PMID- 19884365
OWN - NLM
STAT- MEDLINE
DCOM- 20100315
LR  - 20220318
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 54
IP  - 1
DP  - 2010 Jan
TI  - Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase 
      inhibitor, in healthy volunteers.
PG  - 254-8
LID - 10.1128/AAC.00842-09 [doi]
AB  - S/GSK1349572 is a novel integrase inhibitor with potent in vitro anti-HIV 
      activity, an in vitro resistance profile different from those of other integrase 
      inhibitors, and favorable preclinical safety and pharmacokinetics (PK). 
      Randomized, double-blind, placebo-controlled single-dose and multiple-dose, dose 
      escalation studies evaluated the PK, safety, and tolerability of S/GSK1349572 for 
      healthy subjects. In the single-dose study, two cohorts of 10 subjects each (8 
      active, 2 receiving placebo) received suspension doses of 2, 5, 10, 25, 50, and 
      100 mg in an alternating panel design. In the multiple-dose study, three cohorts 
      of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 
      10, 25, and 50 mg once daily for 10 days. A cytochrome P450 3A (CYP3A) substudy 
      with midazolam was conducted with the 25-mg dose. Laboratory testing, vital 
      signs, electrocardiograms (ECGs), and PK sampling were performed at regular 
      intervals. S/GSK1349572 was well tolerated. Most adverse events (AEs) were mild, 
      with a few moderate AEs reported. Headache was the most common AE. No clinically 
      significant laboratory trends or ECG changes were noted. PK was linear over the 
      dosage range studied. The steady-state geometric mean area under the 
      concentration-time curve over a dosing interval (AUC(0-tau)) and maximum 
      concentration of the drug in plasma (C(max)) ranged from 16.7 microg.h/ml 
      (coefficient of variation [CV], 15%) and 1.5 microg/ml (CV, 24%) at a 10-mg dose 
      to 76.8 microg.h/ml (CV, 19%) and 6.2 microg/ml (CV, 15%) at a 50-mg dose, 
      respectively. The geometric mean steady-state concentration at the end of the 
      dosing interval (C(tau)) with a 50-mg dose was 1.6 microg/ml, approximately 
      25-fold higher than the protein-adjusted 90% inhibitory concentration (0.064 
      microg/ml). The half-life was approximately 15 h. S/GSK1349572 had no impact on 
      midazolam exposure, indicating that it does not modulate CYP3A activity. The PK 
      profile suggests that once-daily, low milligram doses will achieve therapeutic 
      concentrations.
FAU - Min, Sherene
AU  - Min S
AD  - Infectious Diseases MDC, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, 
      NC 27709, USA.
FAU - Song, Ivy
AU  - Song I
FAU - Borland, Julie
AU  - Borland J
FAU - Chen, Shuguang
AU  - Chen S
FAU - Lou, Yu
AU  - Lou Y
FAU - Fujiwara, Tamio
AU  - Fujiwara T
FAU - Piscitelli, Stephen C
AU  - Piscitelli SC
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20091102
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (HIV Integrase Inhibitors)
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - 0 (Oxazines)
RN  - 0 (Piperazines)
RN  - 0 (Pyridones)
RN  - DKO1W9H7M1 (dolutegravir)
SB  - IM
MH  - Adult
MH  - Area Under Curve
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - HIV Integrase Inhibitors/administration & dosage/*adverse 
      effects/*pharmacokinetics
MH  - Headache/chemically induced
MH  - Heterocyclic Compounds, 3-Ring/administration & dosage/*adverse 
      effects/*pharmacokinetics
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Oxazines
MH  - Piperazines
MH  - Pyridones
MH  - Sleep Stages/drug effects
MH  - Young Adult
PMC - PMC2798521
EDAT- 2009/11/04 06:00
MHDA- 2010/03/17 06:00
PMCR- 2009/11/02
CRDT- 2009/11/04 06:00
PHST- 2009/11/04 06:00 [entrez]
PHST- 2009/11/04 06:00 [pubmed]
PHST- 2010/03/17 06:00 [medline]
PHST- 2009/11/02 00:00 [pmc-release]
AID - AAC.00842-09 [pii]
AID - 0842-09 [pii]
AID - 10.1128/AAC.00842-09 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2010 Jan;54(1):254-8. doi: 10.1128/AAC.00842-09. 
      Epub 2009 Nov 2.