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Antiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients

BACKGROUND:: GS-9137 is a potent low-nanomolar strand transfer inhibitor of HIV-1 integrase. METHODS:: The antiviral activity, tolerability, pharmacokinetics, and pharmacodynamics of GS-9137 were evaluated in a randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1- infected pati... Full description

Journal Title: JAIDS Journal of Acquired Immune Deficiency Syndromes 2006, Vol.43(1), pp.1-5
Main Author: Dejesus, K., Edwin
Other Authors: Berger, P., Daniel , Markowitz, P., Martin , Cohen, P., Calvin , Hawkins, P., Trevor , Ruane, P., Peter , Elion, P., Richard , Farthing, P., Charles , Zhong, P., Lijie , Cheng, P., Andrew , Mccoll, P., Damian , Kearney, P., Brian
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ID: ISSN: 1525-4135 ; DOI: 10.1097/01.qai.0000233308.82860.2f
Link: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&NEWS=n&CSC=Y&PAGE=fulltext&D=ovft&AN=00126334-200609000-00001
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title: Antiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients
format: Article
creator:
  • Dejesus, K., Edwin
  • Berger, P., Daniel
  • Markowitz, P., Martin
  • Cohen, P., Calvin
  • Hawkins, P., Trevor
  • Ruane, P., Peter
  • Elion, P., Richard
  • Farthing, P., Charles
  • Zhong, P., Lijie
  • Cheng, P., Andrew
  • Mccoll, P., Damian
  • Kearney, P., Brian
subjects:
  • Acquired Immunodeficiency Syndrome–Drug Therapy
  • Anti-HIV Agents–Administration & Dosage
  • Dose-Response Relationship, Drug–Pharmacokinetics
  • Double-Blind Method–Toxicity
  • Drug Administration Schedule–Administration & Dosage
  • Enzyme Inhibitors–Pharmacokinetics
  • HIV Infections–Toxicity
  • HIV Integrase–Drug Therapy
  • Humans–Metabolism
  • Quinolones–Administration & Dosage
  • Quinolones–Pharmacokinetics
  • Quinolones–Toxicity
  • AIDS/HIV
  • Anti-HIV Agents
  • Enzyme Inhibitors
  • Jtk 303
  • Quinolones
  • HIV Integrase
ispartof: JAIDS Journal of Acquired Immune Deficiency Syndromes, 2006, Vol.43(1), pp.1-5
description: BACKGROUND:: GS-9137 is a potent low-nanomolar strand transfer inhibitor of HIV-1 integrase. METHODS:: The antiviral activity, tolerability, pharmacokinetics, and pharmacodynamics of GS-9137 were evaluated in a randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1- infected patients not receiving antiretroviral therapy with an HIV-1 RNA between 10,000 and 300,000 copies/mL and a CD4 count of 200 cells/μL or greater. GS-9137 or matching placebo was administered with food for 10 days at 5 dosage regimens (200, 400, or 800 mg BID, 800 mg QD, or 50 mg + 100 mg ritonavir QD; 6 active, 2 placebo per dose level). The primary end point was the maximum reduction from baseline in log10 HIV-1 RNA. RESULTS:: Forty patients were enrolled, with a mean baseline viral load of 4.75 log10 copies/mL and a CD4 count of 442 cells/μL. Each GS-9137 dosing regimen exhibited significant, exposure-dependent (mean reductions, −0.98 to −1.99 log10 copies/mL) antiviral activity compared with placebo (P < 0.01). Twice-daily administrations of GS-9137 at doses of 400 or 800 mg or once-daily dosing of 50 mg with ritonavir demonstrated mean reductions from baseline in HIV-1 RNA of 1.91 log10 copies/mL or greater, with all patients exhibiting 1 log10 or greater and 50% having 2 log10 or greater reductions. No patient developed evidence of integrase resistance. GS-9137 showed an adverse event profile similar to placebo, and there were no study drug discontinuations. CONCLUSIONS:: GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.
language:
source:
identifier: ISSN: 1525-4135 ; DOI: 10.1097/01.qai.0000233308.82860.2f
fulltext: fulltext
issn:
  • 1525-4135
  • 15254135
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titleAntiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients
creatorDejesus, K., Edwin ; Berger, P., Daniel ; Markowitz, P., Martin ; Cohen, P., Calvin ; Hawkins, P., Trevor ; Ruane, P., Peter ; Elion, P., Richard ; Farthing, P., Charles ; Zhong, P., Lijie ; Cheng, P., Andrew ; Mccoll, P., Damian ; Kearney, P., Brian
ispartofJAIDS Journal of Acquired Immune Deficiency Syndromes, 2006, Vol.43(1), pp.1-5
identifierISSN: 1525-4135 ; DOI: 10.1097/01.qai.0000233308.82860.2f
descriptionBACKGROUND:: GS-9137 is a potent low-nanomolar strand transfer inhibitor of HIV-1 integrase. METHODS:: The antiviral activity, tolerability, pharmacokinetics, and pharmacodynamics of GS-9137 were evaluated in a randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1- infected patients not receiving antiretroviral therapy with an HIV-1 RNA between 10,000 and 300,000 copies/mL and a CD4 count of 200 cells/μL or greater. GS-9137 or matching placebo was administered with food for 10 days at 5 dosage regimens (200, 400, or 800 mg BID, 800 mg QD, or 50 mg + 100 mg ritonavir QD; 6 active, 2 placebo per dose level). The primary end point was the maximum reduction from baseline in log10 HIV-1 RNA. RESULTS:: Forty patients were enrolled, with a mean baseline viral load of 4.75 log10 copies/mL and a CD4 count of 442 cells/μL. Each GS-9137 dosing regimen exhibited significant, exposure-dependent (mean reductions, −0.98 to −1.99 log10 copies/mL) antiviral activity compared with placebo (P < 0.01). Twice-daily administrations of GS-9137 at doses of 400 or 800 mg or once-daily dosing of 50 mg with ritonavir demonstrated mean reductions from baseline in HIV-1 RNA of 1.91 log10 copies/mL or greater, with all patients exhibiting 1 log10 or greater and 50% having 2 log10 or greater reductions. No patient developed evidence of integrase resistance. GS-9137 showed an adverse event profile similar to placebo, and there were no study drug discontinuations. CONCLUSIONS:: GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.
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subjectAcquired Immunodeficiency Syndrome–Drug Therapy ; Anti-HIV Agents–Administration & Dosage ; Dose-Response Relationship, Drug–Pharmacokinetics ; Double-Blind Method–Toxicity ; Drug Administration Schedule–Administration & Dosage ; Enzyme Inhibitors–Pharmacokinetics ; HIV Infections–Toxicity ; HIV Integrase–Drug Therapy ; Humans–Metabolism ; Quinolones–Administration & Dosage ; Quinolones–Pharmacokinetics ; Quinolones–Toxicity ; AIDS/HIV ; Anti-HIV Agents ; Enzyme Inhibitors ; Jtk 303 ; Quinolones ; HIV Integrase;
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titleAntiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients
descriptionBACKGROUND:: GS-9137 is a potent low-nanomolar strand transfer inhibitor of HIV-1 integrase. METHODS:: The antiviral activity, tolerability, pharmacokinetics, and pharmacodynamics of GS-9137 were evaluated in a randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1- infected patients not receiving antiretroviral therapy with an HIV-1 RNA between 10,000 and 300,000 copies/mL and a CD4 count of 200 cells/μL or greater. GS-9137 or matching placebo was administered with food for 10 days at 5 dosage regimens (200, 400, or 800 mg BID, 800 mg QD, or 50 mg + 100 mg ritonavir QD; 6 active, 2 placebo per dose level). The primary end point was the maximum reduction from baseline in log10 HIV-1 RNA. RESULTS:: Forty patients were enrolled, with a mean baseline viral load of 4.75 log10 copies/mL and a CD4 count of 442 cells/μL. Each GS-9137 dosing regimen exhibited significant, exposure-dependent (mean reductions, −0.98 to −1.99 log10 copies/mL) antiviral activity compared with placebo (P < 0.01). Twice-daily administrations of GS-9137 at doses of 400 or 800 mg or once-daily dosing of 50 mg with ritonavir demonstrated mean reductions from baseline in HIV-1 RNA of 1.91 log10 copies/mL or greater, with all patients exhibiting 1 log10 or greater and 50% having 2 log10 or greater reductions. No patient developed evidence of integrase resistance. GS-9137 showed an adverse event profile similar to placebo, and there were no study drug discontinuations. CONCLUSIONS:: GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.
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abstractBACKGROUND:: GS-9137 is a potent low-nanomolar strand transfer inhibitor of HIV-1 integrase. METHODS:: The antiviral activity, tolerability, pharmacokinetics, and pharmacodynamics of GS-9137 were evaluated in a randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1- infected patients not receiving antiretroviral therapy with an HIV-1 RNA between 10,000 and 300,000 copies/mL and a CD4 count of 200 cells/μL or greater. GS-9137 or matching placebo was administered with food for 10 days at 5 dosage regimens (200, 400, or 800 mg BID, 800 mg QD, or 50 mg + 100 mg ritonavir QD; 6 active, 2 placebo per dose level). The primary end point was the maximum reduction from baseline in log10 HIV-1 RNA. RESULTS:: Forty patients were enrolled, with a mean baseline viral load of 4.75 log10 copies/mL and a CD4 count of 442 cells/μL. Each GS-9137 dosing regimen exhibited significant, exposure-dependent (mean reductions, −0.98 to −1.99 log10 copies/mL) antiviral activity compared with placebo (P < 0.01). Twice-daily administrations of GS-9137 at doses of 400 or 800 mg or once-daily dosing of 50 mg with ritonavir demonstrated mean reductions from baseline in HIV-1 RNA of 1.91 log10 copies/mL or greater, with all patients exhibiting 1 log10 or greater and 50% having 2 log10 or greater reductions. No patient developed evidence of integrase resistance. GS-9137 showed an adverse event profile similar to placebo, and there were no study drug discontinuations. CONCLUSIONS:: GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.
pub© 2006 Lippincott Williams & Wilkins, Inc.
doi10.1097/01.qai.0000233308.82860.2f
date2006-09