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, MF2
Lee, SH4
Kang, HM1
Chung, RK1
Kim, J1 3
Ngai, V2
Lai, CL2
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
2011 Impact Factor: 4.841
2011 SCImago Journal Rankings: 0.486
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 Field
Value
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
2011 Impact Factor: 4.841
2011 SCImago Journal Rankings: 0.486
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
Author Affiliations
  1. Antenna Department of Research and Development
  2. The University of Hong Kong
  3. Sungkyunkwan University
  4. Drug Metabolism and Pharmacokinetics Department