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 50 mg) 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 (n = 9 for DTG 2 and 10 mg, n = 10 for DTG 50 mg, and n = 7 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 (P < 0.001), with a mean decrease of 1.51–2.46 log10 copies/ml. In addition, a well characterized dose–response relationship was observed for viral load decrease. Most patients (seven of 10, 70%) receiving DTG 50 mg achieved plasma HIV-1 RNA less than 50 copies/ml. The pharmacokinetic variability was low (coefficient of variation, range 25–50%). Plasma HIV-1 RNA reduction was best predicted by Cτ 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.
aGlaxoSmithKline, Research Triangle Park, North Carolina
bNorth Texas Infectious Disease Consultants PA, Dallas, Texas
cOrlando Immunology Center, Orlando, Florida
dSouthwest CARE Center, Santa Fe, New Mexico
eID Consultants PA, Charlotte, North Carolina, USA
fShionogi & Co. Ltd, Osaka, Japan
gQuest Clinical Research, San Francisco, California, USA.
Correspondence to Sherene Min, MD, MPH, GlaxoSmithKline, Infectious Diseases, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Tel: +1 919 483 7203; fax: +1 919 315 5814; e-mail: firstname.lastname@example.org
Received 4 May, 2011
Revised 15 June, 2011
Accepted 21 June, 2011
The study presented in part at 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, 19–22 July 2009.