Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects.
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 log(10) copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C(max)], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC(0-τ)], and concentration at the end of the dosing interval [C(τ)]) 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 (E(max)) model using C(τ) (E(max) = 2.0; 50% effective concentration [EC(50)] = 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.
ACLIRES International, Ltd, Hospital Privado Modelo, Buenos Aires, Argentina. zalacarlos@gmail.com
Carlos
C
Zala
Marty
M
St Clair
Kathleen
K
Dudas
Joseph
J
Kim
Yu
Y
Lou
Scott
S
White
Steve
S
Piscitelli
Etienne
E
Dumont
Keith
K
Pietropaolo
Xiao-Jian
XJ
Zhou
Douglas
D
Mayers
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D001118:Argentina; D048588:Benzoxazines; D003521:Cyclopropanes; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D010919:Placebos; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C534138:IDX 899; D007211:Indoles; D010721:Phosphinic Acids; D010919:Placebos; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz