scholarly journals Safety, Tolerability and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B

2021 ◽  
Author(s):  
J. T. Guptill ◽  
S. M. Raja ◽  
V. C. Juel ◽  
E. B. Walter ◽  
M Cohen-Wolkowiez ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Adverse Events ◽  
Clinical Laboratory ◽  
Human Study ◽  
Post Exposure Prophylaxis ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Time Curve ◽  
Post Exposure

Objective Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given post-exposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. Methods This double-blind, single-center, placebo-controlled dose escalation study, randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at pre-specified time points for PK and immunogenicity analyses. Results Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life >20 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent anti-drug antibody responses in the low and middle dosing groups and none at the highest dose. Interpretation NTM-1632 is well-tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and post-exposure prophylaxis.

scholarly journals First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Mammen P. Mammen ◽  
Danielle Armas ◽  
Frank H. Hughes ◽  
Andrew M. Hopkins ◽  
Cindy L. Fisher ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Safety Data ◽  
Healthy Adults ◽  
Antifungal Drug ◽  
Renal Elimination ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Time Curve

ABSTRACT VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus, including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically concerning trends were noted in vital signs, electrocardiograms, physical examinations, or safety laboratory results. Following single infusions of VL-2397, the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1,200 mg as indicated by area under the concentration-time curve over 24 h (AUC24) and maximum concentration (Cmax). No signs of VL-2397 accumulation were observed following i.v. infusions of 300, 600, and 1,200 mg every 24 h (q24h) for 7 days. Renal elimination played a major role in total body clearance, with up to 47% of unmetabolized drug in urine 24 h after administration at single doses of >30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK, and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis.

scholarly journals Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Nadine G. Rouphael ◽  
Selwyn J. Hurwitz ◽  
Mari Hart ◽  
Allison Beck ◽  
Evan J. Anderson ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Laboratory ◽  
Subcutaneous Tissue ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Plasma Exposure ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve

ABSTRACT Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro. (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.)

scholarly journals Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2

2021 ◽  
Author(s):  
Wendy P. Painter ◽  
Wayne Holman ◽  
Jim A. Bush ◽  
Firas Almazedi ◽  
Hamzah Malik ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Adverse Events ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Influenza Viruses ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve ◽  
Multiple Doses

Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses. Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics. EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure. Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.

scholarly journals Safety and Pharmacokinetics of XOMA 3AB, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin A

2014 ◽  
Vol 58 (9) ◽  
pp. 5047-5053 ◽  
Author(s):  
S. U. Nayak ◽  
J. M. Griffiss ◽  
R. McKenzie ◽  
E. J. Fuchs ◽  
R. A. Jurao ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Botulinum Neurotoxin ◽  
Botulinum Toxin A ◽  
Human Study ◽  
Pharmacokinetic Parameters ◽  
Human Mabs ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Time Curve ◽  
Concentration Time

ABSTRACTBotulinum neurotoxin A is a category A bioterrorism agent. Current antitoxin therapies are scarce and produce adverse reactions. XOMA 3AB consists of 3 IgG1 monoclonal antibodies (MAbs), each with a distinct human or humanized variable region, which bind to distinct epitopes on botulinum neurotoxin serotype A. This first-in-human study evaluated the safety and pharmacokinetics (PK) of escalating doses of XOMA 3AB administered intravenously (i.v.) to healthy adults. In this double-blind placebo-controlled dose escalation study, 3 cohorts of 8 healthy subjects received a single intravenous dose of XOMA 3AB or placebo at a 3:1 ratio. Follow-up examinations included physical examinations, hematology and chemistry blood tests, electrocardiograms, and pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. There were no infusion discontinuations or hypersensitivity reactions. Two or more subjects experienced headache, hyperglycemia, or anemia; none was dose related. All adverse events (AEs) were mild to moderate except for an episode of exercise-induced elevation of a subject's creatine phosphokinase (CPK) level, unrelated to XOMA 3AB. Concentration-time plots demonstrated a peak in MAb concentrations 1 to 2 h after completion of the infusion, after which the levels declined in a biexponential decay pattern for all analytes. For each MAb, the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve from 0 to infinity (AUCinf) increased as the dose increased. Clearance of the humanized mouse MAb was more rapid than that of the two fully human MAbs, particularly at the lowest dose. None of the MAbs was immunogenic. At the doses administered, XOMA 3AB was well tolerated. These safety findings support further investigation of XOMA 3AB as a potential agent for botulism treatment and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01357213.)

scholarly journals Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Henglin Yang ◽  
Jingyan Wang ◽  
Hui Liu ◽  
Xingliang Li ◽  
Renhua Nie ◽  
...  
Keyword(s):  
Adverse Events ◽  
Southeast Asia ◽  
Clinical Laboratory ◽  
Protective Efficacy ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Prophylactic Efficacy ◽  
Content Type ◽  
Double Blind Placebo ◽  
Intention To Treat

ABSTRACTNew prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, againstPlasmodium falciparuminfections, whereas both offered 100% prophylactic efficacy againstPlasmodium vivaxandPlasmodium ovale. These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.

scholarly journals First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial Infections

2021 ◽  
Author(s):  
Angela K. Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Vipul K. Gupta ◽  
Myriah Satterfield ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Human Study ◽  
Dna Gyrase ◽  
Plasma Exposure ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Bacterial Dna ◽  
Elimination Pathway

SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria in vitro and in murine and hollow fiber infection models. This Phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 mg to 2000 mg, or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. The median SPR719 T max ranged from 2.8 to 8.0 hours across cohorts, and the t 1/2 ranged from 2.9 to 4.5 hours and was shown to be dose-independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC 0-24 was comparable between Days 7 and 14. Results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720.

scholarly journals OC 8582 A PHASE IA/B STUDY TO ASSESS SAFETY AND IMMUNOGENICITY OF PLACENTAL MALARIA VACCINE CANDIDATE: PRELIMINARY RESULTS OF THE PRIMALVAC TRIAL

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A14.3-A15
Author(s):  
Amadou Konate ◽  
Laura Richert ◽  
Arnaud Chêne ◽  
Jean-Philippe Semblat ◽  
Gwenaelle Roguet ◽  
...  
Keyword(s):  
Adverse Events ◽  
Burkina Faso ◽  
Malaria Vaccine ◽  
Clinical Laboratory ◽  
Placental Malaria ◽  
Safety Data ◽  
Vaccine Trial ◽  
Adult Women ◽  
Serious Adverse Events ◽  
Double Blind

BackgroundAdhesion of P. falciparum-infected erythrocytes (PEs) to placental chondroitin-4-sulfate (CSA) has been linked to severe placental malaria (PM) outcomes. Evidence strongly supports the VAR2CSA variant surface antigen mediating PEs CSA-binding phenotype as the leading candidate for a PM vaccine. This study was conducted to assess the safety and immunogenicity of 3 different dosages (20 µg, 50 µg and 100 µg) of the recombinant VAR2CSA protein (PRIMVAC), formulated with Alhydrogel or GLA-SE administered at days 0, 28 and 56.MethodsA randomised double-blind phase Ia/Ib dose-escalation vaccine trial was conducted in healthy adult women. Within 4 sequential cohorts, volunteers were randomised to 2 arms (PRIMVAC adjuvanted with Alhydrogel or GLA-SE) in the first phase conducted in France and then to 3 arms (PRIMVAC with Alhydrogel or GLA-SE or placebo) in Burkina Faso. Enrolled volunteers were observed for at least 1 hour following each vaccination then seen at 1 day and 7 days later for safety evaluations. Serious adverse events (SAE) were recorded throughout the study duration. Routine clinical laboratory safety analyses were performed prior to first injection and at each subsequent visit.ResultsA total of 68 subjects were recruited in the four study cohorts. No SAE was reported in any of the cohort A volunteers and enrolment in cohort B was started. A Data Safety Monitoring Board (DSMB) reviewed the safety data for cohorts A (20 µg) and B (50 µg) before the trial was initiated in Burkina Faso. The DSMB also reviewed the safety data in Burkina to authorise the progression from the cohort C (50 µg) to cohort D (100 µg). The last vaccination of the last subject occurred in September 2017.ConclusionThis was the first placental malaria vaccine phase Ia/b clinical trial conducted in France and Burkina Faso. No serious adverse events have been recorded. Preliminary safety and immunogenicity results will be presented.

scholarly journals Human Safety, Tolerability, and Pharmacokinetics of a Novel Broad-Spectrum Oral Antiviral Compound, Molnupiravir, with Activity Against SARS-CoV-2

2020 ◽  
Author(s):  
Wendy P. Painter ◽  
Wayne Holman ◽  
Jim A. Bush ◽  
Firas Almazedi ◽  
Hamzah Malik ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Adverse Events ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Influenza Viruses ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Antiviral Compound ◽  
Multiple Doses

AbstractMolnupiravir, EIDD-2801/MK-4482, the prodrug of the ribonucleoside analog ß-d-N4-hydroxycytidine (NHC), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, seasonal and pandemic influenza viruses, and respiratory syncytial virus.Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.Clinical trial identifierThis study was registered at ClinicalTrials.gov with the identifier NCT04392219.

SAT0196 A DOUBLE BLIND, PLACEBO CONTROLLED, SINGLE ASCENDING DOSE (SAD) AND MULTIPLE ASCENDING DOSE (MAD) STUDY OF ALPN-101, A FIRST-IN-CLASS DUAL ICOS/CD28 ANTAGONIST, IN HEALTHY VOLUNTEERS (HV)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1040-1040
Author(s):  
J. Yang ◽  
J. Hillson ◽  
J. Lickliter ◽  
K. Manjarrez ◽  
A. Tercero ◽  
...  
Keyword(s):  
Adverse Events ◽  
Inflammatory Diseases ◽  
Phase 1 ◽  
Human Study ◽  
Keyhole Limpet Hemocyanin ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Expert Review ◽  
High Level ◽  
Dose Dependent

Background:ALPN-101 (ICOSL vIgD-Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD™) designed to inhibit simultaneously the CD28 and ICOS inflammation pathways (1). ALPN-101 is effective in preclinical studies of lupus, arthritis, and Sjögren’s, and shows greater activity than single pathway inhibitors (2,3,4). It is in development for the treatment of multiple rheumatic and other inflammatory diseases.Objectives:To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN-101 in HVMethods:This was a first-in-human study of ALPN-101 (NCT03748836). 72 HV were allocated 4:2 to single intravenous (IV) or subcutaneous (SC) doses of ALPN-101: placebo at 0.001 – 10 mg/kg; 24 HV were allocated 6:2 to repeated IV doses of up to 1 mg/kg weekly x 4. Subjects were followed for 28 (SAD) or 49 (MAD) days to assess safety, PK, target saturation (TS) on T cells, circulating cytokines and PD, the latter based on suppression of IgG responses to keyhole limpet hemocyanin (KLH).Results:ALPN-101 was generally well-tolerated, with no treatment related serious adverse events, no cytokine release, no clinical immunogenicity, and no adverse trends in safety laboratories. Overall, adverse events were reported in 74.2% of subjects on ALPN-101 and 66.7% of subjects on placebo. All events were mild or moderate and resolved without sequelae. Dose-dependent increase in ALPN-101 exposure was observed from 0.012 to 10 mg/kg. The estimated t1/2was 2-8.6 days over 0.3 – 10 mg/kg. SC bioavailability was ~60% at 3 mg/kg. Minimal to modest accumulation was observed with repeat IV dosing. The TS at Cmaxincreased with dose between 0.001–0.03 mg/kg; thereafter the duration of high level TS (>95%) increased with dose (Figure 1). The duration of suppression of IgG anti-KLH response paralleled the duration of high level TS (Figure 2).Figure 1.Mean + SD Target Saturation of ALPN-101 on Circulating CD4+T LymphocytesFigure 2.Mean + SD Serum Anti-KLH IgG Change Relative to BaselineConclusion:ALPN-101 was well tolerated when administered as single doses up to 10 mg/kg or as repeated doses of up to 1 mg/kg weekly for 4 weeks, exhibiting dose-dependent PK, TS and PD including the inhibition of antibody responses to KLH immunization. These findings support future studies to evaluate the efficacy of ALPN-101 in multiple rheumatic and other inflammatory diseases.References:[1]Levin SD et al. Frontiers in Immunology 2020; 10:3086[2]Evans L et al. Arthritis and Rheumatology 2019:71: Supplement: Abstract 1531[3]Dillon S et al. Arthritis and Rheumatology 2018:70: Supplement: Abstract 136[4]Dillon S et al. Arthritis and Rheumatology 2019:71: Supplement: Abstract 2416Disclosure of Interests:Jing Yang Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jan Hillson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jason Lickliter Consultant of: AUD 2500 from QBiotics for participation in an expert review panel for development of their oncology phase 1 trial (in Nov 2015), Kristi Manjarrez Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine immune sciences, Inc., Almudena Tercero Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jennifer Wiley Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Gary Means Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Russell Sanderson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Kay Carley Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Stanford L. Peng Shareholder of: Alpine Immune Sciences, Inc., Employee of: CMO and President of Alpine Immune Sciences, Inc.

scholarly journals Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Nemonoxacin (TG-873870), a Novel Potent Broad-Spectrum Nonfluorinated Quinolone, in Healthy Volunteers

2009 ◽  
Vol 54 (1) ◽  
pp. 405-410 ◽  
Author(s):  
Luke Lin ◽  
Li-Wen Chang ◽  
Cheng-Yuan Tsai ◽  
Ching-Hung Hsu ◽  
David T. Chung ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Adverse Events ◽  
Broad Spectrum ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Peak Time ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Single Dose Study

ABSTRACT 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/MIC90 ratios and free maximum nemonoxacin concentration/MIC90 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.

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