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https://www.readbyqxmd.com/read/28583191/hiv-drug-resistance-against-strand-transfer-integrase-inhibitors
#1
REVIEW
Kaitlin Anstett, Bluma Brenner, Thibault Mesplede, Mark A Wainberg
Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell's chromatin. Three drugs of this class are currently approved for use in HIV-positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials. RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance...
June 5, 2017: Retrovirology
https://www.readbyqxmd.com/read/28546090/safety-and-tolerability-of-long-acting-cabotegravir-injections-in-hiv-uninfected-men-eclair-a-multicentre-double-blind-randomised-placebo-controlled-phase-2a-trial
#2
Martin Markowitz, Ian Frank, Robert M Grant, Kenneth H Mayer, Richard Elion, Deborah Goldstein, Chester Fisher, Magdalena E Sobieszczyk, Joel E Gallant, Hong Van Tieu, Winkler Weinberg, David A Margolis, Krischan J Hudson, Britt S Stancil, Susan L Ford, Parul Patel, Elizabeth Gould, Alex R Rinehart, Kimberly Y Smith, William R Spreen
BACKGROUND: Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection. METHODS: We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA...
May 22, 2017: Lancet HIV
https://www.readbyqxmd.com/read/28546089/long-acting-cabotegravir-for-prevention-hope-versus-reality
#3
Sheena McCormack, Marta Boffito
No abstract text is available yet for this article.
May 22, 2017: Lancet HIV
https://www.readbyqxmd.com/read/28540638/in-silico-dose-prediction-for-long-acting-rilpivirine-and-cabotegravir-administration-to-children-and-adolescents
#4
Rajith K R Rajoli, David J Back, Steve Rannard, Caren Freel Meyers, Charles Flexner, Andrew Owen, Marco Siccardi
BACKGROUND AND OBJECTIVES: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18 years) using physiologically-based pharmacokinetic modelling...
May 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28533248/impact-of-hiv-1-integrase-l74f-v75i-mutations-from-a-clinical-isolate-on-resistance-to-second-generation-integrase-strand-transfer-inhibitors
#5
Atsuko Hachiya, Karen A Kirby, Yoko Ido, Urara Shigemi, Masakazu Matsuda, Reiko Okazaki, Junji Imamura, Stefan G Sarafianos, Yoshiyuki Yokomaku, Yasumasa Iwatani
A novel HIV-1 integrase mutation pattern, L74F/V75I, which conferred resistance to first-generation integrase strand transfer inhibitors (INSTIs), was identified in a clinical case with virological failure under a raltegravir-based regimen. Addition of L74F/V75I to N155H or G140S/Q148H increased resistance levels to second-generation INSTIs, dolutegravir (>385-, 100-fold, respectively) and cabotegravir (153-, 197-fold, respectively). These findings are important for developing an accurate interpretation system of INSTI resistance and the rational design of next-generation INSTIs...
May 22, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28384058/analysis-of-hiv-integrase-resistance-in-black-men-who-have-sex-with-men-in-the-united-states
#6
Iris Chen, Yinfeng Zhang, Vanessa Cummings, Gavin A Cloherty, Matthew Connor, Geetha Beauchamp, Sam Griffith, Scott Rose, Joel Gallant, Hyman M Scott, Steven Shoptaw, Carlos Del Rio, Irene Kuo, Sharon Mannheimer, Hong-Van Tieu, Christopher B Hurt, Sheldon D Fields, Darrell P Wheeler, Kenneth H Mayer, Beryl A Koblin, Susan H Eshleman
Resistance to reverse transcriptase and protease inhibitors was frequently detected in HIV from black men who have sex with men (MSM) enrolled in the HIV prevention trials network (HPTN) 061 study. In this study, integrase strand transfer inhibitor (INSTI) resistance was analyzed in black MSM enrolled in HPTN 061 (134 infected at enrollment and 23 seroconverters) and a follow-up study, HPTN 073 (eight seroconverters). The ViroSeq HIV-1 Integrase Genotyping Kit (Abbott Molecular) was used for analysis. Major INSTI resistance mutations were not detected in any of the samples...
July 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28368071/long-acting-agents-for-hiv-infection-biological-aspects-role-in-treatment-and-prevention-and-patient-s-perspective
#7
Stefano Rusconi, Simone Marcotullio, Antonella Cingolani
Current cART regimens are highly potent and well tolerated, but long-term toxicities, drug-drug interactions, lifetime costs and scarce option for multiclass failed patients could limit the efficacy of treatment itself. Long-acting formulations of antiretrovirals, which could potentially replace daily tablets, have been developed and are under investigation for prevention and treatment of HIV infection. Cabotegravir and rilpivirine represent the first drugs studied in this context. The aim of this review is to summarize the biological bases, the available information on completed and ongoing clinical trials and the potential development of long-acting regimens for the treatment and prevention of HIV infection...
April 2017: New Microbiologica
https://www.readbyqxmd.com/read/28356041/recent-advances-in-antiretroviral-agents-potent-integrase-inhibitors
#8
Mina Psichogiou, Garyphalia Poulakou, Dimitrios Basoulis, Dimitrios Paraskevis, Antonios Markogiannakis, George L Daikos
Integrase strand transfer inhibitors (INSTIs) belong to a novel class of antiretroviral agents that have emerged as the new first-line treatments. Three such compounds are currently available, raltegravir, elvitegravir, dolutegravir and two more under development, bictegravir and cabotegravir. These compounds share the same mode of action but exhibit different pharmacokinetic/ pharmacodynamic properties, and drug-drug interactions. A series of studies in the past decade have established their efficacy compared to previous regimens, both in treatment-naïve and experienced patients...
March 29, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28303548/long-acting-antiretrovirals-where-are-we-now
#9
REVIEW
Amesika N Nyaku, Sean G Kelly, Babafemi O Taiwo
PURPOSE OF REVIEW: Current HIV treatment options require daily use of combination antiretroviral drugs. Many persons living with HIV experience treatment fatigue and suboptimal adherence as a result. Long-acting antiretroviral drugs are being developed to expand options for HIV treatment. Here, we review the agents in development, and evaluate data from recent clinical trials. In addition, we anticipate challenges to successful widespread use of long-acting antiretrovirals. RECENT FINDINGS: Parenteral nanosuspensions of cabotegravir and rilpivirine, and dapivirine vaginal ring are the farthest in clinical development...
April 2017: Current HIV/AIDS Reports
https://www.readbyqxmd.com/read/28279181/a-mature-macrophage-is-a-principal-hiv-1-cellular-reservoir-in-humanized-mice-after-treatment-with-long-acting-antiretroviral-therapy
#10
Mariluz Araínga, Benson Edagwa, R Lee Mosley, Larisa Y Poluektova, Santhi Gorantla, Howard E Gendelman
BACKGROUND: Despite improved clinical outcomes seen following antiretroviral therapy (ART), resting CD4+ T cells continue to harbor latent human immunodeficiency virus type one (HIV-1). However, such cells are not likely the solitary viral reservoir and as such defining where and how others harbor virus is imperative for eradication measures. To such ends, we used HIV-1ADA-infected NOD.Cg-Prkdc (scid) Il2rg (tm1Wjl) /SzJ mice reconstituted with a human immune system to explore two long-acting ART regimens investigating their abilities to affect viral cell infection and latency...
March 9, 2017: Retrovirology
https://www.readbyqxmd.com/read/28087972/lack-of-effect-of-oral-cabotegravir-on-the-pharmacokinetics-of-a-levonorgestrel-ethinyl-oestradiol-containing-oral-contraceptive-in-healthy-adult-women
#11
Christine Trezza, Susan L Ford, Elizabeth Gould, Yu Lou, Chuyun Huang, James M Ritter, Ann M Buchanan, William Spreen, Parul Patel
AIMS: This study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus-1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)-containing oral contraceptive (OC) in healthy women. METHODS: In this open-label, fixed-sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1-10 alone and with oral CAB 30 mg once daily Days 11-21...
July 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27902508/cabotegravir-long-acting-injection-protects-macaques-against-intravenous-challenge-with-sivmac251
#12
Chasity D Andrews, Leslie St Bernard, Amanda Yee Poon, Hiroshi Mohri, Natanya Gettie, William R Spreen, Agegnehu Gettie, Kasi Russell-Lodrigue, James Blanchard, Zhi Hong, David D Ho, Martin Markowitz
OBJECTIVE: We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long acting as preexposure prophylaxis (PrEP) against intravenous simian immunodeficiency virus (SIV) challenge in a model that mimics blood transfusions based on the per-act probability of infection. DESIGN: CAB long acting is an integrase strand transfer inhibitor formulated as a 200 mg/ml injectable nanoparticle suspension that is an effective PrEP agent against rectal and vaginal simian/human immunodeficiency virus transmission in macaques...
February 20, 2017: AIDS
https://www.readbyqxmd.com/read/27799824/profile-of-cabotegravir-and-its-potential-in-the-treatment-and-prevention-of-hiv-1-infection-evidence-to-date
#13
REVIEW
Thomas Whitfield, Adele Torkington, Clare van Halsema
Modern antiretroviral therapy has demonstrated effectiveness in preexposure prophylaxis (PrEP) and treatment of HIV infection. There is a demand for prevention and treatment regimens that could overcome challenges of improving adherence, toxicity, and dosing convenience. Cabotegravir is an integrase strand transfer inhibitor and an analog of dolutegravir. Unlike dolutegravir, cabotegravir has a long half-life and can be formulated into a long-acting nanosuspension for parenteral administration. Initial pharmokinetic studies in humans have demonstrated adequate drug levels with intramuscular (IM) administration at 4 weekly and 8 weekly intervals, with few interactions with commonly used concomitant medications...
2016: HIV/AIDS: Research and Palliative Care
https://www.readbyqxmd.com/read/27162089/effect-of-cabotegravir-on-cardiac-repolarization-in-healthy-subjects
#14
Yu Lou, Ann M Buchanan, Shuguang Chen, Susan L Ford, Elizabeth Gould, David Margolis, William R Spreen, Parul Patel
A randomized, partial-blind, repeat-dose, 3-period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open-label 400-mg dose of the positive control moxifloxacin, with a 21-day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2...
November 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/26713502/choosing-initial-antiretroviral-therapy-current-recommendations-for-initial-therapy-and-newer-or-investigational-agents
#15
REVIEW
Roy M Gulick
There is general consistency among US and European guidelines regarding the initiation of antiretroviral therapy for HIV-infected individuals. Recent and ongoing trials comparing regimens may lead to reevaluation of initial treatment choices. The choice of antiretroviral regimen will also likely be affected by development, evaluation, and availability of newer drugs. This article reviews currently recommended regimens and characteristics of selected current investigational drugs, including the nucleotide analogue reverse transcriptase inhibitor tenofovir alafenamide, the nonnucleoside reverse transcriptase inhibitor doravirine, the integrase strand transfer inhibitor cabotegravir, the HIV entry inhibitor BMS-663068, and the HIV maturation inhibitor BMS-955176...
October 2015: Topics in Antiviral Medicine
https://www.readbyqxmd.com/read/26711252/interspecies-scaling-of-excretory-amounts-using-allometry-retrospective-analysis-with-rifapentine-aztreonam-carumonam-pefloxacin-miloxacin-trovafloxacin-doripenem-imipenem-cefozopran-ceftazidime-linezolid-for-urinary-excretion-and-rifapentine-cabotegravir-and
#16
Nuggehally R Srinivas
1. Interspecies allometry scaling for prediction of human excretory amounts in urine or feces was performed for numerous antibacterials. Antibacterials used for urinary scaling were: rifapentine, pefloxacin, trovafloxacin (Gr1/low; <10%); miloxacin, linezolid, PNU-142300 (Gr2/medium; 10-40%); aztreonam, carumonam, cefozopran, doripenem, imipenem, and ceftazidime (Gr3/high; >50%). Rifapentine, cabotegravir, and dolutegravir was used for fecal scaling (high; >50%). 2. The employment of allometry equation: Y = aW(b) enabled scaling of urine/fecal amounts from animal species...
September 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/26633643/the-promise-and-pitfalls-of-long-acting-injectable-agents-for-hiv-prevention
#17
REVIEW
Raphael J Landovitz, Ryan Kofron, Marybeth McCauley
PURPOSE OF REVIEW: Preexposure prophylaxis for HIV prevention is highly effective when taken as prescribed. Adherence to required dosing regimens for protection may pose challenges. Long-acting agents for HIV prevention may have the potential to improve adherence via favorable pharmacokinetics supportive of infrequent dosing. This review focuses on the potential benefits and considerations for the study and use of 2 long-acting injectable agents, cabotegravir (GSK1265744LA, CAB LA) and rilpivirine (TMC278LA, RPV LA), for use as chemoprophylaxis for HIV prevention...
January 2016: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/26340566/drug-interaction-profile-of-the-hiv-integrase-inhibitor-cabotegravir-assessment-from-in-vitro-studies-and-a-clinical-investigation-with-midazolam
#18
Melinda J Reese, Gary D Bowers, Joan E Humphreys, Elizabeth P Gould, Susan L Ford, Lindsey O Webster, Joseph W Polli
1. Cabotegravir (CAB; GSK1265744) is a potent HIV integrase inhibitor in clinical development as an oral lead-in tablet and long-acting injectable for the treatment and prevention of HIV infection. 2. This work investigated if CAB was a substrate for efflux transporters, the potential for CAB to interact with drug-metabolizing enzymes and transporters to cause clinical drug interactions, and the effect of CAB on the pharmacokinetics of midazolam, a CYP3A4 probe substrate, in humans. 3. CAB is a substrate for Pgp and BCRP; however, its high intrinsic membrane permeability limits the impact of these transporters on its intestinal absorption...
2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/26201299/cabotegravir-plus-rilpivirine-once-a-day-after-induction-with-cabotegravir-plus-nucleoside-reverse-transcriptase-inhibitors-in-antiretroviral-naive-adults-with-hiv-1-infection-latte-a-randomised-phase-2b-dose-ranging-trial
#19
RANDOMIZED CONTROLLED TRIAL
David A Margolis, Cynthia C Brinson, Graham H R Smith, Jerome de Vente, Debbie P Hagins, Joseph J Eron, Sandy K Griffith, Marty H St Clair, Marita C Stevens, Peter E Williams, Susan L Ford, Britt S Stancil, Melinda M Bomar, Krischan J Hudson, Kimberly Y Smith, William R Spreen
BACKGROUND: In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. METHODS: In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction...
October 2015: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/26134155/disposition-and-metabolism-of-cabotegravir-a-comparison-of-biotransformation-and-excretion-between-different-species-and-routes-of-administration-in-humans
#20
RANDOMIZED CONTROLLED TRIAL
Gary David Bowers, Amanda Culp, Melinda J Reese, Glenn Tabolt, Lee Moss, Stephen Piscitelli, Phuong Huynh, David Wagner, Susan L Ford, Elizabeth P Gould, Rennan Pan, Yu Lou, David A Margolis, William R Spreen
1.  Cabotegravir [(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide] is an HIV-1 integrase inhibitor under development as a tablet for both oral lead-in therapy and long-acting (LA) injectable for intramuscular dosing. 2. Metabolism, pharmacokinetics and excretion were investigated in healthy human subjects who received either a single oral dose (28.2 mg) of [(14)C]cabotegravir in a mass balance study, or LA formulations of unlabeled cabotegravir (200-800 mg), intramuscularly or subcutaneously, in a separate study...
2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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