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Stephen C. Piscitelli - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of dolutegravir in hiv seronegative subjects with severe renal impairment
European Journal of Clinical Pharmacology, 2014Co-Authors: Stephen Weller, Julie Borland, Shuguang Chen, Paul Savina, Amanda Peppercorn, Toshihiro Wajima, Brian Wynne, Mark A Johnson, Stephen C. PiscitelliAbstract:Purpose Dolutegravir (DTG), an unboosted HIV Integrase Inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.
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metabolism excretion and mass balance of the hiv 1 Integrase Inhibitor dolutegravir in humans
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Stephen Castellino, Julie Borland, Shuguang Chen, Ivy Song, Stephen C. Piscitelli, David S Wagner, Igor Goljer, Amanda G Culp, Lee Moss, Paul SavinaAbstract:ABSTRACT The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 Integrase Inhibitor, were studied in healthy male subjects following single oral administration of [ 14 C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives ( t 1/2 ) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.
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effects of etravirine on the pharmacokinetics of the Integrase Inhibitor s gsk1265744
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Susan L Ford, Shuguang Chen, William Spreen, Elizabeth Gould, Etienne Dumont, Stephen C. PiscitelliAbstract:ABSTRACT HIV Integrase Inhibitors such as raltegravir and elvitegravir halt HIV progression, but treatment-emergent resistance and cross-resistance have been observed. The nonnucleoside reverse transcriptase Inhibitor etravirine (ETR) may be used in combination with Integrase Inhibitors in patients with drug resistance. This single-center, open-label, two-period, single-sequence crossover study evaluated the effects of ETR coadministration on the pharmacokinetic profile of S/GSK1265744, an investigational Integrase Inhibitor in phase 2 studies. Healthy subjects received 30 mg of S/GSK1265744 alone once daily for 10 days (period 1) and in combination with 200 mg of ETR twice daily for 14 days (period 2). Serial plasma samples for pharmacokinetic analyses were collected on day 10 during period 1 and on day 14 during period 2. All treatments were well tolerated. Etravirine had no effects on S/GSK1265744 geometric mean ratios of the area under the curve from time zero until the end of the dosing interval (1.01; 90% confidence interval [CI], 0.956 to 1.06), of the maximum observed plasma concentration (1.04; 90% CI, 0.987 to 1.09), or of the plasma concentration at the end of the dosing interval (0.999; 90% CI, 0.942 to 1.06). Etravirine pharmacokinetics (PK) parameters observed following coadministration with S/GSK1265744 were in the range of historical values reported for ETR alone in healthy subjects. These results indicate that 30 mg of S/GSK1265744 for 10 days as monotherapy followed by an additional 14 days in combination with ETR was well tolerated in healthy subjects and that no dose adjustment of S/GSK1265744 is required when it is coadministered with ETR.
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effects of etravirine on the pharmacokinetics of the Integrase Inhibitor s gsk1265744
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Susan L Ford, Shuguang Chen, Yu Lou, William Spreen, Elizabeth Gould, Etienne Dumont, Stephen C. PiscitelliAbstract:ABSTRACT HIV Integrase Inhibitors such as raltegravir and elvitegravir halt HIV progression, but treatment-emergent resistance and cross-resistance have been observed. The nonnucleoside reverse transcriptase Inhibitor etravirine (ETR) may be used in combination with Integrase Inhibitors in patients with drug resistance. This single-center, open-label, two-period, single-sequence crossover study evaluated the effects of ETR coadministration on the pharmacokinetic profile of S/GSK1265744, an investigational Integrase Inhibitor in phase 2 studies. Healthy subjects received 30 mg of S/GSK1265744 alone once daily for 10 days (period 1) and in combination with 200 mg of ETR twice daily for 14 days (period 2). Serial plasma samples for pharmacokinetic analyses were collected on day 10 during period 1 and on day 14 during period 2. All treatments were well tolerated. Etravirine had no effects on S/GSK1265744 geometric mean ratios of the area under the curve from time zero until the end of the dosing interval (1.01; 90% confidence interval [CI], 0.956 to 1.06), of the maximum observed plasma concentration (1.04; 90% CI, 0.987 to 1.09), or of the plasma concentration at the end of the dosing interval (0.999; 90% CI, 0.942 to 1.06). Etravirine pharmacokinetics (PK) parameters observed following coadministration with S/GSK1265744 were in the range of historical values reported for ETR alone in healthy subjects. These results indicate that 30 mg of S/GSK1265744 for 10 days as monotherapy followed by an additional 14 days in combination with ETR was well tolerated in healthy subjects and that no dose adjustment of S/GSK1265744 is required when it is coadministered with ETR.
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safety tolerability and pharmacokinetics of the hiv Integrase Inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin results of a phase 1 study among healthy subjects
Journal of Acquired Immune Deficiency Syndromes, 2013Co-Authors: Kelly E Dooley, Julie Borland, Shuguang Chen, Amanda Peppercorn, Ivy Song, Stephen C. Piscitelli, Patrick Sayre, Elizabeth Purdy, Stephanie Everts, Charles FlexnerAbstract:Background Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV Integrase Inhibitor, dolutegravir (DTG). Methods Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period. Results In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (Cτ) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0-24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the Cτ was 0.70 (90% CI: 0.57 to 0.87). Conclusions Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.
Ivy Song - One of the best experts on this subject based on the ideXlab platform.
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effects of enzyme inducers efavirenz and tipranavir ritonavir on the pharmacokinetics of the hiv Integrase Inhibitor dolutegravir
European Journal of Clinical Pharmacology, 2014Co-Authors: Ivy Song, Julie Borland, Shuguang Chen, Phyllis Guta, David Wilfret, Paul Savina, Amanda Peppercorn, Toshihiro Wajima, Stephen Castellino, David S WagnerAbstract:Purpose Dolutegravir (DTG) is an unboosted, Integrase Inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects.
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dolutegravir versus placebo in subjects harbouring hiv 1 with Integrase Inhibitor resistance associated substitutions 48 week results from viking 4 a randomized study
Antiviral Therapy, 2014Co-Authors: Bisher Akil, Ivy Song, Debbie Hagins, Moti Ramgopal, Gary Blick, Gary Richmond, Rafik M Samuel, Naomi Givens, Cindy Vavro, Brian WynneAbstract:BACKGROUND The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG. METHODS VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with Integrase Inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT01568892). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including ≥1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8. RESULTS The study population (n=30) was highly ART-experienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was -1.06 log10 copies/ml for the DTG arm and 0.10 log10 copies/ml for the placebo arm (treatment difference -1.16 log10 copies/ml [-1.52, -0.80]; P<0.001). Overall, 47% and 57% of subjects had plasma HIV-1 RNA <50 and <400 copies/ml at week 24, and 40% and 53% at week 48, respectively. No discontinuations due to drug-related adverse events occurred in the study. CONCLUSIONS The observed day 8 antiviral activity in this highly treatment-experienced population with INI-resistant HIV-1 was attributable to DTG. Longer-term efficacy (after considering baseline ART resistance) and safety during the open-label phase were in-line with the results of the larger VIKING-3 study.
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metabolism excretion and mass balance of the hiv 1 Integrase Inhibitor dolutegravir in humans
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Stephen Castellino, Julie Borland, Shuguang Chen, Ivy Song, Stephen C. Piscitelli, David S Wagner, Igor Goljer, Amanda G Culp, Lee Moss, Paul SavinaAbstract:ABSTRACT The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 Integrase Inhibitor, were studied in healthy male subjects following single oral administration of [ 14 C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives ( t 1/2 ) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.
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safety tolerability and pharmacokinetics of the hiv Integrase Inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin results of a phase 1 study among healthy subjects
Journal of Acquired Immune Deficiency Syndromes, 2013Co-Authors: Kelly E Dooley, Julie Borland, Shuguang Chen, Amanda Peppercorn, Ivy Song, Stephen C. Piscitelli, Patrick Sayre, Elizabeth Purdy, Stephanie Everts, Charles FlexnerAbstract:Background Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV Integrase Inhibitor, dolutegravir (DTG). Methods Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period. Results In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (Cτ) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0-24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the Cτ was 0.70 (90% CI: 0.57 to 0.87). Conclusions Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.
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effect of food on the pharmacokinetics of the Integrase Inhibitor dolutegravir
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Ivy Song, Julie Borland, Shuguang Chen, Amanda Peppercorn, Parul Patel, Toshihiro Wajima, Stephen C. PiscitelliAbstract:Healthy subjects received dolutegravir at 50 mg in a single-dose crossover study while they were in the fasted state or with low-, moderate-, or high-fat meals. Food increased dolutegravir exposure and reduced the rate of absorption. The area under the concentration-time curve from 0 h to infinity (AUC0–∞) increased by 33%, 41%, and 66% when administered with low-, moderate-, or high-fat meals, respectively, compared with fasting. This increase in dolutegravir exposure is not anticipated to impact clinical safety, and therefore dolutegravir can be taken with or without food and without regard to fat content.
Harry Lampiris - One of the best experts on this subject based on the ideXlab platform.
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Elvitegravir: a once-daily, boosted, HIV-1 Integrase Inhibitor.
Expert review of anti-infective therapy, 2012Co-Authors: Harry LampirisAbstract:The development of HIV-1 Integrase strand transfer Inhibitors (INSTIs) has been a major therapeutic breakthrough in the management of HIV-1 infection. The first HIV-1 Integrase Inhibitor, raltegravir, was licensed in 2007 and was subsequently approved for use in treatment-naive patients. Since then, newer members of the INSTI class have been developed, including elvitegravir (EVG), which is in advanced clinical development and is being developed for use in both treatment-naive and treatment-experienced patients. EVG utilizes pharmacokinetic boosting to achieve adequate serum levels with once-daily dosing. Boosting agents with which it is being studied include ritonavir and cobicistat. In addition, EVG is being studied as a once-daily INSTI in a coformulated fixed-dose combination pill with the agents tenofovir disoproxil fumarate, emtricitabine and cobicistat (QUAD pill), which has the additional potential benefit of convenient once-daily dosing. The in vitro activity, pharmacokinetic and pharmacodynamic properties, results of Phase I-III clinical trials, resistance profile and drug-drug interactions of EVG will be reviewed in this article.
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evolution of Integrase resistance during failure of Integrase Inhibitor based antiretroviral therapy
Journal of Acquired Immune Deficiency Syndromes, 2010Co-Authors: Hiroyu Hatano, Jeffrey N. Martin, Harry Lampiris, Signe Fransen, Soumi Gupta, Wei Huang, Rebecca Hoh, Jacob Lalezari, David R BangsbergAbstract:Background: Although Integrase Inhibitors are highly effective in the management of drug-resistant HIV, some patients fail to achieve durable viral suppression. The long-term consequences of Integrase Inhibitor failure have not been well defined. Methods: We identified 29 individuals who exhibited evidence of incomplete viral suppression on a regimen containing an Integrase Inhibitor (23 raltegravir, 6 elvitegravir). Before initiating the Integrase Inhibitor-based regimen, the median CD4 + T-cell count and plasma HIV RNA levels were 62 cells/mm 3 and 4.65 log 10 copies/mL, respectively. Results: At the first failure time-point, the most common Integrase resistance pattern for subjects taking raltegravir was wild-type, followed in order of frequency by Q148H/K/R+G140S, N155H, and Y143R/H/C. The most common resistance pattern for subjects taking elvitegravir was E92Q. Long-term failure was associated with continued viral evolution, emergence of high-level phenotypic resistance, and a decrease in replicative capacity. Conclusions: Although wild-type failure during early Integrase Inhibitor failure is common, most patients eventually develop high-level phenotypic drug resistance. This resistance evolution is gradual and associated with declines in replicative capacity.
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activity of elvitegravir a once daily Integrase Inhibitor against resistant hiv type 1 results of a phase 2 randomized controlled dose ranging clinical trial
The Journal of Infectious Diseases, 2010Co-Authors: Andrew R Zolopa, Brian P Kearney, Harry Lampiris, Lijie Zhong, Steven L Chuck, Daniel S Berger, Jeffrey Enejosa, Andrew K ChengAbstract:Background. This phase 2, randomized, active-controlled, 48-week study assessed the noninferiority of the human immunodeficiency virus (HIV) Integrase Inhibitor elvitegravir to comparator ritonavir-boosted protease Inhibitor (CPI/r) in treatment-experienced subjects. Methods. Subjects had HIV RNA levels ≥1000 copies/mL and ≥1 1 protease resistance mutation. Subjects received nucleoside or nucleotide reverse-transcriptase Inhibitors (NRTIs) with or without T-20 and either CPI/r or once-daily elvitegravir at a dose of 20 mg, 50 mg, or 125 mg (blinded to dose) with ritonavir. After week 8, the independent data monitoring committee stopped the elvitegravir 20 mg arm and allowed subjects in the elvitegravir 50 mg and 125 mg arms to add protease Inhibitors. The primary end point was the time-weighted average change from baseline in HIV RNA level through week 24 (DAVG 24 ). Results. A total of 278 subjects with a median of 11 protease and 3 thymidine analog mutations were randomized and treated. One-half of subjects received NRTIs without expected antiviral activity. Compared with the DAVG 24 for the CPI/r arm (-1.19 log 10 copies/mL), the elvitegravir 50 mg arm was noninferior (-1.44 log 10 copies/mL), and the elvitegravir 125 mg arm was superior (-1.66 log 10 copies/mL; P = .021). Efficacy was impacted by activity of background agents. There was no relationship between elvitegravir dosage and adverse events. Conclusions. Elvitegravir was well-tolerated and produced rapid virologic suppression that was durable with active background therapy. Trial registration. ClinicalTrials.gov identifier number: NCT00298350.
Shuguang Chen - One of the best experts on this subject based on the ideXlab platform.
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effects of enzyme inducers efavirenz and tipranavir ritonavir on the pharmacokinetics of the hiv Integrase Inhibitor dolutegravir
European Journal of Clinical Pharmacology, 2014Co-Authors: Ivy Song, Julie Borland, Shuguang Chen, Phyllis Guta, David Wilfret, Paul Savina, Amanda Peppercorn, Toshihiro Wajima, Stephen Castellino, David S WagnerAbstract:Purpose Dolutegravir (DTG) is an unboosted, Integrase Inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects.
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pharmacokinetics of dolutegravir in hiv seronegative subjects with severe renal impairment
European Journal of Clinical Pharmacology, 2014Co-Authors: Stephen Weller, Julie Borland, Shuguang Chen, Paul Savina, Amanda Peppercorn, Toshihiro Wajima, Brian Wynne, Mark A Johnson, Stephen C. PiscitelliAbstract:Purpose Dolutegravir (DTG), an unboosted HIV Integrase Inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.
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metabolism excretion and mass balance of the hiv 1 Integrase Inhibitor dolutegravir in humans
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Stephen Castellino, Julie Borland, Shuguang Chen, Ivy Song, Stephen C. Piscitelli, David S Wagner, Igor Goljer, Amanda G Culp, Lee Moss, Paul SavinaAbstract:ABSTRACT The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 Integrase Inhibitor, were studied in healthy male subjects following single oral administration of [ 14 C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives ( t 1/2 ) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.
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effects of etravirine on the pharmacokinetics of the Integrase Inhibitor s gsk1265744
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Susan L Ford, Shuguang Chen, William Spreen, Elizabeth Gould, Etienne Dumont, Stephen C. PiscitelliAbstract:ABSTRACT HIV Integrase Inhibitors such as raltegravir and elvitegravir halt HIV progression, but treatment-emergent resistance and cross-resistance have been observed. The nonnucleoside reverse transcriptase Inhibitor etravirine (ETR) may be used in combination with Integrase Inhibitors in patients with drug resistance. This single-center, open-label, two-period, single-sequence crossover study evaluated the effects of ETR coadministration on the pharmacokinetic profile of S/GSK1265744, an investigational Integrase Inhibitor in phase 2 studies. Healthy subjects received 30 mg of S/GSK1265744 alone once daily for 10 days (period 1) and in combination with 200 mg of ETR twice daily for 14 days (period 2). Serial plasma samples for pharmacokinetic analyses were collected on day 10 during period 1 and on day 14 during period 2. All treatments were well tolerated. Etravirine had no effects on S/GSK1265744 geometric mean ratios of the area under the curve from time zero until the end of the dosing interval (1.01; 90% confidence interval [CI], 0.956 to 1.06), of the maximum observed plasma concentration (1.04; 90% CI, 0.987 to 1.09), or of the plasma concentration at the end of the dosing interval (0.999; 90% CI, 0.942 to 1.06). Etravirine pharmacokinetics (PK) parameters observed following coadministration with S/GSK1265744 were in the range of historical values reported for ETR alone in healthy subjects. These results indicate that 30 mg of S/GSK1265744 for 10 days as monotherapy followed by an additional 14 days in combination with ETR was well tolerated in healthy subjects and that no dose adjustment of S/GSK1265744 is required when it is coadministered with ETR.
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effects of etravirine on the pharmacokinetics of the Integrase Inhibitor s gsk1265744
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Susan L Ford, Shuguang Chen, Yu Lou, William Spreen, Elizabeth Gould, Etienne Dumont, Stephen C. PiscitelliAbstract:ABSTRACT HIV Integrase Inhibitors such as raltegravir and elvitegravir halt HIV progression, but treatment-emergent resistance and cross-resistance have been observed. The nonnucleoside reverse transcriptase Inhibitor etravirine (ETR) may be used in combination with Integrase Inhibitors in patients with drug resistance. This single-center, open-label, two-period, single-sequence crossover study evaluated the effects of ETR coadministration on the pharmacokinetic profile of S/GSK1265744, an investigational Integrase Inhibitor in phase 2 studies. Healthy subjects received 30 mg of S/GSK1265744 alone once daily for 10 days (period 1) and in combination with 200 mg of ETR twice daily for 14 days (period 2). Serial plasma samples for pharmacokinetic analyses were collected on day 10 during period 1 and on day 14 during period 2. All treatments were well tolerated. Etravirine had no effects on S/GSK1265744 geometric mean ratios of the area under the curve from time zero until the end of the dosing interval (1.01; 90% confidence interval [CI], 0.956 to 1.06), of the maximum observed plasma concentration (1.04; 90% CI, 0.987 to 1.09), or of the plasma concentration at the end of the dosing interval (0.999; 90% CI, 0.942 to 1.06). Etravirine pharmacokinetics (PK) parameters observed following coadministration with S/GSK1265744 were in the range of historical values reported for ETR alone in healthy subjects. These results indicate that 30 mg of S/GSK1265744 for 10 days as monotherapy followed by an additional 14 days in combination with ETR was well tolerated in healthy subjects and that no dose adjustment of S/GSK1265744 is required when it is coadministered with ETR.
Julie Borland - One of the best experts on this subject based on the ideXlab platform.
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effects of enzyme inducers efavirenz and tipranavir ritonavir on the pharmacokinetics of the hiv Integrase Inhibitor dolutegravir
European Journal of Clinical Pharmacology, 2014Co-Authors: Ivy Song, Julie Borland, Shuguang Chen, Phyllis Guta, David Wilfret, Paul Savina, Amanda Peppercorn, Toshihiro Wajima, Stephen Castellino, David S WagnerAbstract:Purpose Dolutegravir (DTG) is an unboosted, Integrase Inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects.
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pharmacokinetics of dolutegravir in hiv seronegative subjects with severe renal impairment
European Journal of Clinical Pharmacology, 2014Co-Authors: Stephen Weller, Julie Borland, Shuguang Chen, Paul Savina, Amanda Peppercorn, Toshihiro Wajima, Brian Wynne, Mark A Johnson, Stephen C. PiscitelliAbstract:Purpose Dolutegravir (DTG), an unboosted HIV Integrase Inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.
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metabolism excretion and mass balance of the hiv 1 Integrase Inhibitor dolutegravir in humans
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Stephen Castellino, Julie Borland, Shuguang Chen, Ivy Song, Stephen C. Piscitelli, David S Wagner, Igor Goljer, Amanda G Culp, Lee Moss, Paul SavinaAbstract:ABSTRACT The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 Integrase Inhibitor, were studied in healthy male subjects following single oral administration of [ 14 C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives ( t 1/2 ) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.
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safety tolerability and pharmacokinetics of the hiv Integrase Inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin results of a phase 1 study among healthy subjects
Journal of Acquired Immune Deficiency Syndromes, 2013Co-Authors: Kelly E Dooley, Julie Borland, Shuguang Chen, Amanda Peppercorn, Ivy Song, Stephen C. Piscitelli, Patrick Sayre, Elizabeth Purdy, Stephanie Everts, Charles FlexnerAbstract:Background Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV Integrase Inhibitor, dolutegravir (DTG). Methods Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period. Results In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (Cτ) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0-24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the Cτ was 0.70 (90% CI: 0.57 to 0.87). Conclusions Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.
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effect of food on the pharmacokinetics of the Integrase Inhibitor dolutegravir
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Ivy Song, Julie Borland, Shuguang Chen, Amanda Peppercorn, Parul Patel, Toshihiro Wajima, Stephen C. PiscitelliAbstract:Healthy subjects received dolutegravir at 50 mg in a single-dose crossover study while they were in the fasted state or with low-, moderate-, or high-fat meals. Food increased dolutegravir exposure and reduced the rate of absorption. The area under the concentration-time curve from 0 h to infinity (AUC0–∞) increased by 33%, 41%, and 66% when administered with low-, moderate-, or high-fat meals, respectively, compared with fasting. This increase in dolutegravir exposure is not anticipated to impact clinical safety, and therefore dolutegravir can be taken with or without food and without regard to fat content.