Safety and Efficacy of GSK2248761, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Treatment-Naive HIV-1-Infected Subjects

• Published in: Antimicrobial Agents and Chemotherapy 2012-05, Vol.56 (5), p.2570-2575
• Main Authors: Zala, Carlos, St. Clair, Marty, Dudas, Kathleen, Kim, Joseph, Lou, Yu, White, Scott, Piscitelli, Steve, Dumont, Etienne, Pietropaolo, Keith, Zhou, Xiao-Jian, Mayers, Douglas
• Format: Article
• Language: English
• Subjects: Adult; Anti-HIV Agents; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral activity; Antiviral Agents; antiviral properties; Argentina; Benzoxazines; Biological and medical sciences; blood serum; Development; dose response; Dose-response effects; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Viral; drug therapy; Drug-Related Side Effects and Adverse Reactions; enzyme inhibitors; Female; HIV Infections; HIV Infections - drug therapy; HIV Infections - virology; HIV Reverse Transcriptase; HIV Reverse Transcriptase - antagonists & inhibitors; HIV-1; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Human immunodeficiency virus; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Indoles; Indoles - administration & dosage; Indoles - chemical synthesis; Indoles - therapeutic use; Infectious diseases; Male; Medical sciences; Mutation; non-nucleoside reverse transcriptase inhibitors; Pharmacokinetics; Pharmacology. Drug treatments; Phosphinic Acids; Phosphinic Acids - administration & dosage; Phosphinic Acids - chemical synthesis; Phosphinic Acids - therapeutic use; Placebos; Reverse Transcriptase Inhibitors; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - therapeutic use; RNA-directed DNA polymerase; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; viral load; Viral Load - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.05597-11

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log10 copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [Cmax], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC0-τ], and concentration at the end of the dosing interval [Cτ]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (Emax) model using Cτ (Emax = 2.0; 50% effective concentration [EC50] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.