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Ivy Song - One of the best experts on this subject based on the ideXlab platform.
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the effect of Dolutegravir on the pharmacokinetics of metformin in healthy subjects
Journal of Acquired Immune Deficiency Syndromes, 2016Co-Authors: Ivy Song, Brian Wynne, Julie Borland, Jian Zong, Fred Jerva, Maciej J Zamekgliszczynski, Joan E Humphreys, Gary D Bowers, Mike ChoukourAbstract:Background: Dolutegravir is an integrase strand transfer inhibitor (INSTI) licensed for use in HIV-1 infection and is an inhibitor of organic cation transporter 2 (OCT2). This study assessed the effect of Dolutegravir on the pharmacokinetics of metformin, an OCT2 substrate.
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Population pharmacokinetics of Dolutegravir in HIV-infected treatment-naive patients.
British Journal of Clinical Pharmacology, 2015Co-Authors: Jianping Zhang, Stephen C. Piscitelli, Siobhan Hayes, Brian M. Sadler, Ilisse Minto, Julie Brandt, Ivy SongAbstract:Aim Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of Dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates. Methods A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received Dolutegravir (ranging from 10–50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine. Results The pharmacokinetics of Dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h–1, 17.4 l, 2.24 h−1, and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state Dolutegravir plasma exposure was relatively small (
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pharmacokinetics of Dolutegravir when administered with mineral supplements in healthy adult subjects
The Journal of Clinical Pharmacology, 2015Co-Authors: Ivy Song, Brian Wynne, Julie Borland, Niki Arya, Stephen C. PiscitelliAbstract:All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on Dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in Dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) Dolutegravir alone, fasting; (2) Dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) Dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) Dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma Dolutegravir AUC(0–∞), Cmax, and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, Dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements.
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Relative bioavailability of a paediatric granule formulation of the HIV integrase inhibitor Dolutegravir in healthy adult subjects.
Antiviral Therapy, 2013Co-Authors: Parul Patel, Julie Borland, Shuguang Chen, Amanda Peppercorn, Ivy Song, Toshihiro Wajima, Takeshi Funaki, Naomi Fujita, John Hughes, Stephen C. PiscitelliAbstract:BACKGROUND: This study evaluated the pharmacokinetics of a granule formulation of Dolutegravir developed as an alternative to tablets for use in paediatric populations. METHODS: A randomized, open-label study in healthy adults was carried out. Subjects received five treatments in a crossover design: a single dose of Dolutegravir 50 mg as a tablet and Dolutegravir 50 mg in 10 g of granule administered directly to mouth or mixed with purified water, water containing high cation concentrations or milk-based infant formula. Study treatments were separated by 7 days. Safety evaluations and serial pharmacokinetic sampling were done during each treatment period. A non-compartmental pharmacokinetic analysis was performed; geometric least-squares mean ratios and 90% CIs were generated for treatment comparison. Palatability was assessed by questionnaire. RESULTS: Plasma Dolutegravir exposures in all granule treatment arms exceeded those of tablet formulation. The mean area under the curve from time 0 to infinity (AUC(0-∞)) and maximum concentrations were 55-83% and 62-102% higher, respectively. Pharmacokinetics were similar when Dolutegravir was mixed with purified or cation-containing water. Dolutegravir was well tolerated, with no withdrawals due to adverse events. Taste was rated acceptable for all treatments. CONCLUSIONS: The exposure of Dolutegravir after administration of granule formulation alone, with different types of water and with milk formula, exceeded that of the tablet. The similarity of Dolutegravir exposure seen with the granule formulation demonstrates that Dolutegravir granule can be given without restriction on the type of liquid or can be administered directly to the mouth (for example, when potable water is not available).
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Pharmacokinetics of Single-Dose Dolutegravir in HIV-Seronegative Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls
Clinical pharmacology in drug development, 2013Co-Authors: Ivy Song, Julie Borland, Shuguang Chen, Paul Savina, Amanda Peppercorn, Parul Patel, Toshihiro Wajima, Stephen C. PiscitelliAbstract:This study evaluated Dolutegravir pharmacokinetics (PK) in subjects with moderate hepatic impairment compared to matched, healthy controls. In this open-label, parallel-group study, eight adult subjects with moderate hepatic impairment (Child-Pugh Score 7–9) and eight healthy subjects matched for gender, age, and body mass index received a single Dolutegravir 50-mg dose. Following dosing, 72-hour PK sampling was performed to determine total and unbound Dolutegravir concentrations. PK parameters were calculated using non-compartmental analysis. Geometric least squares mean ratios (GMR) and 90% confidence intervals (CIs) in subjects with hepatic impairment versus healthy subjects were generated by analysis of variance. Results showed that PK parameters of total plasma Dolutegravir were similar between subject groups. The unbound fraction was higher in subjects with moderate hepatic impairment than in healthy subjects with GMR (90% CI) of 2.20 (1.62, 2.99) for unbound fraction at 3 hours post-dose and 1.76 (1.23, 2.51) for unbound fraction at 24 hours post-dose; this correlated with lower serum albumin concentrations and was not considered clinically significant. Dolutegravir was well tolerated in both groups; all adverse events were reported as minor. Although free fraction was increased, no dose adjustment is required for patients treated with Dolutegravir who have mild to moderate hepatic impairment.
Stephen C. Piscitelli - One of the best experts on this subject based on the ideXlab platform.
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Population pharmacokinetics of Dolutegravir in HIV-infected treatment-naive patients.
British Journal of Clinical Pharmacology, 2015Co-Authors: Jianping Zhang, Stephen C. Piscitelli, Siobhan Hayes, Brian M. Sadler, Ilisse Minto, Julie Brandt, Ivy SongAbstract:Aim Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of Dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates. Methods A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received Dolutegravir (ranging from 10–50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine. Results The pharmacokinetics of Dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h–1, 17.4 l, 2.24 h−1, and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state Dolutegravir plasma exposure was relatively small (
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pharmacokinetics of Dolutegravir when administered with mineral supplements in healthy adult subjects
The Journal of Clinical Pharmacology, 2015Co-Authors: Ivy Song, Brian Wynne, Julie Borland, Niki Arya, Stephen C. PiscitelliAbstract:All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on Dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in Dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) Dolutegravir alone, fasting; (2) Dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) Dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) Dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma Dolutegravir AUC(0–∞), Cmax, and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, Dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements.
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Effects of boceprevir and telaprevir on the pharmacokinetics of Dolutegravir
British Journal of Clinical Pharmacology, 2014Co-Authors: Mark A. Johnson, Brian Wynne, Julie Borland, Shuguang Chen, Paul Savina, Stephen C. PiscitelliAbstract:Aims The aim was to evaluate the effect of boceprevir and telaprevir on Dolutegravir pharmacokinetics (PK); the effect of Dolutegravir on boceprevir and telaprevir PK was assessed through comparison with historical data for each hepatitis C virus (HCV) drug's prescribing information alone. Methods This was a single-centre, randomized, open-label, two-cohort, two-period, one-way study in healthy adult subjects. Dolutegravir 50 mg once daily was administered for 5 days in Period 1, and Dolutegravir 50 mg once daily was coadministered with either boceprevir 800 mg every 8 h (Cohort 1) or telaprevir 750 mg every 8 h (Cohort 2) for 10 days in Period 2. Results No deaths or serious adverse events were reported during the study. Four subjects were withdrawn from the study because of adverse events (elevated alanine aminotransferase, cellulitis, increased serum creatinine and dizziness). One subject became pregnant during the study. Coadministration of Dolutegravir with boceprevir had no effect on Dolutegravir area under the plasma concentration–time curve (AUC) and maximal plasma concentration (Cmax) and caused a small increase in concentration at the end of the dosing interval (Cτ; 8%). Coadministration of Dolutegravir with telaprevir resulted in increased Dolutegravir plasma exposures compared with those after administration of Dolutegravir alone; AUC0–τ, Cmax and Cτ increased by 25, 19 and 37%, respectively. Coadministration of boceprevir or telaprevir with Dolutegravir had no clinically significant effect on Dolutegravir PK. Plasma boceprevir and telaprevir PK data for either combined treatment were similar to historical data, indicating no effect of Dolutegravir on boceprevir or telaprevir exposure. Conclusions Dolutegravir can be coadministered with boceprevir or telaprevir in patients coinfected with HIV and HCV with no dose adjustment.
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Bioequivalence of a Dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food.
Journal of Acquired Immune Deficiency Syndromes, 2014Co-Authors: Stephen Weller, Brian Wynne, Julie Borland, Shuguang Chen, Paul Savina, Stephen C. PiscitelliAbstract:The integrase inhibitor Dolutegravir and nucleoside analogues abacavir and lamivudine are once-daily treatment options for HIV. This study (NCT01622790) evaluated, first, the bioequivalence (BE) of a fixed-dose combination (FDC) tablet containing Dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (Dolutegravir/abacavir/lamivudine FDC) vs coadministered Dolutegravir 50 mg and abacavir/lamivudine combination tablets (Epzicom) and, second, the effect of food on the Dolutegravir/abacavir/lamivudine FDC tablet. Study part A (66 healthy subjects) was a single-dose, open-label, randomized, 2-period crossover study to evaluate the BE of the Dolutegravir/abacavir/lamivudine FDC tablet and Dolutegravir + abacavir/lamivudine tablets in the fasted state. In study part B, 12 subjects from part A received the Dolutegravir/abacavir/lamivudine FDC tablet with a high-fat meal. BE and food effect were assessed by analysis of variance to determine the ratio of geometric least squares means and associated 90% confidence intervals for key pharmacokinetic parameters for each of Dolutegravir, abacavir, and lamivudine. Sixty-two subjects completed part A. The Dolutegravir/abacavir/lamivudine tablet was bioequivalent to the Dolutegravir + abacavir/lamivudine tablets; 90% confidence intervals for the geometric least squares mean ratios fell within the 0.8-1.25 BE criteria. The effect of food on the Dolutegravir/abacavir/lamivudine FDC tablet was similar to previous food effects observed with the separate formulations. The safety profile was comparable between treatments, with no observed serious or grade 3/4 adverse events. The BE of the Dolutegravir/abacavir/lamivudine FDC tablet was demonstrated; it may be administered without regard to meals.
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Relative bioavailability of a paediatric granule formulation of the HIV integrase inhibitor Dolutegravir in healthy adult subjects.
Antiviral Therapy, 2013Co-Authors: Parul Patel, Julie Borland, Shuguang Chen, Amanda Peppercorn, Ivy Song, Toshihiro Wajima, Takeshi Funaki, Naomi Fujita, John Hughes, Stephen C. PiscitelliAbstract:BACKGROUND: This study evaluated the pharmacokinetics of a granule formulation of Dolutegravir developed as an alternative to tablets for use in paediatric populations. METHODS: A randomized, open-label study in healthy adults was carried out. Subjects received five treatments in a crossover design: a single dose of Dolutegravir 50 mg as a tablet and Dolutegravir 50 mg in 10 g of granule administered directly to mouth or mixed with purified water, water containing high cation concentrations or milk-based infant formula. Study treatments were separated by 7 days. Safety evaluations and serial pharmacokinetic sampling were done during each treatment period. A non-compartmental pharmacokinetic analysis was performed; geometric least-squares mean ratios and 90% CIs were generated for treatment comparison. Palatability was assessed by questionnaire. RESULTS: Plasma Dolutegravir exposures in all granule treatment arms exceeded those of tablet formulation. The mean area under the curve from time 0 to infinity (AUC(0-∞)) and maximum concentrations were 55-83% and 62-102% higher, respectively. Pharmacokinetics were similar when Dolutegravir was mixed with purified or cation-containing water. Dolutegravir was well tolerated, with no withdrawals due to adverse events. Taste was rated acceptable for all treatments. CONCLUSIONS: The exposure of Dolutegravir after administration of granule formulation alone, with different types of water and with milk formula, exceeded that of the tablet. The similarity of Dolutegravir exposure seen with the granule formulation demonstrates that Dolutegravir granule can be given without restriction on the type of liquid or can be administered directly to the mouth (for example, when potable water is not available).
Moti Ramgopal - One of the best experts on this subject based on the ideXlab platform.
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bictegravir combined with emtricitabine and tenofovir alafenamide versus Dolutegravir abacavir and lamivudine for initial treatment of hiv 1 infection week 96 results from a randomised double blind multicentre phase 3 non inferiority trial
The Lancet HIV, 2019Co-Authors: David A Wohl, Andrea Antinori, Cynthia Brinson, Debbie Hagins, Moti Ramgopal, Yazdan Yazdanpanah, A Baumgarten, Amanda Clarke, Melanie A Thompson, Rima K AcostaAbstract:Summary Background Bictegravir co-formulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination is recommended for treatment of HIV-1-infection and might be better tolerated than other integrase inhibitor-based single-tablet regimens, but long-term outcomes data are not available. We assessed the efficacy, safety and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with co-formulated Dolutegravir, abacavir, and lamivudine at week 96. Methods This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 122 outpatient centres in nine countries. We enrolled adults (aged ≥18 years) living with HIV who were treatment naive and HLA-B*5701 negative, did not have hepatitis B virus infection, and had an estimated glomerular filtration rate of at least 50 mL/min. We randomly assigned participants (1:1) to receive co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or co-formulated Dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (the Dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of −12%. This study was registered with ClinicalTrials.gov, number NCT02607930. Findings Between Nov 13, 2015, and July 14, 2016, we screened 739 participants, of whom 108 were excluded and 631 enrolled and randomly assigned to bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or Dolutegravir, abacavir, and lamivudine (n=315). Two participants in the bictegravir group did not receive at least one dose of their assigned drug and were excluded from analyses. At week 96, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to Dolutegravir, abacavir, and lamivudine, with 276 (88%) of 314 participants in the bictegravir group versus 283 (90%) of 315 participants in the Dolutegravir group achieving HIV-1 RNA less than 50 copies per mL (difference −1·9%; 95% CI −6·9 to 3·1). The most common adverse events were nausea (36 [11%] of 314 for the bictegravir group vs 76 [24%] of 315 for the Dolutegravir group), diarrhoea (48 [15%] vs 50 [16%]), and headache (41 [13%] vs 51 [16%]). 36 (11%) participants in the bictegravir group versus 39 (12%) participants in the Dolutegravir group had a serious adverse event. Two individuals died in the bictegravir group (recreational drug overdose and suicide, neither of which was treatment related) and none died in the Dolutegravir group. No participants discontinued because of adverse events in the bictegravir group compared with five (2%) of 315 in the Dolutegravir group. Study drug-related adverse events were reported for 89 (28%) participants in the bictegravir group and 127 (40%) in the Dolutegravir group. Interpretation These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with HIV-1 with no emergent resistance. Funding Gilead Sciences, Inc.
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Dolutegravir versus raltegravir in antiretroviral experienced integrase inhibitor naive adults with hiv week 48 results from the randomised double blind non inferiority sailing study
The Lancet, 2013Co-Authors: Pedro Cahn, Anton Pozniak, Horacio Mingrone, Andrey Shuldyakov, Carlos Brites, Jaime Andradevillanueva, Gary J Richmond, Carlos Beltran Buendia, Jan Fourie, Moti RamgopalAbstract:Summary Background Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. Methods ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily Dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. Findings Analysis included 715 patients (354 Dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on Dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of Dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on Dolutegravir (four vs 17 patients; adjusted difference −3·7%, 95% CI −6·1 to −1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for Dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] Dolutegravir, 14 [4%] raltegravir). Interpretation Once-daily Dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group. Funding ViiV Healthcare.
Brian Wynne - One of the best experts on this subject based on the ideXlab platform.
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efficacy safety and tolerability of Dolutegravir rilpivirine for the maintenance of virological suppression in adults with hiv 1 phase 3 randomised non inferiority sword 1 and sword 2 studies
The Lancet, 2018Co-Authors: Josep M Llibre, Brian Wynne, Chienching Hung, Cynthia Brinson, Francesco Castelli, Pierremarie Girard, Lesley P Kahl, Elizabeth A Blair, Konstantinos Angelis, Kati VandermeulenAbstract:Summary Background Lifelong HIV antiretroviral therapy (ART) has prompted an interest in two-drug regimens to minimise cumulative drug exposure and toxicities. The safety, tolerability, and efficacy of Dolutegravir and rilpivirine suggest potential compatibility and effectiveness as a two-drug regimen. We aimed to investigate this two-drug regimen in a phase 3 study. Methods We identically designed SWORD-1 and SWORD-2, which were open-label, parallel-group, multicentre, phase 3, randomised, non-inferiority studies in 12 countries evaluating efficacy and safety of once-daily Dolutegravir 50 mg plus rilpivirine 25 mg versus current ART regimen (CAR). We included participants aged 18 years or older who were on first or second ART with stable plasma HIV-1 RNA (viral load Findings We screened for participants from April 14, 2015, to Oct 15, 2015, for SWORD-1 and from April 21, 2015, to Sept 25, 2015, for SWORD-2. We randomly assigned 516 participants to Dolutegravir-rilpivirine and 512 to continue with CAR. At week 48 (last patient visit was Nov 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the Dolutegravir-rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of −0·2% (95% CI −3·0 to 2·5) and showed non-inferiority with a predefined margin of −8%. 395 (77%) of 513 participants in the Dolutegravir-rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 [10%] for Dolutegravir-rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking Dolutegravir-rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [ Interpretation Dolutegravir-rilpivirine was non-inferior to CAR over 48 weeks in participants with HIV suppression and showed a safety profile consistent with its components. Results support the use of this two-drug regimen to maintain HIV suppression. Funding ViiV Healthcare and Janssen Pharmaceutica NV.
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fixed dose combination Dolutegravir abacavir and lamivudine versus ritonavir boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with hiv 1 infection aria week 48 results from a randomised open label
The Lancet HIV, 2017Co-Authors: Catherine Orrell, Brian Wynne, Sharon Walmsley, Debbie Hagins, Elena Belonosova, Norma Porteiro, Vicenc Falco, Alicia Aylott, Ann M Buchanan, Cindy VavroAbstract:Summary Background Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of Dolutegravir in women with HIV-1. Methods The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of Dolutegravir plus abacavir and lamivudine once a day (Dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of −12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402. Findings Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the Dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the Dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1–17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor–associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the Dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the Dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the Dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications. Interpretation The non-inferior efficacy and similar safety profile of the Dolutegravir combined regimen compared with the atazanavir regimen support the use of Dolutegravir for HIV-1 infection in treatment-naive women. Funding ViiV Healthcare.
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the effect of Dolutegravir on the pharmacokinetics of metformin in healthy subjects
Journal of Acquired Immune Deficiency Syndromes, 2016Co-Authors: Ivy Song, Brian Wynne, Julie Borland, Jian Zong, Fred Jerva, Maciej J Zamekgliszczynski, Joan E Humphreys, Gary D Bowers, Mike ChoukourAbstract:Background: Dolutegravir is an integrase strand transfer inhibitor (INSTI) licensed for use in HIV-1 infection and is an inhibitor of organic cation transporter 2 (OCT2). This study assessed the effect of Dolutegravir on the pharmacokinetics of metformin, an OCT2 substrate.
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pharmacokinetics of Dolutegravir when administered with mineral supplements in healthy adult subjects
The Journal of Clinical Pharmacology, 2015Co-Authors: Ivy Song, Brian Wynne, Julie Borland, Niki Arya, Stephen C. PiscitelliAbstract:All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on Dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in Dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) Dolutegravir alone, fasting; (2) Dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) Dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) Dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma Dolutegravir AUC(0–∞), Cmax, and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, Dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements.
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Effects of boceprevir and telaprevir on the pharmacokinetics of Dolutegravir
British Journal of Clinical Pharmacology, 2014Co-Authors: Mark A. Johnson, Brian Wynne, Julie Borland, Shuguang Chen, Paul Savina, Stephen C. PiscitelliAbstract:Aims The aim was to evaluate the effect of boceprevir and telaprevir on Dolutegravir pharmacokinetics (PK); the effect of Dolutegravir on boceprevir and telaprevir PK was assessed through comparison with historical data for each hepatitis C virus (HCV) drug's prescribing information alone. Methods This was a single-centre, randomized, open-label, two-cohort, two-period, one-way study in healthy adult subjects. Dolutegravir 50 mg once daily was administered for 5 days in Period 1, and Dolutegravir 50 mg once daily was coadministered with either boceprevir 800 mg every 8 h (Cohort 1) or telaprevir 750 mg every 8 h (Cohort 2) for 10 days in Period 2. Results No deaths or serious adverse events were reported during the study. Four subjects were withdrawn from the study because of adverse events (elevated alanine aminotransferase, cellulitis, increased serum creatinine and dizziness). One subject became pregnant during the study. Coadministration of Dolutegravir with boceprevir had no effect on Dolutegravir area under the plasma concentration–time curve (AUC) and maximal plasma concentration (Cmax) and caused a small increase in concentration at the end of the dosing interval (Cτ; 8%). Coadministration of Dolutegravir with telaprevir resulted in increased Dolutegravir plasma exposures compared with those after administration of Dolutegravir alone; AUC0–τ, Cmax and Cτ increased by 25, 19 and 37%, respectively. Coadministration of boceprevir or telaprevir with Dolutegravir had no clinically significant effect on Dolutegravir PK. Plasma boceprevir and telaprevir PK data for either combined treatment were similar to historical data, indicating no effect of Dolutegravir on boceprevir or telaprevir exposure. Conclusions Dolutegravir can be coadministered with boceprevir or telaprevir in patients coinfected with HIV and HCV with no dose adjustment.
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updated assessment of risks and benefits of Dolutegravir versus efavirenz in new antiretroviral treatment initiators in sub saharan africa modelling to inform treatment guidelines
The Lancet HIV, 2020Co-Authors: Andrew N Phillips, Loveleen Bansimatharu, Francois Venter, Diane V Havlir, Anton Pozniak, Daniel R Kuritzkes, Annemarie M J Wensing, Jens D Lundgren, Deenan PillayAbstract:Summary Background The integrase inhibitor Dolutegravir is being considered in several countries in sub-Saharan Africa instead of efavirenz for people initiating antiretroviral therapy (ART) because of superior tolerability and a lower risk of resistance emergence. WHO requested updated modelling results for its 2019 Antiretroviral Guidelines update, which was restricted to the choice of Dolutegravir or efavirenz in new ART initiators. In response to this request, we modelled the risks and benefits of alternative policies for initial first-line ART regimens. Methods We updated an existing individual-based model of HIV transmission and progression in adults to consider information on the risk of neural tube defects in women taking Dolutegravir at time of conception, as well as the effects of Dolutegravir on weight gain. The model accounted for drug resistance in determining viral suppression, with consequences for clinical outcomes and mother-to-child transmission. We sampled distributions of parameters to create various epidemic setting scenarios, which reflected the diversity of epidemic and programmatic situations in sub-Saharan Africa. For each setting scenario, we considered the situation in 2018 and compared ART initiation policies of an efavirenz-based regimen in women intending pregnancy, and a Dolutegravir-based regimen in others, and a Dolutegravir-based regimen, including in women intending pregnancy. We considered predicted outcomes over a 20-year period from 2019 to 2039, used a 3% discount rate, and a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted. Findings Considering updated information on risks and benefits, a policy of ART initiation with a Dolutegravir-based regimen rather than an efavirenz-based regimen, including in women intending pregnancy, is predicted to bring population health benefits (10 990 DALYs averted per year) and to be cost-saving (by $2·9 million per year), leading to a reduction in the overall population burden of disease of 16 735 net DALYs per year for a country with an adult population size of 10 million. The policy involving ART initiation with a Dolutegravir-based regimen in women intending pregnancy was cost-effective in 87% of our setting scenarios and this finding was robust in various sensitivity analyses, including around the potential negative effects of weight gain. Interpretation In the context of a range of modelled setting scenarios in sub-Saharan Africa, we found that a policy of ART initiation with a Dolutegravir-based regimen, including in women intending pregnancy, was predicted to bring population health benefits and be cost-effective, supporting WHO's strong recommendation for Dolutegravir as a preferred drug for ART initiators. Funding Bill & Melinda Gates Foundation.
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risks of cardiovascular or central nervous system adverse events and immune reconstitution inflammatory syndrome for Dolutegravir versus other antiretrovirals meta analysis of randomized trials
Current Opinion in Hiv and Aids, 2017Co-Authors: Andrew Hill, Nikkita Mitchell, Sophie Hughes, Anton PozniakAbstract:Purpose of reviewResults from nonrandomized cohort studies suggest higher risks of CNS adverse events for Dolutegravir, versus other ARVs. There have been two case reports of myocarditis on Dolutegravir. Integrase inhibitors have been associated with IRIS in two cohort studies. Meta-analysis of rand
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Dolutegravir versus raltegravir in antiretroviral experienced integrase inhibitor naive adults with hiv week 48 results from the randomised double blind non inferiority sailing study
The Lancet, 2013Co-Authors: Pedro Cahn, Anton Pozniak, Horacio Mingrone, Andrey Shuldyakov, Carlos Brites, Jaime Andradevillanueva, Gary J Richmond, Carlos Beltran Buendia, Jan Fourie, Moti RamgopalAbstract:Summary Background Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. Methods ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily Dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. Findings Analysis included 715 patients (354 Dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on Dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of Dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on Dolutegravir (four vs 17 patients; adjusted difference −3·7%, 95% CI −6·1 to −1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for Dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] Dolutegravir, 14 [4%] raltegravir). Interpretation Once-daily Dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group. Funding ViiV Healthcare.