Safety, tolerability, and pharmacokinetics of TG-1000, a new molecular entity against influenza virus: first-in-human study.

Background: The cap-snatching mechanism of influenza virus mRNA transcription is strongly suppressed by TG-1000, a prodrug rapidly metabolized into TG-0527, is a potent cap-dependent nucleic acid endonuclease inhibitor. Herein, we aimed to assess the safety, tolerability, and pharmacokinetics of TG-1000 in healthy participants and the effect of food on the pharmacokinetics and safety of TG-1000. Method: The study was divided into 2 parts: Part A [Single Ascending-Dose (SAD) study, 10-160 mg] and Part B [Food-Effect (FE) study, 40 mg] were launched sequentially. The study included 66 participants for both investigations. We administered different TG-1000 capsules or placebo doses per the study protocol and collected blood samples for pharmacokinetic assessments at specific times. In plasma, TG-1000 and its active metabolite TG-0527 were assayed, and PK parameters were determined. Results: In SAD, the increase in AUC was less than the proportional increase in dose over the 20-160 mg dose range, while the increase in Cmax was proportional to the increase in dose. In the 10-160 mg dose range, T1/2, λz and Tmax of TG-0527 were dose-independent; and T1/2 and Tmax were within 33.8-39.4 h and 3.02-6 h, respectively. In FE, the AUC0-inf, AUC0-last, and Cmax of TG-0527 decreased by approximately 17.52%, 18.76%, and 41.35%, respectively, and the Tmax delay was around 1.50 h. No serious adverse events occurred during the studies. Conclusion: Overall, TG-1000 was well tolerated and exhibited an acceptable safety and PK profile, supporting further clinical investigation of TG-1000 for the treatment of influenza.

Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC-100), a Novel C-X-C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem/Progenitor Cells, in Mice and Healthy Subjects.

Adequate mobilization of hematopoietic stem cells (HSCs), especially CD34+ cells, is necessary for stem cell transplantation in patients with hematological malignancies or autoimmune diseases. Burixafor is an inhibitor of the C-X-C Chemokine Receptor 4 that disrupts the C-X-C motif chemokine 12 (CXCL12)/CXCR4 axis in the bone marrow, releasing HSCs into circulation. In mice, a single intravenous dose of burixafor was rapidly absorbed (time to maximum concentration, 5 minutes) and increased peripheral white blood cell counts within 30 minutes. Additionally, burixafor was administered to 64 healthy subjects in a randomized, double-blind, placebo-controlled, single-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics. Subjects received burixafor intravenous doses ranging from 0.10 to 4.40 mg/kg in 8 cohorts. Single doses were generally safe and well tolerated. Gastrointestinal events were reported at doses of 2.24 mg/kg or greater. Exposure (maximum concentration and area under the concentration-time curve) increased in an approximately dose-proportional manner. Time to maximum concentration occurred with a median of 0.26-0.30 hours that was not dose proportional. As expected, white blood cell, CD133+ cell, and CD34+ cell concentrations generally increased with the increases in burixafor dose from 0.10 to 3.14 mg/kg. At maximal levels, the CD34+ cell counts increased 3- to 14-fold from baseline levels. These results provide support for continued clinical development of burixafor.

Block Copolymer Modified Nanonetwork Epoxy Resin for Superior Energy Dissipation.

Herein, this work aims to fabricate well-ordered nanonetwork epoxy resin modified with poly(butyl acrylate)-b-poly(methyl methacrylate) (PBA-b-PMMA) block copolymer (BCP) for enhanced energy dissipation using a self-assembled diblock copolymer of polystyrene-b-poly(dimethylsiloxane) (PS-b-PDMS) with gyroid and diamond structures as templates. A systematic study of mechanical properties using nanoindentation of epoxy resin with gyroid- and diamond-structures after modification revealed significant enhancement in energy dissipation, with the values of 0.36 ± 0.02 nJ (gyroid) and 0.43 ± 0.03 nJ (diamond), respectively, when compared to intrinsic epoxy resin (approximately 0.02 ± 0.002 nJ) with brittle characteristics. This enhanced property is attributed to the synergic effect of the deliberate structure with well-ordered nanonetwork texture and the toughening of BCP-based modifiers at the molecular level. In addition to the deliberate structural effect from the nanonetwork texture, the BCP modifier composed of epoxy-philic hard segment and epoxy-phobic soft segment led to dispersed soft-segment domains in the nanonetwork-structured epoxy matrix with superior interfacial strength for the enhancement of applied energy dissipation.

Effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin in healthy Chinese volunteers.

PURPOSE: To investigate the effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin in humans. METHODS: Two independent, open-label, randomized, crossover studies were conducted in 24 (12 per study) healthy Chinese volunteers. In Study 1, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with 1.5 g of probenecid divided into three doses within 25 hours. In Study 2, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with multiple doses of cimetidine (400 mg thrice daily for 7 days). The plasma and urine nemonoxacin concentrations were determined using validated liquid chromatography-tandem mass spectrometry methods. RESULTS: Coadministration of nemonoxacin with probenecid reduced the renal clearance (CLr) of nemonoxacin by 22.6%, and increased the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) by 26.2%. Coadministration of nemonoxacin with cimetidine reduced the CLr of nemonoxacin by 13.3% and increased AUC0-∞ by 9.4%. Coadministration of nemonoxacin with probenecid or cimetidine did not significantly affect the maximum concentration of nemonoxacin or the percentage of the administered dose recovered in the urine. CONCLUSION: Although probenecid reduced the CLr and increased the plasma exposure of nemonoxacin, these effects are unlikely to be clinically meaningful at therapeutic doses. Cimetidine had weaker, clinically meaningless effects on the pharmacokinetics of nemonoxacin.

Determination of a novel nonfluorinated quinolone, nemonoxacin, in human feces and its glucuronide conjugate in human urine and feces by high-performance liquid chromatography-triple quadrupole mass spectrometry.

Three methods were developed and validated for determination of nemonoxacin in human feces and its major metabolite, nemonoxacin acyl-ß- d-glucuronide, in human urine and feces. Nemonoxacin was extracted by liquid-liquid extraction in feces homogenate samples and nemonoxacin acyl-ß- d-glucuronide by a solid-phase extraction procedure for pretreatment of both urine and feces homogenate sample. Separation was performed on a C18 reversed-phase column under isocratic elution with the mobile phase consisting of acetonitrile and 0.1% formic acid. Both analytes were determined by liquid chromatography-tandem mass spectrometry with positive electrospray ionization in selected reaction monitoring mode and gatifloxacin as the internal standard. The lower limit of quantitation (LLOQ) of nemonoxacin in feces was 0.12 µg/g and the calibration curve was linear in the concentration range of 0.12-48.00 µg/g. The LLOQ of the metabolite was 0.0010 µg/mL and 0.03 µg/g in urine and feces matrices, while the linear range was 0.0010-0.2000 µg/mL and 0.03-3.00 µg/g, respectively. Validation included selectivity, accuracy, precision, linearity, recovery, matrix effect, carryover, dilution integrity and stability, indicating that the methods can quantify the corresponding analytes with excellent reliability. The validated methods were successfully applied to an absolute bioavailability clinical study of nemonoxacin malate capsule.

Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers.

This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 µg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 µg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 µg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 µg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

Effects of an Al(3+)- and Mg(2+)-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin (TG-873870) in healthy Chinese volunteers.

AIM: To evaluate the effects of an Al(3+)- and Mg(2+)-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin in healthy humans. METHODS: Two single-dose, open-label, randomized, crossover studies were conducted in 24 healthy male Chinese volunteers (12 per study). In Study 1, the subjects orally received nemonoxacin (500 mg) alone, or an antacid (containing 318 mg of Al(3+) and 496 mg of Mg(2+)) plus nemonoxacin administered 2 h before, concomitantly or 4 h after the antacid. In Study 2, the subjects orally received nemonoxacin (500 mg) alone, or nemonoxacin concomitantly with ferrous sulfate (containing 60 mg of Fe(2+)) or calcium carbonate (containing 600 mg of Ca(2+)). RESULTS: Concomitant administration of nemonoxacin with the antacid significantly decreased the area under the concentration-time curve from time 0 to infinity (AUC0-∞) for nemonoxacin by 80.5%, the maximum concentration (Cmax) by 77.8%, and urine recovery (Ae) by 76.3%. Administration of nemonoxacin 4 h after the antacid decreased the AUC0-∞ for nemonoxacin by 58.0%, Cmax by 52.7%, and Ae by 57.7%. Administration of nemonoxacin 2 h before the antacid did not affect the absorption of nemonoxacin. Administration of nemonoxacin concomitantly with ferrous sulfate markedly decreased AUC0-∞ by 63.7%, Cmax by 57.0%, and Ae by 59.7%, while concomitant administration of nemonoxacin with calcium carbonate mildly decreased AUC0-∞ by 17.8%, Cmax by 14.3%, and Ae by 18.4%. CONCLUSION: Metal ions, Al(3+), Mg(2+), and Fe(2+) markedly decreased the absorption of nemonoxacin in healthy Chinese males, whereas Ca(2+) had much weaker effects. To avoid the effects of Al(3+) and Mg(2+)-containing drugs, nemonoxacin should be administered ≥2 h before them.

A liquid chromatography-tandem mass spectrometry assay for the determination of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, in human plasma and urine and its application to a single-dose pharmacokinetic study in healthy Chinese volunteers.

Nemonoxacin (TG-873870) is a novel C-8-methoxy nonfluorinated quinolone with higher activity than ciprofloxacin, levofloxacin and moxifloxacin against Gram-positive pathogens including methicillin-susceptible or methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae with various resistant phenotypes. A rapid, sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated to determine the concentration of nemonoxacin in human plasma and urine. Protein precipitation and liquid-liquid extraction were employed for plasma and urine sample preparations, respectively, and extract was then injected into the system. Separation was performed on a C(18) reversed-phase column using acetonitrile-0.1% formic acid as a mobile phase. Both analyte and internal standard (gatifloxacin) were determined using electrospray ionization and the MS data acquisition via the selected reaction monitoring in positive-ion mode. The lower limit of quantification was 5 ng/mL and the calibration curves were linear in the concentration range of 5-1000 ng/mL. The accuracy, precision, selectivity, linearity, recovery, matrix effect and stability were validated for TG-873870 in human plasma and urine. The method was successfully applied to a pharmacokinetic study enrolling 12 healthy Chinese volunteers administered nemonoxacin malate capsules.

Dose escalation study of the safety, tolerability, and pharmacokinetics of nemonoxacin (TG-873870), a novel potent broad-spectrum nonfluorinated quinolone, in healthy volunteers.

Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- and quinolone-resistant Streptococcus pneumoniae, and vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. The safety, tolerability, and pharmacokinetics of nemonoxacin were investigated in a double-blind, ascending-single-dose study involving 56 healthy subjects (48 males and 8 females) who were randomly assigned to 1 of 7 dose cohorts. In each successive cohort, two subjects received a placebo and six received single oral doses of 25, 50, 125, 250, 500, 1,000, or 1,500 mg nemonoxacin. Nemonoxacin was well tolerated up to the maximum dose of 1,500 mg. No severe or serious adverse events were observed. The most frequent adverse events were contact dermatitis, pruritus, and erythema. No clinically significant abnormalities were noted in the electrocardiograms, vital signs, or laboratory tests. The plasma concentrations increased over the dose range, and at 500 mg, the free area under the plasma concentration-time curve/MIC(90) ratios and free maximum nemonoxacin concentration/MIC(90) ratios against drug-sensitive/drug-resistant S. pneumoniae and S. aureus were greater than 227 and 24, respectively. The peak time and elimination half-life of nemonoxacin were 1 to 2 h and 9 to 16 h, respectively. The oral clearance was approximately 0.22 liter/h/kg. The plasma protein binding was approximately 16%. The results of this study support further evaluation of the multiple-dose safety, tolerability, and pharmacokinetics of nemonoxacin.

Multiple-dose safety, tolerability, and pharmacokinetics of oral nemonoxacin (TG-873870) in healthy volunteers.

Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with broad-spectrum activities against Gram-positive and Gram-negative aerobic, anaerobic, and atypical pathogens, as well as against methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus, and multiple-resistant bacterial pathogens. We conducted a randomized, double-blind, placebo-controlled, dose-escalating study to ascertain the safety, tolerability, and pharmacokinetics of nemonoxacin. We enrolled 46 healthy volunteers and used a once-daily oral-dosing range of 75 to 1,000 mg for 10 days. Additionally, the food effect was evaluated in subjects in the 500-mg cohort. Nemonoxacin was generally safe and well tolerated, with no significant changes in the clinical laboratory tests or electrocardiograms. Adverse effects, including headache, contact dermatitis, and rash, were mild and resolved spontaneously. Nemonoxacin was rapidly absorbed within 2 h postdosing, and generally, a steady state was reached after 3 days. The maximum plasma concentration and the area under the plasma concentration-time curve were dose proportional over the dosing range. The elimination half-life was approximately 7.5 h and 19.7 h on days 1 and 10, respectively. Approximately 37 to 58% of the drug was excreted in the urine. Food affected the pharmacokinetics, with decreases in the maximum plasma concentration and area under the plasma concentration-time curve of 46% and 27%, respectively. However, the free AUC/MIC(90) of nemonoxacin was more than 100 under both the fasting and fed conditions, predicting the efficacy of nemonoxacin against most of the tested pathogens. In conclusion, the results support further clinical investigation of once-daily nemonoxacin administration for antibiotic-sensitive and antibiotic-resistant bacterial infections.