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Safety and Efficacy of GSK2248761, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Treatment-Naive HIV-1-Infected Subjects

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK...

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Published in:Antimicrobial Agents and Chemotherapy 2012-05, Vol.56 (5), p.2570-2575
Main Authors: Zala, Carlos, St. Clair, Marty, Dudas, Kathleen, Kim, Joseph, Lou, Yu, White, Scott, Piscitelli, Steve, Dumont, Etienne, Pietropaolo, Keith, Zhou, Xiao-Jian, Mayers, Douglas
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cited_by cdi_FETCH-LOGICAL-a564t-e03bbce34f38a84a90d691a0cb1985a18ae3b098c1873a50100204839a6edd8e3
cites cdi_FETCH-LOGICAL-a564t-e03bbce34f38a84a90d691a0cb1985a18ae3b098c1873a50100204839a6edd8e3
container_end_page 2575
container_issue 5
container_start_page 2570
container_title Antimicrobial Agents and Chemotherapy
container_volume 56
creator Zala, Carlos
St. Clair, Marty
Dudas, Kathleen
Kim, Joseph
Lou, Yu
White, Scott
Piscitelli, Steve
Dumont, Etienne
Pietropaolo, Keith
Zhou, Xiao-Jian
Mayers, Douglas
description GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log10 copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [Cmax], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC0-τ], and concentration at the end of the dosing interval [Cτ]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (Emax) model using Cτ (Emax = 2.0; 50% effective concentration [EC50] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.
doi_str_mv 10.1128/AAC.05597-11
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Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log10 copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [Cmax], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC0-τ], and concentration at the end of the dosing interval [Cτ]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (Emax) model using Cτ (Emax = 2.0; 50% effective concentration [EC50] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. 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Antiparasitic agents ; Antiviral activity ; Antiviral Agents ; antiviral properties ; Argentina ; Benzoxazines ; Biological and medical sciences ; blood serum ; Development ; dose response ; Dose-response effects ; Double-Blind Method ; Drug Administration Schedule ; Drug Resistance, Viral ; drug therapy ; Drug-Related Side Effects and Adverse Reactions ; enzyme inhibitors ; Female ; HIV Infections ; HIV Infections - drug therapy ; HIV Infections - virology ; HIV Reverse Transcriptase ; HIV Reverse Transcriptase - antagonists &amp; inhibitors ; HIV-1 ; HIV-1 - drug effects ; HIV-1 - enzymology ; HIV-1 - genetics ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Human viral diseases ; Humans ; Immunodeficiencies ; Immunodeficiencies. Immunoglobulinopathies ; Immunopathology ; Indoles ; Indoles - administration &amp; dosage ; Indoles - chemical synthesis ; Indoles - therapeutic use ; Infectious diseases ; Male ; Medical sciences ; Mutation ; non-nucleoside reverse transcriptase inhibitors ; Pharmacokinetics ; Pharmacology. Drug treatments ; Phosphinic Acids ; Phosphinic Acids - administration &amp; dosage ; Phosphinic Acids - chemical synthesis ; Phosphinic Acids - therapeutic use ; Placebos ; Reverse Transcriptase Inhibitors ; Reverse Transcriptase Inhibitors - administration &amp; dosage ; Reverse Transcriptase Inhibitors - chemical synthesis ; Reverse Transcriptase Inhibitors - therapeutic use ; RNA-directed DNA polymerase ; Viral diseases ; Viral diseases of the lymphoid tissue and the blood. 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All Rights Reserved. 2012 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a564t-e03bbce34f38a84a90d691a0cb1985a18ae3b098c1873a50100204839a6edd8e3</citedby><cites>FETCH-LOGICAL-a564t-e03bbce34f38a84a90d691a0cb1985a18ae3b098c1873a50100204839a6edd8e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.asm.org/doi/pdf/10.1128/AAC.05597-11$$EPDF$$P50$$Gasm2$$H</linktopdf><linktohtml>$$Uhttps://journals.asm.org/doi/full/10.1128/AAC.05597-11$$EHTML$$P50$$Gasm2$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,3188,3189,27924,27925,52751,52752,52753,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=25795907$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22314532$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zala, Carlos</creatorcontrib><creatorcontrib>St. Clair, Marty</creatorcontrib><creatorcontrib>Dudas, Kathleen</creatorcontrib><creatorcontrib>Kim, Joseph</creatorcontrib><creatorcontrib>Lou, Yu</creatorcontrib><creatorcontrib>White, Scott</creatorcontrib><creatorcontrib>Piscitelli, Steve</creatorcontrib><creatorcontrib>Dumont, Etienne</creatorcontrib><creatorcontrib>Pietropaolo, Keith</creatorcontrib><creatorcontrib>Zhou, Xiao-Jian</creatorcontrib><creatorcontrib>Mayers, Douglas</creatorcontrib><title>Safety and Efficacy of GSK2248761, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Treatment-Naive HIV-1-Infected Subjects</title><title>Antimicrobial Agents and Chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. 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GSK2248761 PK (maximum drug concentration in serum [Cmax], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC0-τ], and concentration at the end of the dosing interval [Cτ]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (Emax) model using Cτ (Emax = 2.0; 50% effective concentration [EC50] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.</description><subject>Adult</subject><subject>Anti-HIV Agents</subject><subject>Anti-HIV Agents - administration &amp; dosage</subject><subject>Anti-HIV Agents - chemical synthesis</subject><subject>Anti-HIV Agents - therapeutic use</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral activity</subject><subject>Antiviral Agents</subject><subject>antiviral properties</subject><subject>Argentina</subject><subject>Benzoxazines</subject><subject>Biological and medical sciences</subject><subject>blood serum</subject><subject>Development</subject><subject>dose response</subject><subject>Dose-response effects</subject><subject>Double-Blind Method</subject><subject>Drug Administration Schedule</subject><subject>Drug Resistance, Viral</subject><subject>drug therapy</subject><subject>Drug-Related Side Effects and Adverse Reactions</subject><subject>enzyme inhibitors</subject><subject>Female</subject><subject>HIV Infections</subject><subject>HIV Infections - drug therapy</subject><subject>HIV Infections - virology</subject><subject>HIV Reverse Transcriptase</subject><subject>HIV Reverse Transcriptase - antagonists &amp; inhibitors</subject><subject>HIV-1</subject><subject>HIV-1 - drug effects</subject><subject>HIV-1 - enzymology</subject><subject>HIV-1 - genetics</subject><subject>Human immunodeficiency virus</subject><subject>Human immunodeficiency virus 1</subject><subject>Human viral diseases</subject><subject>Humans</subject><subject>Immunodeficiencies</subject><subject>Immunodeficiencies. Immunoglobulinopathies</subject><subject>Immunopathology</subject><subject>Indoles</subject><subject>Indoles - administration &amp; dosage</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - therapeutic use</subject><subject>Infectious diseases</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mutation</subject><subject>non-nucleoside reverse transcriptase inhibitors</subject><subject>Pharmacokinetics</subject><subject>Pharmacology. 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Aids</topic><topic>viral load</topic><topic>Viral Load - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zala, Carlos</creatorcontrib><creatorcontrib>St. Clair, Marty</creatorcontrib><creatorcontrib>Dudas, Kathleen</creatorcontrib><creatorcontrib>Kim, Joseph</creatorcontrib><creatorcontrib>Lou, Yu</creatorcontrib><creatorcontrib>White, Scott</creatorcontrib><creatorcontrib>Piscitelli, Steve</creatorcontrib><creatorcontrib>Dumont, Etienne</creatorcontrib><creatorcontrib>Pietropaolo, Keith</creatorcontrib><creatorcontrib>Zhou, Xiao-Jian</creatorcontrib><creatorcontrib>Mayers, Douglas</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial Agents and Chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zala, Carlos</au><au>St. Clair, Marty</au><au>Dudas, Kathleen</au><au>Kim, Joseph</au><au>Lou, Yu</au><au>White, Scott</au><au>Piscitelli, Steve</au><au>Dumont, Etienne</au><au>Pietropaolo, Keith</au><au>Zhou, Xiao-Jian</au><au>Mayers, Douglas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Safety and Efficacy of GSK2248761, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Treatment-Naive HIV-1-Infected Subjects</atitle><jtitle>Antimicrobial Agents and Chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2012-05-01</date><risdate>2012</risdate><volume>56</volume><issue>5</issue><spage>2570</spage><epage>2575</epage><pages>2570-2575</pages><issn>0066-4804</issn><eissn>1098-6596</eissn><coden>AACHAX</coden><abstract>GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log10 copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [Cmax], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC0-τ], and concentration at the end of the dosing interval [Cτ]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (Emax) model using Cτ (Emax = 2.0; 50% effective concentration [EC50] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.</abstract><cop>Washington, DC</cop><pub>American Society for Microbiology</pub><pmid>22314532</pmid><doi>10.1128/AAC.05597-11</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0066-4804
ispartof Antimicrobial Agents and Chemotherapy, 2012-05, Vol.56 (5), p.2570-2575
issn 0066-4804
1098-6596
language eng
recordid cdi_proquest_miscellaneous_1017975555
source American Society for Microbiology; Open Access: PubMed Central
subjects Adult
Anti-HIV Agents
Anti-HIV Agents - administration & dosage
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - therapeutic use
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral activity
Antiviral Agents
antiviral properties
Argentina
Benzoxazines
Biological and medical sciences
blood serum
Development
dose response
Dose-response effects
Double-Blind Method
Drug Administration Schedule
Drug Resistance, Viral
drug therapy
Drug-Related Side Effects and Adverse Reactions
enzyme inhibitors
Female
HIV Infections
HIV Infections - drug therapy
HIV Infections - virology
HIV Reverse Transcriptase
HIV Reverse Transcriptase - antagonists & inhibitors
HIV-1
HIV-1 - drug effects
HIV-1 - enzymology
HIV-1 - genetics
Human immunodeficiency virus
Human immunodeficiency virus 1
Human viral diseases
Humans
Immunodeficiencies
Immunodeficiencies. Immunoglobulinopathies
Immunopathology
Indoles
Indoles - administration & dosage
Indoles - chemical synthesis
Indoles - therapeutic use
Infectious diseases
Male
Medical sciences
Mutation
non-nucleoside reverse transcriptase inhibitors
Pharmacokinetics
Pharmacology. Drug treatments
Phosphinic Acids
Phosphinic Acids - administration & dosage
Phosphinic Acids - chemical synthesis
Phosphinic Acids - therapeutic use
Placebos
Reverse Transcriptase Inhibitors
Reverse Transcriptase Inhibitors - administration & dosage
Reverse Transcriptase Inhibitors - chemical synthesis
Reverse Transcriptase Inhibitors - therapeutic use
RNA-directed DNA polymerase
Viral diseases
Viral diseases of the lymphoid tissue and the blood. Aids
viral load
Viral Load - drug effects
title Safety and Efficacy of GSK2248761, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Treatment-Naive HIV-1-Infected Subjects
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