Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection.

Abstract:

:We conducted this double-blind, parallel-group, placebo-controlled, randomized, multiple-ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9851 (formerly PSI-7851) in treatment-naïve patients infected with hepatitis C virus (HCV) genotype 1. Thirty-two patients received active doses up to 400 mg of GS-9851 once daily for 3 days. GS-9851 and the metabolite GS-566500 (formerly PSI-352707) were rapidly cleared from the plasma, with half-life (t(1/2)) values of approximately 1 h for GS-9851 and 3 h for GS-566500. Accumulation (21%) was observed only for GS-331007 (formerly PSI-6206) after multiple dosing. GS-331007 was the primary drug-related moiety in the plasma and urine. Increases in the GS-9851, GS-566500, and GS-331007 maximum concentrations in plasma (C(max)) and area under the concentration-time curve (AUC) were less than dose proportional, particularly at the highest doses. The decline in plasma HCV RNA levels was dose dependent, and a mean maximal change from the baseline of -1.95 log(10) IU/ml was obtained for 400 mg GS-9851, compared with -0.090 log(10) IU/ml for the placebo. Most patients had a decrease in HCV RNA of ≥1.0 log(10) IU/ml after 3 days' dosing with 400 mg GS-9851. No virologic resistance was observed. GS-9851 was generally well tolerated, with no notable differences in adverse event frequency across doses. The pharmacokinetic profile observed in this study was similar to that seen in a single-ascending-dose study in healthy subjects.

authors

Lawitz E,Rodriguez-Torres M,Denning JM,Albanis E,Cornpropst M,Berrey MM,Symonds WT

doi

10.1128/AAC.01263-12

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

1209-17

issue

3

eissn

0066-4804

issn

1098-6596

pii

AAC.01263-12

journal_volume

57

pub_type

杂志文章,随机对照试验
  • Impaired fitness and transmission of macrolide-resistant Campylobacter jejuni in its natural host.

    abstract::Campylobacter jejuni is a major zoonotic pathogen transmitted to humans via the food chain and is prevalent in chickens, a natural reservoir for this pathogenic organism. Due to the importance of macrolide antibiotics in clinical therapy of human campylobacteriosis, development of macrolide resistance in Campylobacter...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.05516-11

    authors: Luangtongkum T,Shen Z,Seng VW,Sahin O,Jeon B,Liu P,Zhang Q

    更新日期:2012-03-01 00:00:00

  • Use of a temperature-sensitive, protoplast-forming Neurospora crassa strain for the detection of antifungal antibiotics.

    abstract::Protoplasts of the temperature-sensitive osmotic-1 mutant of Neurospora crassa grew and divided as cell wall-less cells when incubated under certain conditions at 37 degrees C. Each protoplast regenerated cell wall and formed a mycelium when the temperature was shifted to 22 degrees C. Cell wall regeneration, but not ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.23.5.757

    authors: Selitrennikoff CP

    更新日期:1983-05-01 00:00:00

  • Specific inhibition of the eubacterial DNA ligase by arylamino compounds.

    abstract::All known DNA ligases catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA via very similar mechanisms. The ligase family can, however, be divided into two classes: eubacterial ligases, which require NAD(+) as a cofactor, and other ligases, from viruses, archaea, and eukar...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.43.11.2766

    authors: Ciarrocchi G,MacPhee DG,Deady LW,Tilley L

    更新日期:1999-11-01 00:00:00

  • Two novel antibiotic resistance genes, tet(44) and ant(6)-Ib, are located within a transferable pathogenicity island in Campylobacter fetus subsp. fetus.

    abstract::New tetracycline and streptomycin resistance genes, tet(44) and ant(6)-Ib, were identified in Campylobacter fetus subsp. fetus within a transferable pathogenicity island that is typically unique to Campylobacter fetus subsp. venerealis. The 640-amino-acid tetracycline resistance determinant, Tet 44, belongs to a class...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00304-10

    authors: Abril C,Brodard I,Perreten V

    更新日期:2010-07-01 00:00:00

  • Cefamandole: in vitro and clinical pharmacokinetics.

    abstract::Cefamandole has a broader spectrum and greater potency than the other cephalosporins. It includes Haemophilus influenzae, most strains of Enterobacter, and many strains of indole-positive Proteus and Bacteroides, with a lower minimal inhibitory concentration for Escherichia coli, Klebsiella, etc. Concentrations of dru...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章

    doi:10.1128/aac.10.5.814

    authors: Griffith RS,Black HR,Brier GL,Wolny JD

    更新日期:1976-11-01 00:00:00

  • Evaluation of a new line probe assay for rapid identification of gyrA mutations in Mycobacterium tuberculosis.

    abstract::Resistance of Mycobacterium tuberculosis to fluoroquinolones (FQ) results mostly from mutations in the gyrA gene. We developed a reverse hybridization-based line probe assay in which oligonucleotide probes carrying the wild-type gyrA sequence, a serine-to-threonine (S95T) polymorphism, and gyrA mutations (A90V, A90V-S...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.49.7.2928-2933.2005

    authors: Giannoni F,Iona E,Sementilli F,Brunori L,Pardini M,Migliori GB,Orefici G,Fattorini L

    更新日期:2005-07-01 00:00:00

  • Emergence of gentamicin- and carbenicillin-resistant Pseudomonas aeruginosa in a hospital environment.

    abstract::Strains of Pseudomonas aeruginosa resistant to either gentamicin or carbenicillin have been noted since their introduction into clinical use. During a 6-month period, twice-weekly cultures were obtained from all patients treated with either gentamicin or carbenicillin and from all patients with a positive culture for ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.9.3.474

    authors: Gaman W,Cates C,Snelling CF,Lank B,Ronald AR

    更新日期:1976-03-01 00:00:00

  • In vitro inhibition of bacterial DNA gyrase by cinodine, a glycocinnamoylspermidine antibiotic.

    abstract::Cinodine, a broad-spectrum glycocinnamoylspermidine antibiotic, binds to DNA and irreversibly inhibits bacterial and phase DNA synthesis. Cinodine was found to inhibit the activity of Micrococcus luteus DNA gyrase in vitro, but it did not inhibit the activities of two other DNA-binding enzymes, namely, topoisomerase I...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.34.7.1450

    authors: Osburne MS,Maiese WM,Greenstein M

    更新日期:1990-07-01 00:00:00

  • Comparison of oral fluconazole and clotrimazole troches as treatment for oral candidiasis in patients infected with human immunodeficiency virus.

    abstract::Thirty-nine adult patients with human immunodeficiency virus infection and oral candidiasis were randomly assigned to receive either one fluconazole capsule (100 mg) or five clotrimazole troches (10 mg each) daily for 14 days. Among 36 evaluable patients, clinical resolution rates were 100 and 65%, respectively (P = 0...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1128/aac.34.11.2267

    authors: Koletar SL,Russell JA,Fass RJ,Plouffe JF

    更新日期:1990-11-01 00:00:00

  • Dextromethorphan efficiently increases bactericidal activity, attenuates inflammatory responses, and prevents group a streptococcal sepsis.

    abstract::Group A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from mild throat and skin infections to severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), a dextrorotatory morphinan and a widely used antituss...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00950-10

    authors: Li MH,Luo YH,Lin CF,Chang YT,Lu SL,Kuo CF,Hong JS,Lin YS

    更新日期:2011-03-01 00:00:00

  • In vitro activity of A-56619 (difloxacin), A-56620, and other new quinolone antimicrobial agents against genital pathogens.

    abstract::The in vitro activities of two new carboxyquinolones, A-56619 (difloxacin) and A-56620, were compared with those of ciprofloxacin, norfloxacin, and ofloxacin against genital tract pathogens. All the quinolones were highly active against Neisseria gonorrhoeae. A-56619 had the lowest MICs against Chlamydia trachomatis (...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.30.6.948

    authors: Liebowitz LD,Saunders J,Fehler G,Ballard RC,Koornhof HJ

    更新日期:1986-12-01 00:00:00

  • Characterization of a respiratory syncytial virus L protein inhibitor.

    abstract::The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibito...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02540-14

    authors: Tiong-Yip CL,Aschenbrenner L,Johnson KD,McLaughlin RE,Fan J,Challa S,Xiong H,Yu Q

    更新日期:2014-07-01 00:00:00

  • Combination antimicrobial susceptibility testing of multidrug-resistant Stenotrophomonas maltophilia from cystic fibrosis patients.

    abstract::Stenotrophomonas maltophilia is increasingly being isolated from the respiratory tract of individuals with cystic fibrosis, and, because of its multidrug-resistant nature, the selection of suitable treatment regimens can be problematical. Etest methodology was used to facilitate MIC and antimicrobial combination testi...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00072-12

    authors: Milne KE,Gould IM

    更新日期:2012-08-01 00:00:00

  • Antibiotic resistance and single-nucleotide polymorphism cluster grouping type in a multinational sample of resistant Mycobacterium tuberculosis isolates.

    abstract::A single-nucleotide polymorphism-based cluster grouping (SCG) classification system for Mycobacterium tuberculosis was used to examine antibiotic resistance type and resistance mutations in relationship to specific evolutionary lineages. Drug resistance and resistance mutations were seen across all SCGs. SCG-2 had hig...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00619-07

    authors: Brimacombe M,Hazbon M,Motiwala AS,Alland D

    更新日期:2007-11-01 00:00:00

  • Effect of transcriptional activators SoxS, RobA, and RamA on expression of multidrug efflux pump AcrAB-TolC in Enterobacter cloacae.

    abstract::Control of membrane permeability is a key step in regulating the intracellular concentration of antibiotics. Efflux pumps confer innate resistance to a wide range of toxic compounds such as antibiotics, dyes, detergents, and disinfectants in members of the Enterobacteriaceae. The AcrAB-TolC efflux pump is involved in ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01085-12

    authors: Pérez A,Poza M,Aranda J,Latasa C,Medrano FJ,Tomás M,Romero A,Lasa I,Bou G

    更新日期:2012-12-01 00:00:00

  • Post-β-lactamase-inhibitor effect of tazobactam in combination with ceftolozane on extended-spectrum-β-lactamase-producing strains.

    abstract::The post-β-lactamase-inhibitor effect (PBLIE) of tazobactam combined with ceftolozane was evaluated by time-kill assays on two clinical Escherichia coli strains producing CTX-M-15 with or without TEM-1. The organisms were exposed (2 h) to 4 μg/ml/4 μg/ml of ceftolozane-tazobactam (4× MIC), 4 μg/ml of ceftolozane, and ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02398-13

    authors: Sader HS,Rhomberg PR,Jones RN

    更新日期:2014-01-01 00:00:00

  • In vitro activity of a new fluoroquinolone, CP-99,219, against strains of Neisseria gonorrhoeae.

    abstract::The susceptibilities of 216 strains of Neisseria gonorrhoeae to a new fluoroquinolone, CP-99,219 were determined. For strains for which the MICs of ciprofloxacin were < or = 0.06 microgram/ml, the MICs at which 90% of the isolates are inhibited (MIC90s) of CP-99,219, ciprofloxacin, and ofloxacin were 0.008, 0.015, and...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.39.4.987

    authors: Knapp JS,Neal SW,Parekh MC,Rice RJ

    更新日期:1995-04-01 00:00:00

  • Antimicrobial effect of halocidin-derived peptide in a mouse model of Listeria infection.

    abstract::Halocidin is an antimicrobial peptide found in the tunicate. A series of experiments were previously conducted in an attempt to develop a novel antibiotic derived from halocidin, as the peptide was determined to evidence profound antimicrobial activity against a variety of antibiotic-resistant microbes, with significa...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00635-07

    authors: Jang WS,Lee SC,Lee YS,Shin YP,Shin KH,Sung BH,Kim BS,Lee SH,Lee IH

    更新日期:2007-11-01 00:00:00

  • A substituted tetrahydro-tetrazolo-pyrimidine is a specific and novel inhibitor of hepatitis B virus surface antigen secretion.

    abstract::The high levels of hepatitis B virus (HBV) surface antigen (HBsAg)-bearing subviral particles in the serum of chronically infected individuals are thought to play a role in suppressing the HBV-specific immune response. Current therapeutics are not directed at reducing this viral antigenemia; thus, our group has focuse...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00541-07

    authors: Dougherty AM,Guo H,Westby G,Liu Y,Simsek E,Guo JT,Mehta A,Norton P,Gu B,Block T,Cuconati A

    更新日期:2007-12-01 00:00:00

  • Effect of protein binding on drug penetration into blister fluid.

    abstract::The effect of protein binding on drug penetration into blister fluid was evaluated by using cefonicid, ceftizoxime, and cefotaxime. Drug concentrations in a chamber with a high surface area/volume ratio (i.e., paper disk) follow changes in serum more closely than do those in a chamber with a low surface area/volume ra...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.32.1.128

    authors: Shyu WC,Quintiliani R,Nightingale CH,Dudley MN

    更新日期:1988-01-01 00:00:00

  • Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients.

    abstract::Nosocomial pneumonia and sepsis, as well as severe diffuse peritonitis, must be treated early in order to prevent complications such as septic shock and organ dysfunctions. With the availability of new broad-spectrum and highly bactericidal antibiotics, the need of combining beta-lactams with aminoglycosides for the t...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1128/aac.38.6.1309

    authors: Cometta A,Baumgartner JD,Lew D,Zimmerli W,Pittet D,Chopart P,Schaad U,Herter C,Eggimann P,Huber O

    更新日期:1994-06-01 00:00:00

  • Interaction of azthreonam and related monobactams with beta-lactamases from gram-negative bacteria.

    abstract::Monobactams containing 3 beta-aminothiazolyl oxime side chains (SQ 81,377, SQ 81,402, azthreonam, and SQ 26,917) have poor affinities for the broad-spectrum beta-lactamases TEM-2 and K1. Addition of a 4-methyl substituent significantly increased stability to hydrolysis by these enzymes. P99 cephalosporinase from Enter...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.22.3.414

    authors: Bush K,Freudenberger JS,Sykes RB

    更新日期:1982-09-01 00:00:00

  • Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species.

    abstract::Streptomyces bacteria are renowned for their ability to produce bioactive secondary metabolites. Recently, synthetic biology has enabled the production of intermediates and shunt products, which may have altered biological activities compared to the end products of the pathways. Here, we have evaluated the potential o...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00991-15

    authors: Oja T,San Martin Galindo P,Taguchi T,Manner S,Vuorela PM,Ichinose K,Metsä-Ketelä M,Fallarero A

    更新日期:2015-10-01 00:00:00

  • Penicillin-binding proteins in a Staphylococcus aureus strain resistant to specific beta-lactam antibiotics.

    abstract::The penicillin-binding proteins (PBPs) of a clinical isolate of Staphylococcus aureus specifically resistant to oral cephalosporins were compared with those of a susceptible strain. In the resistant strain, PBP3 (75,000 molecular weight) was missing or had substantially (greater than 100-fold) reduced affinity for pen...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.22.1.172

    authors: Georgopapadakou NH,Smith SA,Bonner DP

    更新日期:1982-07-01 00:00:00

  • Nonnucleoside inhibitors of norovirus RNA polymerase: scaffolds for rational drug design.

    abstract::Norovirus (NoV) is the leading cause of acute gastroenteritis worldwide, causing over 200,000 deaths a year. NoV is nonenveloped, with a single-stranded RNA genome, and is primarily transmitted person to person. The viral RNA-dependent RNA polymerase (RdRp) is critical for the production of genomic and subgenomic RNA ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02799-13

    authors: Eltahla AA,Lim KL,Eden JS,Kelly AG,Mackenzie JM,White PA

    更新日期:2014-06-01 00:00:00

  • Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing.

    abstract::In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章

    doi:10.1128/AAC.45.1.30-37.2001

    authors: Sadler BM,Gillotin C,Lou Y,Stein DS

    更新日期:2001-01-01 00:00:00

  • In vitro activity of gemifloxacin (SB 265805) against anaerobes.

    abstract::Gemifloxacin mesylate (SB 265805), a new fluoronaphthyridone, was tested against 359 recent clinical anaerobic isolates by the National Committee for Clinical Laboratory Standards reference agar dilution method with supplemented brucella blood agar and an inoculum of 10(5) CFU/spot. Comparative antimicrobials tested i...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.43.9.2231

    authors: Goldstein EJ,Citron DM,Warren Y,Tyrrell K,Merriam CV

    更新日期:1999-09-01 00:00:00

  • Regulation of heme polymerizing activity and the antimalarial action of chloroquine.

    abstract::Mice infected with Plasmodium berghei served as donors of erythrocytes with a high level of parasitemia for the study of ferriprotoporphyrin IX (FP) polymerization. Six hours after treatment of these mice with 3 micromol of chloroquine per 25 g of body weight, there were significant losses of heme polymerase I (HPA I)...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.41.11.2461

    authors: Fitch CD,Chou AC

    更新日期:1997-11-01 00:00:00

  • Role of beta-lactamase in in vivo development of ceftazidime resistance in experimental Pseudomonas aeruginosa endocarditis.

    abstract::Two ceftazidime-resistant variants of Pseudomonas aeruginosa (PA-48, PA-60), obtained from cardiac vegetations of rabbits with endocarditis receiving ceftazidime therapy, were studied for mechanisms of resistance. Both resistant variants were stably derepressed for the type Id beta-lactamase, which was ceftazidime ind...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.31.2.253

    authors: Bayer AS,Peters J,Parr TR Jr,Chan L,Hancock RE

    更新日期:1987-02-01 00:00:00

  • Role of extracellular iron in the action of the quinone antibiotic streptonigrin: mechanisms of killing and resistance of Neisseria gonorrhoeae.

    abstract::The quinone antibiotic streptonigrin is believed to kill bacteria by promoting formation of oxygen radicals. This antibiotic has also been used to select resistant bacterial mutants, some of which vary in iron utilization. We examined the effects of streptonigrin on Neisseria gonorrhoeae and several types of gonococca...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.31.10.1507

    authors: Cohen MS,Chai Y,Britigan BE,McKenna W,Adams J,Svendsen T,Bean K,Hassett DJ,Sparling PF

    更新日期:1987-10-01 00:00:00