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  IAS 2013: 7th IAS Conference on HIV
Pathogenesis Treatment and Prevention
June 30 - July 3 2013
Kuala Lumpur, Malaysia
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High Levels of Two Antiretrovirals With Monthly or Quarterly Injections in Healthy Volunteers: GSK744 LAP + TMC278 LA
  7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
Monthly or quarterly injections of nanosuspension GSK744 (an integrase inhibitor) and TMC278 LA (long-acting injectable rilpivirine) yielded prolonged concentrations above the 90% inhibitory concentration (IC90) for GKS744 and equivalent to concentrations with oral rilpivirine in healthy volunteers. There were no drug-related serious adverse events or grade 3 or 4 lab abnormalities in this first repeat-dose 16-week study of these long-acting injected agents.
Long-acting antiretrovirals could become preferred agents for HIV preexposure prophylaxis (PrEP) as well as for treatment of chronic HIV infection. GlaxoSmithKline and Janssen investigators conducted this trial (clinicaltrials.gov NCT01593046) to assess the safety, tolerability, and pharmacokinetics of GSK744 long-acting parenteral with repeated intramuscular or subcutaneous doses in healthy adults, administered with TMC278 LA injected intramuscularly.
Study participants had to be 18 to 64 years old with a body mass index between 18.5 and 31 kg/m(2). People with behaviors putting them at high risk of HIV infection could not enter the trial.
Everyone took oral GSK744 at 30 mg/day for 14 days, followed by 7 days without drug. Then participants were divided into four cohorts, all starting on day 1 with an 800-mg intramuscular loading dose of GSK744 then randomized to 200 mg subcutaneously at weeks 4, 8, and 12 (cohort 1), 200 mg intramuscularly at weeks 4, 8, and 12 (cohort 2), 400 mg intramuscularly at weeks 4, 8, and 12 (cohort 3), or 800 mg intramuscularly at week 12 (cohort 4). Cohorts 2 and 3 added an intramuscular 1200-mg loading dose of TMC278 at week 8 then received 900 mg intramuscularly at week 12 (cohort 2) or 600 mg intramuscularly at week 12. Treatment continued through week 16, and follow-up will continue for 52 weeks after the last dose.
Among 47 people enrolled, 17 were women and age averaged 39.5. Thirty-five people were white, 10 black, and 2 another race or ethnicity. Seven people withdrew during the oral GSK744 lead-in phase, only 1 because of an adverse event. Three people withdrew during the injection phase, 1 because of an adverse event. All adverse events were mild or moderate.
There were no drug-related serious adverse events or clinically significant trends in lab abnormalities, ECGs, or vital signs. Local injection site reactions were common (80% receiving intramuscular GSK744, 100% receiving subcutaneous GSK744, and 95% receiving intramuscular TMC278) but usually well tolerated and self-limited.
With either the 4-week or 12-week GSK744 regimen, plasma concentrations of the drug exceeded 4 times the protein binding-adjusted IC90. Rilpivirine plasma concentrations after intramuscular injection of TMC278 LA were comparable to concentrations achieved by HIV-positive people taking 25 mg of oral rilpivirine daily.
GSK744 area under the concentration-time curve (AUC) was 1210 ug x h/mL in cohort 1 (monthly dosing), 1320 ug x h/mL in cohort in cohort 2 (monthly dosing), 2440 ug x h/mL in cohort 3 (monthly dosing), and 3000 ug x h/mL in cohort 4 (quarterly dosing). Respective GSK744 trough concentrations were 1.68, 1.93, 3.33, and 1.08 ug/mL. TMC278 AUC was 75.9 ug x h/mL in cohort 2 and 66.7 ug x h/mL in cohort 3. Respective trough concentrations were 0.09 and 0.09 ug/mL.
The investigators concluded that intramuscular injections of GSK744 every 4 weeks or quarterly will yield plasma concentrations well above the protein binding-adjusted IC90 for this integrase inhibitor. Monthly injections of TMC278 LA, they added, will yield plasma concentrations comparable to those attained with the approved oral dose of this nonnucleoside. Ongoing studies include evaluation of these two agents administered orally as a maintenance regimen for HIV-positive people. Pending results of that trial, injection of long-acting nanosuspensions of these antiretrovirals may be tested in people with HIV.
1. Spreen W, Williams P, Margolis D, et al. First study of repeat dose co-administration of GSK1265744 and TMC278 long-acting parenteral nanosuspensions: pharmacokinetics, safety and tolerability in healthy adults. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract WEAB0103. http://www.natap.org/2013/IAS/IAS_36.htm