RESUMEN
UNLABELLED: We aimed to determine the antiviral activity and safety of a new nucleotide analogue, LB80380, in chronic hepatitis B (CHB) patients with lamivudine-resistant virus. Sixty-five patients with lamivudine-resistant virus were randomized to receive five ascending daily doses (30, 60, 90, 150, 240 mg) of LB80380. LB80380 was given together with lamivudine for the first 4 weeks, followed by 8 weeks of LB80380 monotherapy. This was then followed by 24 weeks of adefovir. Hepatitis B virus (HBV) DNA levels, serology, liver biochemistry, and safety were monitored. The extent of the HBV DNA reduction at week 12 was dose-dependent. The mean reduction from baseline was 2.81, 3.21, 3.92, 4.16, and 4.00 log(10) copies/mL for the five ascending dose groups. The dose-proportionate effect was statistically significant (P < 0.001) with a decrease of HBV DNA levels by an average of 1.54 log(10) copies/mL for every 1-unit increase in log(10) dose of LB80380. In 93.4% of patients, HBV DNA decreased by >2 log(10) copies/mL, and 11.5% of patients had undetectable HBV DNA levels (<300 copies/mL) by week 12. HBV DNA suppression was maintained during the 24 weeks of adefovir treatment. Hepatitis B e antigen seroconversion and normalization of alanine aminotransferase were seen in 14.6% and 24.6% of patients, respectively, at week 12; 44.6% of patients experienced mild and self-limiting adverse events, none of which were attributed to the study drug. CONCLUSION: LB80380 at doses of up to 240 mg is safe, well tolerated, and effective at reducing viral load in CHB patients with lamivudine-resistant virus for a period of 12 weeks.
Asunto(s)
Guanina/análogos & derivados , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/inmunología , Organofosfonatos/uso terapéutico , Adulto , ADN Viral/sangre , Farmacorresistencia Viral , Femenino , Guanina/efectos adversos , Guanina/uso terapéutico , Virus de la Hepatitis B/genética , Hepatitis B Crónica/sangre , Humanos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Organofosfonatos/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto JovenRESUMEN
LB80380, 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 (T(max)) 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 T(max) 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.
Asunto(s)
Hepacivirus/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Nucleótidos/farmacocinética , Profármacos/farmacocinética , Administración Oral , Adolescente , Adulto , Animales , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Hepatitis B Crónica/virología , Humanos , Hígado/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Nucleótidos/administración & dosificación , Nucleótidos/efectos adversos , Nucleótidos/química , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: LB80380 is potent antiviral agent against hepatitis B virus (HBV) in vitro and in the woodchuck model. It has an excellent preclinical safety profile including lower potential for renal toxicity than adefovir. It is effective against both wild-type and YMDD mutant HBV. LB80380 is converted to its parent drug, LB80331, after oral absorption, and further metabolized to its active form, LB80317. AIMS/METHODS: This randomized placebo-controlled Phase I/II clinical study of LB80380 was conducted to assess the safety, antiviral activity and pharmacokinetics of its parent drug LB80331 and its active form LB80317 in 29 Asian adults with chronic hepatitis B positive for hepatitis B e antigen in four escalating dose groups (30, 60, 120 and 240 mg once per day) for 4 weeks with a 12-week follow-up period. RESULTS: The mean maximum HBV DNA reduction was 3.05, 4.20, 3.67 and 3.68 log10 copies/ml for 30, 60, 120 and 240 mg per day, respectively. Viral dynamic analysis suggested a high degree of inhibition of HBV replication at doses of 60 mg or higher per day. LB80380 was well tolerated at all dose groups, and no dose-related clinical or laboratory adverse event was reported. CONCLUSION: LB80380 is shown to be a potent and safe antiviral agent for HBV. Marked HBV DNA suppression was observed in all dose groups. The HBV DNA suppression was approximately constant at doses of 60 mg and higher over the 28-day dosing period. The dose response of LB80380 will be evaluated further in large clinical studies.