Ivy Song

Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study

Background.u2003The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose. Methods.u2003VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24. Results.u2003Mean change in HIV-1 RNA at day 8 was −1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily. Conclusions.u2003DTG 50 mg BID–based therapy was effective in this highly treatment-experienced population with INI-resistant virus. Clinical Trials Registration.u2003www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574).

Antiviral activity, safety, and pharmacokinetics/ pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults

Objective:To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of dolutegravir (DTG), a next-generation HIV integrase inhibitor (INI), as short-term monotherapy. Design:A phase IIa, randomized, double-blind, dose-ranging study. Methods:In this study, INI-naive, HIV-1-infected adults currently off antiretroviral therapy were randomized to receive DTG (2, 10, or 50u200amg) or placebo once daily for 10 days in an eight active and two placebo randomization scheme per DTG dose. Placebo patients were pooled for the purpose of analysis. Results:Thirty-five patients (nu200a=u200a9 for DTG 2 and 10u200amg, nu200a=u200a10 for DTG 50u200amg, and nu200a=u200a7 for placebo) were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all DTG dose groups compared with placebo (Pu200a<u200a0.001), with a mean decrease of 1.51–2.46u200alog10u200acopies/ml. In addition, a well characterized dose–response relationship was observed for viral load decrease. Most patients (seven of 10, 70%) receiving DTG 50u200amg achieved plasma HIV-1 RNA less than 50u200acopies/ml. The pharmacokinetic variability was low (coefficient of variation, range 25–50%). Plasma HIV-1 RNA reduction was best predicted by C&tgr; using an Emax model. The most common adverse events were diarrhea, fatigue, and headache; the majority of adverse events were mild or moderate in severity. Conclusion:Dolutegravir demonstrated potent antiviral activity, good short-term tolerability, low pharmacokinetic variability, and a predictable pharmacokinetics/pharmacodynamics relationship, which support once-daily dosing without a pharmacokinetic booster in integrase-naive patients in future studies.

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

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 (C&tgr;) 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 C&tgr; 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.

Lack of interaction between the HIV integrase inhibitor S/GSK1349572 and tenofovir in healthy subjects.

Background: The potential for a drug interaction between S/GSK1349572 and tenofovir disoproxil fumarate (TDF) was evaluated in an open-label, repeat dose, 3-period, drug-drug interaction study in healthy subjects. Methods: S/GSK1349572 was administered at 50 mg once daily for 5 days (period 1) followed by a 6-day washout period. TDF 300 mg once daily was then administered for 7 days (period 2). The combination of S/GSK1349572 and TDF was then coadministered for 5 days (period 3). Pharmacokinetic parameters were determined and compared between periods. Results: Fifteen subjects completed all periods and follow-up. S/GSK1349572 and TDF were generally well tolerated with few adverse events reported. No clinically significant trends in post-dose laboratory abnormalities, vital signs, or electrocardiogram values were noted. Pharmacokinetic parameters of S/GSK1349572 and tenofovir during combination therapy were similar to those when given alone, demonstrating no significant drug interaction. S/GSK1349572 geometric least squares mean ratios (90% confidence interval) for AUC(0-τ), Cmax, and Cτ were 1.01 (0.908, 1.11), 0.969 (0.867, 1.08), and 0.920 (0.816, 1.04), respectively. Tenofovir geometric least squares mean ratios (90% confidence interval) for AUC(0-τ), Cmax, and Cτ were 1.12 (1.01, 1.24), 1.09 (0.974, 1.23), and 1.19 (1.04, 1.35), respectively. Conclusion: S/GSK1349572 and TDF can be coadministered without dose adjustment.

Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study.

BACKGROUNDnThe 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.nnnMETHODSnVIKING-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.nnnRESULTSnThe 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 u2028-1.06 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.nnnCONCLUSIONSnThe 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.

The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects.

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. Design:This was an open-label, parallel-group, 3-period crossover study in healthy adult subjects. Subjects were enrolled into 1 of 2 treatment cohorts (15 subjects/cohort) receiving metformin 500 mg q12h for 5 days in period 1; metformin 500 mg q12h plus dolutegravir 50 mg q24h (cohort 1) or 50 mg q12h (cohort 2) for 7 days in period 2; and metformin 500 mg q12h for 10 days in period 3. There were no washout periods between treatments. Effects of dolutegravir on metformin transport and paracellular permeability were evaluated in vitro. Results:Co-administration of dolutegravir 50 mg q24h increased metformin area under the curve(0–&tgr;) by 79% and Cmax by 66%, whereas dolutegravir 50 mg q12h increased metformin area under the curve(0–&tgr;) and Cmax by 145% and 111%, respectively. Metformin t(1/2) remained unchanged. Increased metformin exposure during dolutegravir co-administration returned to period 1 levels after dolutegravir discontinuation in period 3. Co-administration of dolutegravir and metformin was well tolerated. In vitro, dolutegravir was not a clinically relevant inhibitor of OCT1, OCT3, multidrug and toxin extrusion protein 1, multidrug and toxin extrusion protein 2-K, or plasma membrane monoamine transporter, and it did not affect metformin paracellular permeability or uptake into an intestinal cell line. Conclusions:Dolutegravir significantly increased metformin plasma exposure, which can be partially explained by OCT2 inhibition. It is recommended that dose adjustments of metformin be considered to maintain optimal glycemic control when patients are starting/stopping dolutegravir while taking metformin.

Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics

AIMnTo evaluate potential pharmacogenetic effects of UGT1A1 polymorphisms on the pharmacokinetics (PK) of dolutegravir (Tivicay®; ViiV Healthcare, NC, USA), an HIV-1 integrase inhibitor.nnnPATIENTS & METHODSnAnalysis of pooled data from nine Phase I and II clinical studies was undertaken for 89 subjects receiving repeat dolutegravir 50 mg once daily (tablet formulation) who were genotyped for known UGT1A1 functional variants.nnnRESULTSnGeometric mean ratio (92% CI) for subjects carrying low (*28/*28 and *28/*37) and reduced activity (*1/*6, *1/*28, *1/*37, *28/*36 and *36/*37) polymorphisms compared with subjects with normal activity (*1/*1 and *1/*36) showed decreased oral clearance (CL/F; 0.765 [92% CI: 0.659-0.889]), increased area under the concentration-time curve (AUC(0-τ); 1.307 [1.125-1.518]) and C(max) (1.221 [1.063-1.402]), respectively.nnnCONCLUSIONnIncreased dolutegravir exposure in carriers of UGT1A1 reduced function polymorphisms is not clinically significant based on accumulated safety data so dose adjustment in these individuals is not required.

Pharmacokinetics of Single-Dose Dolutegravir in HIV-Seronegative Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls

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 3u2009hours post‐dose and 1.76 (1.23, 2.51) for unbound fraction at 24u2009hours 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.

Safety and Pharmacokinetics of GSK364735, a Human Immunodeficiency Virus Type 1 Integrase Inhibitor, following Single and Repeated Administration in Healthy Adult Subjects

ABSTRACT GSK364735 is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor with potent in vitro antiviral activity. This study was a double-blind, randomized, placebo-controlled, dose escalation, phase I study to assess single- and repeated-dose safety, tolerability, pharmacokinetics (PK), and food effect of GSK364735 in healthy subjects. In part A, three alternating cohorts of 10 subjects (8 receiving the active drug and 2 receiving a placebo) received single doses of 50 to 400 mg while fasting or 200 mg and 400 mg coadministered with food. In part B, five cohorts received repeated doses of 100 to 600 mg daily coadministered with food for 8 days. Safety was assessed throughout the study. Serial blood samples were analyzed for GSK364735 plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. PK parameters were estimated using noncompartmental methods. Seventy-nine (30 in part A and 49 in part B) subjects were enrolled and received GSK364735 or placebo. GSK364735 was readily absorbed following oral dose administration, with the maximum concentration achieved between 0.75 to 5.0 h postdose. GSK364735 exposure increased less than dose proportionally, demonstrated wide variability, and appeared to reach a plateau at 100- to 200-mg doses. Food increased GSK364735 exposure by 28 to 91%. GSK364735 was safe and well tolerated after single- and repeated-dose administration. No serious or severe adverse events (AEs) or AEs leading to withdrawal and few drug-related AEs were reported. Despite solubility-limited absorption, GSK364735 exceeded therapeutic trough concentrations for the majority of doses studied. The PK and safety profile supported the continued investigation of GSK364735 in HIV-infected subjects.

Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir

PurposeDolutegravir (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.MethodsThe first study was an open-label crossover where 12 subjects received DTG 50xa0mgxa0every 24 hours (q24h) for 5xa0days, followed by DTG 50xa0mg and EFV 600xa0mg q24h for 14xa0days. The second study was an open-label crossover where 18 subjects received DTG 50xa0mgxa0q24h for 5xa0days followed by TPV/r 500/200xa0mg every 12 hours (q12h) for 7xa0days and then DTG 50xa0mg q24h and TPV/r 500/200xa0mg q12h for a further 5xa0days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90xa0% confidence intervals were generated.ResultsThe combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75xa0% in DTG AUC(0–τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76xa0% in DTG AUC(0–τ), Cmax and Cτ, respectively.ConclusionsGiven the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50xa0mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.