A Phase I, Randomized, Partially Blinded, Placebo- and Moxifloxacin-Controlled, 4-Period Crossover Study to Evaluate the Effect of GSK1322322 on Cardiac Conduction as Assessed by 12-lead Electrocardiogram in Healthy Volunteers (PDF112166)

This is a randomized, partially-blinded, placebo and moxifloxacin-controlled, single dose, 4-period, balanced crossover study. The primary objective of this study is to separately assess the effects of a therapeutic and supratherapeutic dose of GSK1322322 on the cardiac conduction (corrected QT interval [QTc]) compared with placebo in eligible healthy male and female subjects. Avelox (moxifloxacin hydrochloride) will be used as an open-label positive control in order to validate the sensitivity of the study in detecting QTc change. Approximately 56 healthy subjects will participate in the study for approximately 9 weeks i.e. 30 day Screening period, 4-week Treatment period, and a 7-10 day Follow-up period. There will be 4 treatment periods separated by at least 1 week. Subjects will be admitted to the clinical unit on Day -1 of each dosing period. Each subject will receive each of the four treatment sequences (GSK1322322 1200 milligram [mg] intravenous [IV] over 60 minutes x 1 dose, GSK1322322 3000 mg IV over 60 minutes x 1 dose, GSK1322322 Placebo IV over 60 minutes x 1 dose, moxifloxacin 400 mg administered orally x 1 dose) on Day 1 of each Treatment period in a randomized fashion. Twelve-lead electrocardiogram (ECG), continuous Holter monitoring, laboratory tests, vital sign measurements, and serial pharmacokinetic samples will be collected for up to 24 hours following each treatment. If no clinically significant abnormalities are noted, subjects will be discharged from the clinical research unit after the completion of all assessments on Day 2 in each period and return approximately one week later for the next dosing period. Each individual subject will follow the same dosing schedule at every period. A Follow-up visit will be conducted 7-10 days after administration of the last dose of study medication in treatment period 4.

开始日期2014-08-01

申办/合作机构

GSK Plc

NCT01953809 / Withdrawn临床1期

A Phase 1, Randomized, Single Blind Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of an Oral Contraceptive Containing Norethindrone and Ethinyl Estradiol When Co-administered With GSK1322322 in Healthy Adult Women of Childbearing Age Who Are of Non-Childbearing Potential Due to Surgical Sterilization or IUD Placement (PDF112163)

This study is being conducted to confirm that GSK1322322 has no negative impact on hormone levels and contraceptive efficacy when co-administered with a frequently prescribed oral contraceptive thereby to facilitate the use of GSK1322322 in women of child-bearing potential receiving oral contraceptive (OC) pre-infection. This study is designed to investigate steady-state plasma ethinyl estradiol (EE) and norethindrone (NE) pharmacokinetic (PK) following administration of Ortho-Novum (EE/NE) 1 tablet every 24 hours (q24h) fed with and without GSK1322322 1500 milligram (mg) q12h fed. Each subject will participate in the study for approximately 12 weeks: a 30 day screening period, 4-week run-in period, three 7 day treatment periods, and a 3-5 day follow-up period. The study is planned to enroll approximately 24 subjects (18 active/6 placebo).

开始日期2014-08-01

申办/合作机构

GSK Plc

NCT01818011 / Terminated临床1期

A Three-Part Phase I, Open-Label, Single Ascending Dose, and A Single-Blind, Placebo-Controlled, Repeat Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Relative Bioavailability of Intravenous and Oral GSK1322322 in Healthy Volunteers and Healthy Male Japanese Subjects

The primary objectives of this study are to assess the safety, tolerability and pharmacokinetics of GSK1322322 following intravenous (IV) and oral administration. GSK1322322 shows broad spectrum antibacterial activity against pathogens involved in respiratory tract infections as well as methicillin-resistant S. Aureus (MRSA).
This study consists of three parts (Part A, Part B and Part C). The results from Part A of this study will enable use of large-scale, commercial tablets produced for administration to patients in pivotal clinical trials of GSK1322322. The results from Parts B and C will support enrolment of Japanese subjects in future clinical studies. Additionally, the results will support the dose selection for further clinical development of GSK1322322 in hospitalized patients with severe bacterial infections in Japan and other Asian populations.
In Part A, subjects will undergo screening, 4 treatment periods receiving single dose of each of: 1500 mg Initial, fit-for-purpose tablet (product code AP), 1500 mg Over granulated tablet (product code AR), and the 1500 mg and 2000 mg of intended commercial tablets (product code AU).
In Part B of the study subjects will undergo screening, and be randomized to receive 3 doses of GSK1322322 oral cohort (100 mg, 1500 mg and 2000 mg) or IV cohort (600 mg, 900 mg and 1200 mg) each in 3 treatment periods.
Part C will be a single-blind, placebo-controlled, repeat dose study of GSK1322322 in healthy Japanese male subjects. GSK1322322 will be administered (fasted) via IV for 4 days BID, followed by administration of GSK1322322 orally (fed) for 6 days BID. A follow-up evaluation will be conducted 7-10 days following last dose of for each subjects in each Part of the study.
Approximately 12 subjects will be enrolled in each part of the study such that approximately 8, 6, and 9 subjects complete dosing and critical assessments in part A,B, and C respectively.

开始日期2013-08-07

申办/合作机构

GSK Plc

100 项与 Lanopepden mesylate 相关的临床结果

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100 项与 Lanopepden mesylate 相关的转化医学

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100 项与 Lanopepden mesylate 相关的专利（医药）

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项与 Lanopepden mesylate 相关的文献（医药）

2018-03-01·Molecular informatics4区 · 医学

Virtual Screening Approach of Bacterial Peptide Deformylase Inhibitors Results in New Antibiotics

4区 · 医学

Article

作者: Okay, Sezer ; Boucherit, Hanane ; Chikhi, Abdelouahab ; Bensegueni, Abderrahmane ; Merzoug, Amina

Abstract:

The increasing resistance of bacteria to antibacterial therapy poses an enormous health problem, it renders the development of new antibacterial agents with novel mechanism of action an urgent need. Peptide deformylase, a metalloenzyme which catalytically removes N‐formyl group from N‐terminal methionine of newly synthesized polypeptides, is an important target in antibacterial drug discovery. In this study, we report the structure‐based virtual screening of ZINC database in order to discover potential hits as bacterial peptide deformylase enzyme inhibitors with more affinity as compared to GSK1322322, previously known inhibitor. After virtual screening, fifteen compounds of the top hits predicted were purchased and evaluated in vitro for their antibacterial activities against one Gram positive (Staphylococcus aureus) and three Gram negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella. pneumoniae) bacteria in different concentrations by disc diffusion method. Out of these, three compounds, ZINC00039650, ZINC03872971 and ZINC00126407, exhibited significant zone of inhibition. The results obtained were confirmed using the dilution method. Thus, these proposed compounds may aid the development of more efficient antibacterial agents.

2016-01-01·Antimicrobial agents and chemotherapy2区 · 医学

Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection

2区 · 医学

Article

作者: Novick, Steven J. ; Straub, Robert J. ; DeMarsh, Peter ; Aubart, Kelly ; Rittenhouse, Stephen ; Hoover, Jennifer ; Zalacain, Magdalena ; Lewandowski, Thomas

ABSTRACT:

GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with goodin vitroactivity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized thein vivopharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection withStreptococcus pneumoniaeandHaemophilus influenzae(mouse lung model) and withStaphylococcus aureus(rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependentin vivoefficacy against multiple isolates ofS. pneumoniae,H. influenzae, andS. aureus. Dose fractionation studies with twoS. pneumoniaeandS. aureusisolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index inS. pneumoniae(R2, 0.83), whereasfAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors forS. aureus(R2, 0.9 and 0.91, respectively). Median dailyfAUC/MIC values required for stasis and for a 1-log10reduction in bacterial burden were 8.1 and 14.4 for 11S. pneumoniaeisolates (R2, 0.62) and 7.2 and 13.0 for fiveH. influenzaeisolates (R2, 0.93). The data showed that for eightS. aureusisolates,fAUC correlated better with efficacy thanfAUC/MIC (R2, 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 μg/ml). MedianfAUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log10reductions, respectively, forS. aureus.

2015-09-01·Antimicrobial agents and chemotherapy2区 · 医学

Cellular Pharmacokinetics and Intracellular Activity of the Novel Peptide Deformylase Inhibitor GSK1322322 against Staphylococcus aureus Laboratory and Clinical Strains with Various Resistance Phenotypes: Studies with Human THP-1 Monocytes and J774 Murine Macrophages

2区 · 医学

Article

作者: Peyrusson, Frédéric ; Butler, Deborah ; Tulkens, Paul M. ; Van Bambeke, Françoise

ABSTRACT:

GSK1322322 is a peptide deformylase inhibitor active againstStaphylococcus aureusstrains resistant to currently marketed antibiotics. Our aim was to assess the activity of GSK1322322 against intracellularS. aureususing anin vitropharmacodynamic model and, in parallel, to examine its cellular pharmacokinetics and intracellular disposition. For intracellular activity analysis, we used an established model of human THP-1 monocytes and tested one fully susceptibleS. aureusstrain (ATCC 25923) and 8 clinical strains with resistance to oxacillin, vancomycin, daptomycin, macrolides, clindamycin, linezolid, or moxifloxacin. Uptake, accumulation, release, and subcellular distribution (cell fractionation) of [14C]GSK1322322 were examined in uninfected murine J774 macrophages and uninfected and infected THP-1 monocytes. GSK1322322 demonstrated a uniform activity against the intracellular forms of allS. aureusstrains tested, disregarding their resistance phenotypes, with a maximal relative efficacy (Emax) of a 0.5 to 1 log10CFU decrease compared to the original inoculum within 24 h and a static concentration (Cs) close to its MIC in broth. Influx and efflux were very fast (<5 min to equilibrium), and accumulation was about 4-fold, with no or a minimal effect of the broad-spectrum eukaryotic efflux transporter inhibitors gemfibrozil and verapamil. GSK1322322 was recovered in the cell-soluble fraction and was dissociated from the main subcellular organelles and from bacteria (in infected cells). The results of this study show that GSK1322322, as a typical novel deformylase inhibitor, may act against intracellular forms ofS. aureus. They also suggest that GSK1322322 has the ability to freely diffuse into and out of eukaryotic cells as well as within subcellular compartments.

100 项与 Lanopepden mesylate 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10713	-	-	DB11912

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
皮肤和皮肤结构感染	临床2期	美国	GSK Plc	2010-08-17
细菌性皮肤疾病	临床2期	美国	GSK Plc	2010-08-17
细菌感染	临床1期	美国	GSK Plc	2009-04-27

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临床结果

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分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01209078 (CTgov)	临床2期	细菌性皮肤疾病 \| 皮肤和皮肤结构感染	84	GSK1322322 (GSK1322322 1500 mg BID)	鹽齋構遞範築衊網鏇窪(網繭獵鹹鑰鬱齋選積夢) = 壓觸蓋衊艱窪製鏇憲積積顧艱製鏇選顧膚廠憲 (獵鹹鑰鹹襯蓋願窪艱繭, 艱膚餘願獵鑰選憲簾構 ~ 觸壓鑰壓窪構簾鹹觸鑰) 更多	-	2017-12-04
				Linezolid (Linezolid 600 mg BID)	鹽齋構遞範築衊網鏇窪(網繭獵鹹鑰鬱齋選積夢) = 選遞餘遞積顧鹽範壓淵積顧艱製鏇選顧膚廠憲 (獵鹹鑰鹹襯蓋願窪艱繭, 衊繭淵餘鹹繭窪窪衊鏇 ~ 糧獵醖鏇鬱衊夢鏇壓淵) 更多
NCT01209078 (Pubmed)	临床2期	皮肤和皮肤结构感染	84	GSK1322322 1,500 mg b.i.d.	餘繭選願憲繭選繭憲醖(糧醖鹽淵鬱積遞鏇鏇獵) = mild-to-moderate drug-related adverse events, most commonly, diarrhea 鬱淵鑰鑰齋願襯願簾獵 (鑰艱窪遞醖襯夢築廠夢 ) 更多	-	2014-11-01
				Linezolid 600 mg b.i.d.
NCT01610388 (Pubmed \| Antimicrob Agents Chemother)	临床1期	细菌感染	61	GSK1322322	夢遞構襯構齋醖簾齋膚(鑰積膚遞遞壓衊餘憲遞) = 遞鹽選鏇糧觸醖製醖憲衊鬱齋齋餘繭膚簾構鏇 (膚願鹽蓋壓齋鑰夢齋齋 ) 更多	-	2014-01-01