 - 9.81 and OR 2.78, 95% CrI 1.28 - 5.71, respectively). The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that lesinurad 400 mg + XOI was more likely to achieve the best target sUA level (SUCRA = 0.968), followed by lesinurad 200 mg + XOI (SUCRA = 0.526), and XOI (SUCRA = 0.006). The frequency of treatment-emergent adverse events (TEAEs) in the XOI group was significantly lower than that in the lesinurad 400 mg + XOI group (OR 0.59, 95% CrI 0.39 - 0.90). CONCLUSION: Lesinurad 200 mg + XOI and lesinurad 400 mg + XOI were more effective than XOI for hyperuricemic patients with gout, but lesinurad 400 mg + XOI had a significant risk of TEAE development.

Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial.

BACKGROUND: Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. METHODS: In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%). RESULTS: There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. CONCLUSIONS: Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated. CLINICAL TRIALS REGISTRATION: NCT02559310.

Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study.

BACKGROUND: In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus lesinurad as combination therapy. METHODS: Patients receiving combined lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study ("200CONT", "400CONT"), whereas those receiving only febuxostat 80 mg were randomized to lesinurad 200 or 400 mg with febuxostat ("200CROSS", "400CROSS"). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of lesinurad exposure, 800 days). RESULTS: Of 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT (n = 64), 200CROSS (n = 33), 400CONT (n = 65), and 400CROSS (n = 34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged lesinurad exposure in the extension study. CONCLUSIONS: Patients receiving lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01510769 . Registered on 13 January 2012.

Metabolism and disposition of lesinurad, a uric acid reabsorption inhibitor, in humans.

The objectives of this study were to determine the absolute bioavailability of lesinurad and to characterized its disposition in humans. The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of lesinurad with an intravenous infusion of [14C]lesinurad microdose. The bioavailability of lesinurad was determined to be 100%. The disposition of lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14C]lesinurad dose. Metabolism of lesinurad occurred post-systemically with low circulating levels of metabolites <3% of total radioactivity as 74.2% of total radioactivity was attributed to lesinurad. In vitro metabolism studies identified CYP2C9 as the predominant isoform, and summation of metabolites indicated that it was responsible for ∼50% of metabolism.

Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout.

Objective: Lesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy. Methods: Safety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years). Results: In the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals. Conclusion: At the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified.