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Article: Pharmacokinetics of LB80331 and LB80317 following oral administration of LB80380, a new antiviral agent for chronic hepatitis B (CHB), in healthy adult subjects, CHB patients, and mice
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TitlePharmacokinetics of LB80331 and LB80317 following oral administration of LB80380, a new antiviral agent for chronic hepatitis B (CHB), in healthy adult subjects, CHB patients, and mice
 
AuthorsYuen, MF1 1
Lee, SH4
Kang, HM2
Chung, RK2
Kim, J2 3
Ngai, V1
Lai, CL1
 
Issue Date2009
 
CitationAntimicrobial Agents And Chemotherapy, 2009, v. 53 n. 5, p. 1779-1785 [How to Cite?]
DOI: http://dx.doi.org/10.1128/AAC.01290-08
 
AbstractLB80380, a dipivoxil ester prodrug of LB80331 (metabolite, LB80317), is a novel antiviral agent for chronic hepatitis B (CHB). The pharmacokinetics of LB80331/LB80317 were evaluated in two clinical studies and a study with mice. The clinical studies were dose-escalating pharmacokinetic studies with six healthy subjects per single-dose group and six CHB patients per repeated-dose group. The mouse study was designed to measure the amounts of the phosphorylated portions of LB80331 and LB80317 in the liver. In healthy subjects receiving a single dose of LB80380, the plasma level of LB80331 increased as the dose increased. Although a high-fat diet delayed the time to the maximum concentration in plasma (Tmax) of LB80331, the area under the concentration-time curve from time zero to infinity was similar between the subjects in the fasted group and those in the group who consumed a high-fat diet. In CHB patients, the mean Tmax of LB80331 was 1.0 to 2.0 h postdosing at steady state. The steady-state plasma concentration of LB80331 declined in a monoexponential manner, and the apparent elimination half-life was 2.5 to 3.3 h. The steady-state plasma concentration of LB80317 was maximum at 3 to 8 h postdoing and declined in a monoexponential manner; the apparent elimination half-life was 45 to 62 h at the 30- to 240-mg doses, while LB80317 was measurable in plasma only at higher doses of 120 and 240 mg after the administration of the first dose of LB80380. Forty percent of the amount of LB80331/LB80317 in the mouse liver was detected as the phosphorylated form. In conclusion, LB80380 is rapidly absorbed and converted to LB80331. LB80317 has a long half-life at steady-state, supporting the use of a once-daily dosing regimen. The ingestion of a high-fat diet delays the rate of absorption of LB80380 without affecting the extent of absorption. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
 
ISSN0066-4804
2012 Impact Factor: 4.565
2012 SCImago Journal Rankings: 1.963
 
DOIhttp://dx.doi.org/10.1128/AAC.01290-08
 
ISI Accession Number IDWOS:000265528700009
Funding AgencyGrant Number
LG Life Sciences, Ltd
Funding Information:

This study was sponsored by LG Life Sciences, Ltd.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorYuen, MF
 
dc.contributor.authorLee, SH
 
dc.contributor.authorKang, HM
 
dc.contributor.authorChung, RK
 
dc.contributor.authorKim, J
 
dc.contributor.authorNgai, V
 
dc.contributor.authorLai, CL
 
dc.date.accessioned2010-05-31T03:48:23Z
 
dc.date.available2010-05-31T03:48:23Z
 
dc.date.issued2009
 
dc.description.abstractLB80380, a dipivoxil ester prodrug of LB80331 (metabolite, LB80317), is a novel antiviral agent for chronic hepatitis B (CHB). The pharmacokinetics of LB80331/LB80317 were evaluated in two clinical studies and a study with mice. The clinical studies were dose-escalating pharmacokinetic studies with six healthy subjects per single-dose group and six CHB patients per repeated-dose group. The mouse study was designed to measure the amounts of the phosphorylated portions of LB80331 and LB80317 in the liver. In healthy subjects receiving a single dose of LB80380, the plasma level of LB80331 increased as the dose increased. Although a high-fat diet delayed the time to the maximum concentration in plasma (Tmax) of LB80331, the area under the concentration-time curve from time zero to infinity was similar between the subjects in the fasted group and those in the group who consumed a high-fat diet. In CHB patients, the mean Tmax of LB80331 was 1.0 to 2.0 h postdosing at steady state. The steady-state plasma concentration of LB80331 declined in a monoexponential manner, and the apparent elimination half-life was 2.5 to 3.3 h. The steady-state plasma concentration of LB80317 was maximum at 3 to 8 h postdoing and declined in a monoexponential manner; the apparent elimination half-life was 45 to 62 h at the 30- to 240-mg doses, while LB80317 was measurable in plasma only at higher doses of 120 and 240 mg after the administration of the first dose of LB80380. Forty percent of the amount of LB80331/LB80317 in the mouse liver was detected as the phosphorylated form. In conclusion, LB80380 is rapidly absorbed and converted to LB80331. LB80317 has a long half-life at steady-state, supporting the use of a once-daily dosing regimen. The ingestion of a high-fat diet delays the rate of absorption of LB80380 without affecting the extent of absorption. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationAntimicrobial Agents And Chemotherapy, 2009, v. 53 n. 5, p. 1779-1785 [How to Cite?]
DOI: http://dx.doi.org/10.1128/AAC.01290-08
 
dc.identifier.doihttp://dx.doi.org/10.1128/AAC.01290-08
 
dc.identifier.epage1785
 
dc.identifier.hkuros161054
 
dc.identifier.isiWOS:000265528700009
Funding AgencyGrant Number
LG Life Sciences, Ltd
Funding Information:

This study was sponsored by LG Life Sciences, Ltd.

 
dc.identifier.issn0066-4804
2012 Impact Factor: 4.565
2012 SCImago Journal Rankings: 1.963
 
dc.identifier.issue5
 
dc.identifier.pmid19223649
 
dc.identifier.scopuseid_2-s2.0-66149096185
 
dc.identifier.spage1779
 
dc.identifier.urihttp://hdl.handle.net/10722/59358
 
dc.identifier.volume53
 
dc.languageeng
 
dc.publisher.placeUnited States
 
dc.relation.ispartofAntimicrobial Agents and Chemotherapy
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAdministration, Oral
 
dc.subject.meshAdolescent
 
dc.subject.meshAdult
 
dc.subject.meshAnimals
 
dc.subject.meshClinical Trials, Phase I as Topic
 
dc.subject.meshClinical Trials, Phase II as Topic
 
dc.subject.meshDose-Response Relationship, Drug
 
dc.subject.meshDouble-Blind Method
 
dc.subject.meshFemale
 
dc.subject.meshHepacivirus - drug effects
 
dc.subject.meshHepatitis B, Chronic - drug therapy - virology
 
dc.subject.meshHumans
 
dc.subject.meshLiver - metabolism
 
dc.subject.meshMale
 
dc.subject.meshMice
 
dc.subject.meshMiddle Aged
 
dc.subject.meshNucleotides - administration & dosage - adverse effects - chemistry - pharmacokinetics
 
dc.subject.meshProdrugs - administration & dosage - adverse effects - metabolism - pharmacokinetics
 
dc.subject.meshRandomized Controlled Trials as Topic
 
dc.subject.meshTreatment Outcome
 
dc.subject.meshYoung Adult
 
dc.titlePharmacokinetics of LB80331 and LB80317 following oral administration of LB80380, a new antiviral agent for chronic hepatitis B (CHB), in healthy adult subjects, CHB patients, and mice
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Antenna Department of Research and Development
  3. Sungkyunkwan University
  4. Drug Metabolism and Pharmacokinetics Department