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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

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
Authors
Issue Date2009
Citation
Antimicrobial Agents And Chemotherapy, 2009, v. 53 n. 5, p. 1779-1785 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/59358
ISSN
2014 Impact Factor: 4.476
2014 SCImago Journal Rankings: 2.005
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
LG Life Sciences, Ltd
Funding Information:

This study was sponsored by LG Life Sciences, Ltd.

References

 

DC FieldValueLanguage
dc.contributor.authorYuen, MFen_HK
dc.contributor.authorLee, SHen_HK
dc.contributor.authorKang, HMen_HK
dc.contributor.authorChung, RKen_HK
dc.contributor.authorKim, Jen_HK
dc.contributor.authorNgai, Ven_HK
dc.contributor.authorLai, CLen_HK
dc.date.accessioned2010-05-31T03:48:23Z-
dc.date.available2010-05-31T03:48:23Z-
dc.date.issued2009en_HK
dc.identifier.citationAntimicrobial Agents And Chemotherapy, 2009, v. 53 n. 5, p. 1779-1785en_HK
dc.identifier.issn0066-4804en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59358-
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.en_HK
dc.languageengen_HK
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen_HK
dc.subject.meshAdministration, Oralen_HK
dc.subject.meshAdolescenten_HK
dc.subject.meshAdulten_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshClinical Trials, Phase I as Topicen_HK
dc.subject.meshClinical Trials, Phase II as Topicen_HK
dc.subject.meshDose-Response Relationship, Drugen_HK
dc.subject.meshDouble-Blind Methoden_HK
dc.subject.meshFemaleen_HK
dc.subject.meshHepacivirus - drug effectsen_HK
dc.subject.meshHepatitis B, Chronic - drug therapy - virologyen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLiver - metabolismen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMiddle Ageden_HK
dc.subject.meshNucleotides - administration & dosage - adverse effects - chemistry - pharmacokineticsen_HK
dc.subject.meshProdrugs - administration & dosage - adverse effects - metabolism - pharmacokineticsen_HK
dc.subject.meshRandomized Controlled Trials as Topicen_HK
dc.subject.meshTreatment Outcomeen_HK
dc.subject.meshYoung Adulten_HK
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 miceen_HK
dc.typeArticleen_HK
dc.identifier.emailYuen, MF:mfyuen@hkucc.hku.hken_HK
dc.identifier.emailLai, CL:hrmelcl@hku.hken_HK
dc.identifier.authorityYuen, MF=rp00479en_HK
dc.identifier.authorityLai, CL=rp00314en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1128/AAC.01290-08en_HK
dc.identifier.pmid19223649en_HK
dc.identifier.pmcidPMC2681521-
dc.identifier.scopuseid_2-s2.0-66149096185en_HK
dc.identifier.hkuros161054en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-66149096185&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume53en_HK
dc.identifier.issue5en_HK
dc.identifier.spage1779en_HK
dc.identifier.epage1785en_HK
dc.identifier.isiWOS:000265528700009-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYuen, MF=7102031955en_HK
dc.identifier.scopusauthoridLee, SH=26643533500en_HK
dc.identifier.scopusauthoridKang, HM=15725582900en_HK
dc.identifier.scopusauthoridChung, RK=35209793200en_HK
dc.identifier.scopusauthoridKim, J=37106935700en_HK
dc.identifier.scopusauthoridNgai, V=15061738300en_HK
dc.identifier.scopusauthoridLai, CL=7403086396en_HK

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