PMID- 17923489
OWN - NLM
STAT- MEDLINE
DCOM- 20080424
LR  - 20211020
IS  - 0066-4804 (Print)
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Linking)
VI  - 51
IP  - 12
DP  - 2007 Dec
TI  - Safety and pharmacokinetics of GSK364735, a human immunodeficiency virus type 1 
      integrase inhibitor, following single and repeated administration in healthy 
      adult subjects.
PG  - 4284-9
AB  - 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.
FAU - Reddy, Y Sunila
AU  - Reddy YS
AD  - GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709, USA.
FAU - Min, Sherene S
AU  - Min SS
FAU - Borland, Julie
AU  - Borland J
FAU - Song, Ivy
AU  - Song I
FAU - Lin, Jiang
AU  - Lin J
FAU - Palleja, Sandra
AU  - Palleja S
FAU - Symonds, William T
AU  - Symonds WT
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20071008
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (HIV Integrase Inhibitors)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Area Under Curve
MH  - Cohort Studies
MH  - Dizziness/chemically induced
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - Food
MH  - HIV Integrase Inhibitors/administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - HIV-1/*drug effects
MH  - Headache/chemically induced
MH  - Humans
MH  - Male
MH  - Middle Aged
PMC - PMC2167967
EDAT- 2007/10/10 09:00
MHDA- 2008/04/25 09:00
PMCR- 2008/04/01
CRDT- 2007/10/10 09:00
PHST- 2007/10/10 09:00 [pubmed]
PHST- 2008/04/25 09:00 [medline]
PHST- 2007/10/10 09:00 [entrez]
PHST- 2008/04/01 00:00 [pmc-release]
AID - AAC.00716-07 [pii]
AID - 0716-07 [pii]
AID - 10.1128/AAC.00716-07 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2007 Dec;51(12):4284-9. doi: 10.1128/AAC.00716-07. 
      Epub 2007 Oct 8.