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Larissa Wenning - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics safety and 48 week efficacy of oral Raltegravir in hiv 1 infected children aged 2 through 18 years
Clinical Infectious Diseases, 2014Co-Authors: Sharon Nachman, Larissa Wenning, Edward P. Acosta, Hedy Teppler, Stephen A Spector, Brenda Homony, Bobbie Graham, Terence Fenton, Nan Zheng, Lisa M FrenkelAbstract:Novel, potent, and well-tolerated antiretroviral (ARV) medications in appropriate formulations are acutely needed for pediatric patients of all ages infected with human immunodeficiency virus (HIV), especially for those failing ARV therapy, those with ARV resistance, or those suffering from ARV-related toxicities. Perinatally infected youth are often heavily pretreated and have very limited therapeutic options that can lead to sustained benefit. Raltegravir is the first Food and Drug Administration– and European Medicines Agency–approved HIV integrase strand transfer inhibitor with demonstrated safety and efficacy in HIV type 1 (HIV-1)–infected adults. Raltegravir at a dose of 400 mg twice daily was approved for use in the treatment of HIV infection in adults based on data from 2 phase III studies in treatment-experienced adults, Blocking Integrase in Treatment-Experienced Patients with a Novel Compound Against HIV, Merck (BENCHMRK-1) and 2 [1, 2], and a phase III study in treatment-naive adults (STARTMRK) [3]. Data extending to 240 weeks for these 3 studies are now available and demonstrate both durable efficacy and a favorable long-term safety profile of Raltegravir in adults [4, 5]. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1066 study was designed to assess the safety and pharmacokinetics (PK) of Raltegravir in HIV-infected children aged 4 weeks to <19 years using 3 different formulations with the goal of determining the appropriate Raltegravir dose in age-based subgroups. After dose selection, the study provided additional data on safety, efficacy, and population PK. This report describes findings from subjects aged 2 to <19 years of age who received either the film-coated or chewable tablet formulations.
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Raltegravir in vitro effect on bilirubin binding
Pediatric Infectious Disease Journal, 2013Co-Authors: Diana F Clarke, Larissa Wenning, Ronald J Wong, David K Stevenson, Mark MirochnickAbstract:Drugs that displace bilirubin from albumin may increase the risk of kernicterus in neonates. We evaluated the effect of Raltegravir on bilirubin-albumin binding in pooled neonatal serum using the peroxidase method. Raltegravir had minimal effect on bilirubin-albumin binding at concentrations of 5 and 10 µM, caused a small but statistically significant increase in unbound bilirubin at 100 µM and caused potentially harmful increases at 500 and 1000 µM. Our data suggest that the effect of Raltegravir on neonatal bilirubin binding is unlikely to be clinically significant at typical peak concentrations reached with usual dosing.
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clinical pharmacology profile of Raltegravir an hiv 1 integrase strand transfer inhibitor
The Journal of Clinical Pharmacology, 2011Co-Authors: Diana M Brainard, Julie A Stone, Larissa Wenning, John A Wagner, Marian IwamotoAbstract:Raltegravir is an HIV-1 integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. Data from healthy volunteers demonstrate that Raltegravir is rapidly absorbed with a mean half-life of approximately 7 to 12 hours, with steady state achieved in approximately 2 days. Raltegravir is characterized by both high intra- and interindividual variabilities, although neither gender, race, age, body mass index, food intake, nor renal or hepatic insufficiency has a clinically meaningful effect on Raltegravir pharmacokinetics. Raltegravir lacks activity as a perpetrator of drug-drug interactions and demonstrates a low propensity to be subject to drug-drug interactions. Raltegravir is metabolized primarily by UGT1A1 and is not affected by P450 inhibitors or inducers. Inhibitors of UGT1A1 (eg, atazanavir) can increase plasma concentrations of Raltegravir, although this increase has not been found to be clinically meaningful. Likewise, inducers of UGT1A1 (eg, rifampin) can reduce plasma concentrations of Raltegravir, and the clinical significance of this reduction is being investigated in ongoing clinical studies. Raltegravir demonstrates favorable clinical pharmacology and a drug interaction profile that permits administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment.
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effect of rifampin a potent inducer of drug metabolizing enzymes on the pharmacokinetics of Raltegravir
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Larissa Wenning, William D Hanley, Amelia S. Petry, Diana M Brainard, Kalyan Ghosh, Eric Mangin, Thomas Marbury, Jolene Kay Berg, Jeffrey A Chodakewitz, Julie A StoneAbstract:Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor that is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin (rifampicin). Two pharmacokinetic studies were performed in healthy subjects: study 1 examined the effect of administration of 600-mg rifampin once daily on the pharmacokinetics of a single dose of 400-mg Raltegravir, and study 2 examined the effect of 600-mg rifampin once daily on the pharmacokinetics of 800-mg Raltegravir twice daily compared to 400-mg Raltegravir twice daily without rifampin. Raltegravir coadministered with rifampin resulted in lower plasma Raltegravir concentrations: in study 1, the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the plasma Raltegravir concentration determined 12 h postdose (C12), area under the concentration-time curve from 0 h to ∞ (AUC0-∞), and maximum concentration of drug in plasma (Cmax) (400-mg Raltegravir plus rifampin/400-mg Raltegravir) were 0.39 (0.30, 0.51), 0.60 (0.39, 0.91), and 0.62 (0.37, 1.04), respectively. In study 2, the GMRs and 90% CIs for Raltegravir C12, AUC0-12, and Cmax (800-mg Raltegravir plus rifampin/400-mg Raltegravir) were 0.47 (0.36, 0.61), 1.27 (0.94, 1.71), and 1.62 (1.12, 2.33), respectively. Doubling the Raltegravir dose to 800 mg when coadministered with rifampin therefore compensates for the effect of rifampin on Raltegravir exposure (AUC0-12) but does not overcome the effect of rifampin on Raltegravir trough concentrations (C12). Coadministration of rifampin and Raltegravir is not contraindicated; however, caution should be used, since Raltegravir trough concentrations in the presence of rifampin are likely to be at the lower limit of clinical experience.
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pharmacokinetics of Raltegravir in individuals with ugt1a1 polymorphisms
Clinical Pharmacology & Therapeutics, 2009Co-Authors: Larissa Wenning, James Kost, Sheila Breidinger, Amelia S. Petry, Bo Jin, I Delepeleire, E J Carlini, Steven D Young, T Rushmore, Frank WagnerAbstract:Raltegravir is a human immunodeficiency virus-1 (HIV-1) integrase strand transfer inhibitor metabolized by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). In this study, 30 subjects with a UGT1A1*28/*28 genotype (associated with decreased activity of UGT1A1) and 27 UGT1A1*1/*1 control subjects (matched by race, age, gender, and body mass index) received a single 400-mg dose of Raltegravir after fasting. No serious adverse experiences were reported, and there were no discontinuations due to adverse experiences. The geometric mean ratio (GMR) (UGT1A1*28/*28 to UGT1A1*1/*1) and 90% confidence interval (CI) were 1.41 (0.96, 2.09) for Raltegravir area under the concentration-time curve (AUC(0-infinity)), 1.40 (0.86, 2.28) for maximum plasma concentration (C(max)), and 1.91 (1.43, 2.55) for concentration at the 12-h time point (C(12 h)). No clinically important differences in time to maximum concentration (T(max)) or half-life were observed. Plasma concentrations of Raltegravir are modestly higher in individuals with the UGT1A1*28/*28 genotype than in those with the UGT1A1*1/*1 genotype. This increase is not clinically significant, and therefore no dose adjustment of Raltegravir is required for individuals with the UGT1A1*28/*28 genotype.
John A Wagner - One of the best experts on this subject based on the ideXlab platform.
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clinical pharmacology profile of Raltegravir an hiv 1 integrase strand transfer inhibitor
The Journal of Clinical Pharmacology, 2011Co-Authors: Diana M Brainard, Julie A Stone, Larissa Wenning, John A Wagner, Marian IwamotoAbstract:Raltegravir is an HIV-1 integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. Data from healthy volunteers demonstrate that Raltegravir is rapidly absorbed with a mean half-life of approximately 7 to 12 hours, with steady state achieved in approximately 2 days. Raltegravir is characterized by both high intra- and interindividual variabilities, although neither gender, race, age, body mass index, food intake, nor renal or hepatic insufficiency has a clinically meaningful effect on Raltegravir pharmacokinetics. Raltegravir lacks activity as a perpetrator of drug-drug interactions and demonstrates a low propensity to be subject to drug-drug interactions. Raltegravir is metabolized primarily by UGT1A1 and is not affected by P450 inhibitors or inducers. Inhibitors of UGT1A1 (eg, atazanavir) can increase plasma concentrations of Raltegravir, although this increase has not been found to be clinically meaningful. Likewise, inducers of UGT1A1 (eg, rifampin) can reduce plasma concentrations of Raltegravir, and the clinical significance of this reduction is being investigated in ongoing clinical studies. Raltegravir demonstrates favorable clinical pharmacology and a drug interaction profile that permits administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment.
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minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor Raltegravir in healthy subjects
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Matt S Anderson, Thomas N Kakuda, Jutta Miller, Randall Stoltz, William D Hanley, Julie A Stone, Larissa Wenning, Richard M. W. Hoetelmans, James Kost, John A WagnerAbstract:Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and Raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and Raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg Raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg Raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of Raltegravir, while Raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For Raltegravir coadministered with etravirine relative to Raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC0-12), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (Cmax), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C12); the GMR (90% CI) for etravirine coadministered with Raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC0-12, 1.04 (0.97, 1.12) for Cmax, and 1.17 (1.10, 1.26) for C12. All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and Raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.
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lack of a significant drug interaction between Raltegravir and tenofovir
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Larissa Wenning, James Kost, Sheila Breidinger, Joshua Chen, Hedy Teppler, Kenneth C Lasseter, Evan J Friedman, Jon E Stek, Keith Gottesdiener, John A WagnerAbstract:Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved Raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved Raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with Raltegravir monotherapy versus Raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on Raltegravir. The Raltegravir area under the concentration time curve from 0 to 12 h (AUC(0-12)) and peak plasma drug concentration (C(max)) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on Raltegravir concentration at 12 h postdose (C(12)) in healthy subjects (GMR [TDF plus Raltegravir-Raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C(24), AUC, and C(max) GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of Raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments.
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Raltegravir thorough qt qtc study a single supratherapeutic dose of Raltegravir does not prolong the qtcf interval
The Journal of Clinical Pharmacology, 2008Co-Authors: Marian Iwamoto, Julie A Stone, Larissa Wenning, James Kost, Sheila Breidinger, Thomas Marbury, Keith Gottesdiener, G C Misty, Daniel M Bloomfield, John A WagnerAbstract:Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg Raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of Raltegravir was less than 10 ms at every time point. For the Raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM Raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of Raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.
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metabolism and disposition in humans of Raltegravir mk 0518 an anti aids drug targeting the human immunodeficiency virus 1 integrase enzyme
Drug Metabolism and Disposition, 2007Co-Authors: Kelem Kassahun, John A Wagner, Marian Iwamoto, Neal Azrolan, Ian Mcintosh, Donghui Cui, David Hreniuk, Shelia Merschman, Kenneth C Lasseter, Larissa WenningAbstract:Raltegravir is a potent human immunodeficiency virus 1 (HIV-1) integrase strand transfer inhibitor that is being developed as a novel anti-AIDS drug. The absorption, metabolism, and excretion of Raltegravir were studied in healthy volunteers after a single oral dose of 200 mg (200 μCi) of [14C]Raltegravir. Plasma, urine, and fecal samples were collected at specified intervals up to 240 h postdose, and the samples were analyzed for total radioactivity, parent compound, and metabolites. Radioactivity was eliminated in substantial amounts in both urine (32%) and feces (51%). The elimination of radioactivity was rapid, since the majority of the recovered dose was attributable to samples collected through 24 h. In extracts of urine, two components were detected and were identified as Raltegravir and the glucuronide of Raltegravir (M2), and each accounted for 9% and 23% of the dose recovered in urine, respectively. Only a single radioactive peak, which was identified as Raltegravir, was detected in fecal extracts; Raltegravir in feces is believed to be derived, at least in part, from the hydrolysis of M2 secreted in bile, as demonstrated in rats. The major entity in plasma was Raltegravir, which represented 70% of the total radioactivity, with the remaining radioactivity accounted for by M2. Studies using cDNA-expressed UDP-glucuronosyltransferases (UGTs), form-selective chemical inhibitors, and correlation analysis indicated that UGT1A1 was the main UGT isoform responsible for the formation of M2. Collectively, the data indicate that the major mechanism of clearance of Raltegravir in humans is UGT1A1-mediated glucuronidation.
Martin Markowitz - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Raltegravir for treatment of hiv for 5 years in the benchmrk studies final results of two randomised placebo controlled trials
Lancet Infectious Diseases, 2013Co-Authors: Joseph J Eron, David A Cooper, José M. Gatell, Bonaventura Clotet, Martin Markowitz, Jurgen K Rockstroh, Roy T Steigbigel, Princy Kumar, Mauro Schechter, Patrick YeniAbstract:Summary Background Two randomised, placebo-controlled trials—BENCHMRK-1 and BENCHMRK-2—investigated the efficacy and safety of Raltegravir, an HIV-1 integrase strand-transfer inhibitor. We report final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study). Methods Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to Raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label Raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240. Findings 1012 patients were screened for inclusion. 462 were treated with Raltegravir and 237 with placebo. At week 156, 51% in the Raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per μL versus 63 cells per μL. After week 156, 251 patients (54%) from the Raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to Raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per μL. Virological failure occurred in 166 Raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2. Interpretation Raltegravir has a favourable long-term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options. Funding Merck Sharp & Dohme.
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long term efficacy and safety of Raltegravir combined with optimized background therapy in treatment experienced patients with drug resistant hiv infection week 96 results of the benchmrk 1 and 2 phase iii trials
Clinical Infectious Diseases, 2010Co-Authors: Roy T Steigbigel, Joseph J Eron, David A Cooper, José M. Gatell, Hedy Teppler, Jurgen K Rockstroh, Princy Kumar, Mauro Schechter, C Katlama, Martin MarkowitzAbstract:BENCHMRK-1 and -2 are ongoing double-blind phase III studies of Raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), Raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone.
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sustained antiretroviral effect of Raltegravir after 96 weeks of combination therapy in treatment naive patients with hiv 1 infection
Journal of Acquired Immune Deficiency Syndromes, 2009Co-Authors: Martin Markowitz, Bach Yen Nguyen, Eduardo Gotuzzo, Fernando Mendo, Winai Ratanasuwan, Colin Kovacs, Guillermo Prada, Javier O Moralesramirez, Clyde S Crumpacker, Robin IsaacsAbstract:Objectives:The purpose of this study was to evaluate the safety and efficacy of Raltegravir vs efavirenz-based antiretroviral therapy after 96 weeks in treatment-naive patients with HIV-1 infection.Methods:Multicenter, double-blind, randomized study of Raltegravir (100, 200, 400, or 600 mg twice a d
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Raltegravir with optimized background therapy for resistant hiv 1 infection
The New England Journal of Medicine, 2008Co-Authors: Roy T Steigbigel, David A Cooper, José M. Gatell, Martin Markowitz, Jeffrey L Lennox, Princy Kumar, Mauro Schechter, Joseph E Eron, Mona R Loutfy, Jurgen K RockstrohAbstract:Results In the combined studies, 699 of 703 randomized patients (462 and 237 in the Raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 Raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 Raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the Raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detect ed in 3.5% of Raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the Raltegravir and placebo groups. Conclusions In HIV-infected patients with limited treatment options, Raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)
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Raltegravir an integrase inhibitor for hiv 1
Expert Opinion on Investigational Drugs, 2008Co-Authors: Teresa H Evering, Martin MarkowitzAbstract:Background: The need to develop antiretroviral agents with novel mechanisms of action persists for the treatment of both antiretroviral- experienced and antiretroviral-naive patients with HIV/AIDS. This is mandated, in part, by the perpetual advent of antiretroviral-resistant HIV-1 strains. Raltegravir has been shown to specifically inhibit the essential, HIV-1-encoded, integrase enzyme. As a result, this agent represents a promising chemotherapeutic agent for the treatment of HIV/AIDS. Objective: To form an evidence-based determination of the clinical efficacy, pharmacokinetics and safety profile of Raltegravir. Method: We discuss available peer-reviewed publications, preliminary data presented in abstract from relevant scientific meetings and data available from the US Food and Drug Administration (FDA). Results/conclusion: Current evidence strongly supports Raltegravir use in highly active antiretroviral therapy (HAART) regimens constructed to treat patients failing current therapies with multi-drug-re...
Hedy Teppler - One of the best experts on this subject based on the ideXlab platform.
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impact of low birth weight and prematurity on neonatal Raltegravir pharmacokinetics impaact p1097
Journal of Acquired Immune Deficiency Syndromes, 2020Co-Authors: Diana F Clarke, Edward P. Acosta, Stephen A Spector, Jos Lommerse, Mae Cababasay, Jiajia Wang, Anne Chain, Elizabeth Smith, Hedy TepplerAbstract:Background HIV treatment of neonates requires identifying appropriate antiretroviral dosing regimens. Our aims were to characterize Raltegravir elimination kinetics in low birth weight (LBW) neonates after maternal dosing and to develop a pharmacokinetic model to predict Raltegravir plasma concentrations for term and preterm neonates. Methods Mothers living with HIV who received Raltegravir during pregnancy and their LBW neonates participated in IMPAACT P1097 study. Up to 6 serial plasma samples were collected from each infant over the first 2 postnatal weeks to characterize Raltegravir elimination. Safety laboratory evaluations were obtained, and infants were monitored for 6 weeks for signs of Raltegravir toxicity. An integrated maternal-neonatal pharmacokinetic model was developed to predict neonatal Raltegravir plasma concentrations. Results Sixteen mothers and their 18 LBW neonates were enrolled. The median (range) Raltegravir elimination half-life was 24.4 (10.1-83) hours (N = 17 neonates). No adverse events related to Raltegravir in utero exposure were observed. Pharmacokinetic modeling revealed that Raltegravir clearance in full-term LBW neonates was well described by allometric scaling but clearance in preterm LBW neonates was better described using slower clearance maturation kinetics. Simulations suggest receipt of the current dosing recommendations in a 34-week gestation neonate would result in plasma concentrations up to 2.5-fold higher than those observed in full-term LBW infants. Conclusions Modeling suggests that prematurity reduces Raltegravir clearance and a modified Raltegravir dosing regimen will be necessary to avoid elevated plasma Raltegravir concentrations.
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Raltegravir ral in neonates dosing pharmacokinetics pk and safety in hiv 1 exposed neonates at risk of infection impaact p1110
Journal of Acquired Immune Deficiency Syndromes, 2020Co-Authors: Diana F Clarke, Edward P. Acosta, Hedy Teppler, Mae Cababasay, Jiajia Wang, Anne Chain, Bobbie Graham, Stephanie Popson, Betsy Smith, Rohan HazraAbstract:Background Adequate pharmacokinetic and safety data in neonates are lacking for most antiretroviral agents. Raltegravir is a selective HIV-1 integrase strand transfer inhibitor available in a granule formulation suitable for use in neonates and young infants as prophylaxis or treatment of HIV infection. Methods IMPAACT P1110 is a phase 1, multicenter, noncomparative dose-finding study of Raltegravir in infants exposed to HIV-1 infection. A 2-cohort adaptive design was utilized where pharmacokinetic data from infants in cohort 1 who received 2 single doses of Raltegravir 3 mg/kg were included in population modeling and simulations to guide selection of a daily dose for infants in cohort 2. Results A total of 52 infants enrolled in IMPAACT 1110: cohort 1 (N = 16) and cohort 2 (N = 36). Using simulations based on population PK modeling incorporating cohort 1 data, the following daily dosing regimen was selected for study: 1.5 mg/kg daily from birth through day 7; 3 mg/kg twice daily from days 8-28 of life; and 6 mg/kg twice daily after 4 weeks of age through 6 weeks of age. The geometric mean protocol exposure targets for AUC, Ctrough, and Cmax were met or slightly exceeded in all infants. The chosen neonatal Raltegravir dosing regimen was safe and well tolerated in full-term neonates during treatment over the first 6 weeks of life and follow-up to age 24 weeks. Conclusions Raltegravir can be safely administered to full-term infants using the daily dosing regimen studied. This regimen is not recommended for use in premature infants in a new version of P1110.
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safety and efficacy at 240 weeks of different Raltegravir formulations in children with hiv 1 a phase 1 2 open label non randomised multicentre trial
The Lancet HIV, 2018Co-Authors: Sharon Nachman, Hedy Teppler, Anthony Rodgers, Carmelita Alvero, Brenda Homony, Bobbie Graham, Terence Fenton, Lisa M Frenkel, Renee Browning, Rohan HazraAbstract:Summary Background Raltegravir is an integrase inhibitor approved for use in adults and children with HIV-1 infection, but there are no data on the long-term use of this medication in children. We aimed to assess the long-term safety, tolerability, pharmacokinetics, and efficacy of multiple Raltegravir formulations in children aged 4 weeks to 18 years with HIV-1 infection. Methods In this phase 1/2 open-label multicentre trial (IMPAACT P1066), done in 43 IMPAACT network sites in the USA, South Africa, Brazil, Botswana, and Argentina, eligible participants were children aged 4 weeks to 18 years with HIV-1 infection who had previously received antiretroviral therapy (ART), had HIV-1 RNA higher than 1000 copies per mL, and no exposure to integrase inhibitors. Participants were separated into five age groups and enrolled in six cohorts. Three formulations of open-label Raltegravir—adult tablets, chewable tablets, and granules for oral suspension—were added to individualised optimised background therapy, according to the age and weight of participants. The primary outcome at 48 weeks has been previously reported. In the 240-week follow-up, outcomes of interest included graded clinical and laboratory safety of Raltegravir formulations during the study and virological efficacy (with virological success defined as HIV-1 RNA reduction of >1 log10 from baseline or HIV-1 RNA ClinicalTrials.gov , number NCT00485264 . Findings Between August, 2007, and December, 2012, 220 patients were assessed for eligibility, and 153 were enrolled and treated. Of these patients, 122 received only the final selected dose of Raltegravir (63 received adult tablets, 33 chewable tablets, and 26 oral granules), and one was not treated. There were few serious clinical or laboratory safety events noted, with two patients having a drug-related adverse event (skin rash), which led one patient to discontinue the study treatment. The addition of Raltegravir to an individually optimised ART regimen resulted in virological success at week 240 in 19 (44·2%, 95% CI 29·1–60·1) of 43 patients receiving 400 mg tablets, 24 (77·4%, 58·9–90·4) of 31 patients receiving the chewable tablets, and 13 (86·7%, 59·5–98·3) of 15 patients receiving oral granules. Among patients with virological failure, Raltegravir resistance was noted in 19 (38%) of 50 patients who had virological rebound after initial suppression and had samples at virological failure available for testing. Interpretation Our study suggests that Raltegravir can be used for the treatment of HIV-1 infection in children as young as 4 weeks, with the expectation of long-term safety and efficacy, but should be used with caution among older children who had previous extensive antiretroviral therapy. Funding National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Mental Health, and Merck.
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Raltegravir pharmacokinetics in neonates following maternal dosing
Journal of Acquired Immune Deficiency Syndromes, 2014Co-Authors: Diana F Clarke, Edward P. Acosta, Hedy Teppler, Matthew L Rizk, Yvonne J Bryson, Stephen A Spector, Lynne M Mofenson, Edward Handelsman, Carolee Welebob, Deborah PersaudAbstract:: International Maternal Pediatric Adolescent AIDS Clinical Trials P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to Raltegravir in infants born to HIV-infected pregnant women receiving Raltegravir-based antiretroviral therapy. Twenty-two mother-infant pairs were enrolled; evaluable pharmacokinetic data were available from 19 mother-infant pairs. Raltegravir readily crossed the placenta, with a median cord blood/maternal delivery plasma Raltegravir concentration ratio of 1.48 (range, 0.32-4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t1/2 26.6 (range, 9.3-184) hours]. Prolonged Raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive Raltegravir concentrations must be avoided in the neonate because Raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Subtherapeutic concentrations, which could lead to inadequate viral suppression and development of Raltegravir resistance, must also be avoided. Two ongoing International Maternal Pediatric Adolescent AIDS Clinical Trials studies are further investigating the pharmacology of Raltegravir in neonates.
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pharmacokinetics safety and 48 week efficacy of oral Raltegravir in hiv 1 infected children aged 2 through 18 years
Clinical Infectious Diseases, 2014Co-Authors: Sharon Nachman, Larissa Wenning, Edward P. Acosta, Hedy Teppler, Stephen A Spector, Brenda Homony, Bobbie Graham, Terence Fenton, Nan Zheng, Lisa M FrenkelAbstract:Novel, potent, and well-tolerated antiretroviral (ARV) medications in appropriate formulations are acutely needed for pediatric patients of all ages infected with human immunodeficiency virus (HIV), especially for those failing ARV therapy, those with ARV resistance, or those suffering from ARV-related toxicities. Perinatally infected youth are often heavily pretreated and have very limited therapeutic options that can lead to sustained benefit. Raltegravir is the first Food and Drug Administration– and European Medicines Agency–approved HIV integrase strand transfer inhibitor with demonstrated safety and efficacy in HIV type 1 (HIV-1)–infected adults. Raltegravir at a dose of 400 mg twice daily was approved for use in the treatment of HIV infection in adults based on data from 2 phase III studies in treatment-experienced adults, Blocking Integrase in Treatment-Experienced Patients with a Novel Compound Against HIV, Merck (BENCHMRK-1) and 2 [1, 2], and a phase III study in treatment-naive adults (STARTMRK) [3]. Data extending to 240 weeks for these 3 studies are now available and demonstrate both durable efficacy and a favorable long-term safety profile of Raltegravir in adults [4, 5]. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1066 study was designed to assess the safety and pharmacokinetics (PK) of Raltegravir in HIV-infected children aged 4 weeks to <19 years using 3 different formulations with the goal of determining the appropriate Raltegravir dose in age-based subgroups. After dose selection, the study provided additional data on safety, efficacy, and population PK. This report describes findings from subjects aged 2 to <19 years of age who received either the film-coated or chewable tablet formulations.
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once daily etravirine Raltegravir 400 800 mg q24h dual therapy maintains viral suppression over 48 weeks in hiv infected patients switching from a twice daily etravirine Raltegravir 200 400 mg q12h regimen
Journal of Antimicrobial Chemotherapy, 2021Co-Authors: Romain Palich, Olivier Bouchaud, Laurence Weiss, Cathia Soulié, Gilles Peytavin, Roland Tubiana, Clotilde Allavena, Ana Montoya Ferrer, Claudine Duvivier, Julie BotteroAbstract:BACKGROUND Etravirine/Raltegravir dual therapy has been shown to be highly effective as a twice-daily (q12h) regimen in suppressed HIV-infected patients enrolled in the ANRS-163 study. OBJECTIVES As a once-daily (q24h) regimen is easier for daily life, we aimed to evaluate the capacity of etravirine/Raltegravir (400/800 mg) q24h to maintain viral suppression in patients on etravirine/Raltegravir q12h. METHODS Patients on a suppressive etravirine/Raltegravir q12h regimen for at least 96 weeks were switched to etravirine/Raltegravir q24h in this prospective, multicentre, open-label, single-arm study. Primary outcome was the rate of virological failure (VF: confirmed pVL >50 copies/mL, single pVL >400 copies/mL or single pVL >50 copies/mL with ART change) at Week 48 (W48). Secondary outcomes included treatment strategy success rate (no VF and no treatment discontinuation), regimen tolerability, plasma drug concentrations and resistance profile in the case of VF. RESULTS A total of 111 patients were enrolled, with a median (IQR) age of 57 years (52-62), CD4 count of 710 cells/mm3 (501-919) and viral suppression for 7.9 years (5.9-10.7). Two patients experienced viral rebound at W24 and W48, leading to a VF rate of 2.0% (95% CI 0.5-7.8) at W48, associated with INSTI resistance in one case. Both had past NNRTI mutations. Ten patients discontinued treatment for adverse events (n = 2), investigator or patient decisions (n = 3), lost to follow-up (n = 3), death (n = 1) or pregnancy (n = 1). Overall, the strategy success rate was 89% (95% CI 81.5-93.6) at W48. In a subgroup of 64 patients, median (IQR) plasma C24h concentrations were 401 ng/mL (280-603) for etravirine and 62 ng/mL (31-140) for Raltegravir. CONCLUSIONS Switching patients virally suppressed on etravirine/Raltegravir q12h to the same regimen but given q24h was highly effective in maintaining virological suppression in HIV-infected patients.
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lack of a clinically significant pharmacokinetic interaction between etravirine and Raltegravir using an original approach based on drug metabolism protein binding and penetration in seminal fluid a pharmacokinetic substudy of the anrs 163 etral stud
Pharmacotherapy, 2019Co-Authors: Minh Patrick Le, Soizic Le Mestre, Olivier Bouchaud, Laurence Weiss, Lambert Assoumou, Jean Michel Molina, Cathia Soulié, Marc-antoine Valantin, Yazdan Yazdanpanah, Francois RaffiAbstract:Study objective: The ANRS163-ETRAL study showed that etravirine 200 mg/Raltegravir 400 mg twice-daily dual therapy was highly effective in the treatment of human immunodeficiency virus (HIV)-infected patients older than 45 years, with virologic and therapeutic success rates at week 48 of 99.4% and 94.5%, respectively. The objective of this study was to determine whether a clinically significant pharmacokinetic interaction between etravirine and Raltegravir exists by assessing steady-state total and unbound etravirine, Raltegravir, and inactive Raltegravir-glucuronide concentrations 12 hours after last intake (C12h ) in blood plasma (BP) and seminal plasma (SP). Design: Pharmacokinetic analysis of data from the ANRS163-ETRAL study. Patients: One hundred forty-six HIV-1-infected patients (of the 165 patients included in the ANRS-163 ETRAL study) who were receiving etravirine 200 mg and Raltegravir 400 mg twice daily. Measurements and main results: Blood was collected from all 146 patients at weeks 2-4, 12, 24, and 48, and semen was collected from 21 patients at week 48. The extent of BP and SP protein binding was determined by using ultrafiltration assay. Total and unbound etravirine, Raltegravir, and Raltegravir-glucuronide C12h were determined by ultra high performance liquid chromatography coupled with tandem mass spectrometry and interpreted by using the in vitro calculated protein-bound 95% inhibitory concentration (PBIC95 ) for wild-type (WT) HIV: etravirine (116 ng/ml) and Raltegravir (15 ng/ml). Median (interquartile range [IQR]) total BP etravirine C12h (536 ng/ml [376-719]) and Raltegravir (278 ng/ml [97-690]) were adequate in 99% and 96% of patients, respectively. Median (IQR) SP:BP C12h ratio and BP unbound fraction were etravirine 0.3 (0.2-0.5) and 99%, respectively. The BP Raltegravir metabolic ratio (Raltegravir glucuronide:Raltegravir ratio) was 1.7, suggesting only weak induction of Raltegravir glucuronidation by etravirine. Only three patients had etravirine and Raltegravir C12h < PBIC95 simultaneously. Conclusion: No clinically significant pharmacokinetic interaction between etravirine and Raltegravir was detected. Total etravirine and Raltegravir BP concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (> 95%), despite twice-daily administration. The long half-life of etravirine and higher unbound fraction SP of Raltegravir (57%) ensured adequate concentrations of dual therapy in genital compartments. Our results indicate that etravirine and Raltegravir have good, complementary pharmacokinetic profiles, suggesting that they could be used in a dual-treatment strategy.
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quasispecies variant dynamics during emergence of resistance to Raltegravir in hiv 1 infected patients
Journal of Antimicrobial Chemotherapy, 2009Co-Authors: Isabelle Malet, Cathia Soulié, Olivier Delelis, Jean-françois Mouscadet, Luba Tchertanov, Marc Wirden, Gilles Peytavin, C Katlama, Philippe Mottaz, Vincent CalvezAbstract:Received 9 October 2008; returned 21 November 2008; revised 12 December 2008; accepted 8 January 2009 Objectives: Raltegravir is the first approved inhibitor of HIV-1 integrase (IN). In most patients, Raltegravir failure is associated with mutations in the IN gene, through two different genetic pathways: 155 (N155H) or 148 (Q148K/R/H). The objective of this study was to characterize the dynamics of HIV-1 quasispecies variant populations in patients who failed to respond to Raltegravir treatment. Patients and methods: Bulk genotyping and clonal analysis were performed during the follow-up of 10 patients who failed to respond to Raltegravir treatment. Results: Treatment failed through the 155 pathway in six patients and through the 148 pathway in two patients; two further patients switched from the 155 to the 148 pathway. In the two patients switching from the 155 to the 148 pathway, clonal analysis showed that Q148R/H and N155H mutations were present on different strands, suggesting that these two pathways are independent. This was consistent with our finding that each genetic profile was associated with different secondary mutations. We observed a greater variability among quasispecies associated with the 155 pathway, and IC50 determinations showed that the fold resistance to Raltegravir, relative to wild-type, was 10 for the N155H mutant and 50 for the G140S1Q148H mutant. Conclusions: Clonal analysis strongly suggests that the two main genetic pathways, 155 and 148, involved in the development of resistance to Raltegravir are independent and exclusive. Moreover, the switch of the resistance profile from 155 to 148 may be related to the higher level of resistance to Raltegravir conferred by the 148 pathway and also to the higher instability of the 155 pathway.
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mutations associated with failure of Raltegravir treatment affect integrase sensitivity to the inhibitor in vitro
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Isabelle Malet, Cathia Soulié, Marc-antoine Valantin, Olivier Delelis, Luba Tchertanov, Jacques Reynes, Brigitte Montes, Marc Wirden, Gilles Peytavin, Jean-françois MouscadetAbstract:Raltegravir (MK-0518) is a potent inhibitor of human immunodeficiency virus (HIV) integrase and is clinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received salvage therapy including Raltegravir and who subsequently developed virological failure under Raltegravir therapy were studied. For each patient, the sequences of the integrase-coding region were determined and compared to that at the beginning of the treatment. Four different mutation profiles were identified in these nine patients: E92Q, G140S Q148H, N155H, and E157Q mutations. For four patients, each harboring a different profile, the wild-type and mutated integrases were produced, purified, and assayed in vitro. All the mutations identified altered the activities of integrase protein: both 3′ processing and strand transfer activities were moderately affected in the E92Q mutant; strand transfer was markedly impaired in the N155H mutant; both activities were strongly impaired in the G140S Q148H mutant; and the E157Q mutant was almost completely inactive. The sensitivities of wild-type and mutant integrases to Raltegravir were compared. The E92Q and G140S Q148H profiles were each associated with a 7- to 8-fold decrease in sensitivity, and the N155H mutant was more than 14-fold less sensitive to Raltegravir. At least four genetic profiles (E92Q, G140S Q148H, N155H, and E157Q) can be associated with in vivo treatment failure and resistance to Raltegravir. These mutations led to strong impairment of enzymes in vitro in the absence of Raltegravir: strand transfer activity was affected, and in some cases 3′ processing was also impaired.
