PMID- 21060109
OWN - NLM
STAT- MEDLINE
DCOM- 20110502
LR  - 20211020
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 55
IP  - 1
DP  - 2011 Jan
TI  - Safety and pharmacokinetics of IDX184, a liver-targeted nucleotide polymerase 
      inhibitor of hepatitis C virus, in healthy subjects.
PG  - 76-81
LID - 10.1128/AAC.01101-10 [doi]
AB  - IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the 
      active triphosphate of 2'-methylguanosine (2'-MeG), a potent and specific 
      polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single 
      ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered 
      sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. 
      Plasma and urine pharmacokinetic sampling was performed over a period of 120 h 
      after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a 
      mean half-life (t(1/2)) of approximately 1 h, while plasma concentrations of 
      2'-MeG gradually increased. Consistent with a liver-targeting approach, plasma 
      exposure of IDX184 and 2'-MeG was low and was also dose related: the mean maximum 
      concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 
      2'-MeG, and the respective mean total area under the curve ranged from 1.2 to 
      22.7 and 17.3 to 334 ng.h/ml. Mean 2'-MeG plasma concentrations 24 h after dosing 
      were 0.6 to 3 ng/ml for the 25- to 100-mg doses. Mean 2'-MeG t(1/2) values ranged 
      from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 
      0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2'-MeG, 
      respectively. IDX184 was safe and well tolerated; no serious adverse events 
      (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were 
      observed. The incidence of AEs and laboratory abnormalities was low and was 
      similar among subjects receiving IDX184 or a placebo. All AEs were mild to 
      moderate and resolved at the end of study. The favorable safety and 
      pharmacokinetic profiles support further clinical evaluation of IDX184 in 
      HCV-infected patients.
FAU - Zhou, Xiao-Jian
AU  - Zhou XJ
AD  - Idenix Pharmaceuticals Inc., Cambridge, MA 02139, USA. zhou.xj@idenix.com
FAU - Pietropaolo, Keith
AU  - Pietropaolo K
FAU - Chen, Jie
AU  - Chen J
FAU - Khan, Samina
AU  - Khan S
FAU - Sullivan-Bolyai, John
AU  - Sullivan-Bolyai J
FAU - Mayers, Douglas
AU  - Mayers D
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20101108
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Antiviral Agents)
RN  - 0 (IDX184)
RN  - 0 (Placebos)
RN  - 85-32-5 (Guanosine Monophosphate)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antiviral Agents/adverse effects/*pharmacokinetics/*therapeutic use
MH  - Female
MH  - Guanosine Monophosphate/adverse effects/*analogs & 
      derivatives/pharmacokinetics/therapeutic use
MH  - Hepacivirus/drug effects/*enzymology
MH  - Hepatitis C/blood/*drug therapy/*virology
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Placebos
MH  - Young Adult
PMC - PMC3019633
EDAT- 2010/11/10 06:00
MHDA- 2011/05/03 06:00
PMCR- 2010/11/08
CRDT- 2010/11/10 06:00
PHST- 2010/11/10 06:00 [entrez]
PHST- 2010/11/10 06:00 [pubmed]
PHST- 2011/05/03 06:00 [medline]
PHST- 2010/11/08 00:00 [pmc-release]
AID - AAC.01101-10 [pii]
AID - 1101-10 [pii]
AID - 10.1128/AAC.01101-10 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2011 Jan;55(1):76-81. doi: 10.1128/AAC.01101-10. 
      Epub 2010 Nov 8.