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

Abstract

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.

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

“…85 Interestingly, the absorption of the prodrug was delayed by high fat diet. 85 Initial data in mice showed that ca. 40% of the active metabolite was generated in the liver.…”

Pharmacokinetic evaluation of besifovir for the treatment of HBV infection

“…The t 1/2 is much longer (45 -62 hours) compared to LB80331. The AUC and C max between LB80317 and LB80331 correlate strongly (r=0.9181 and r=0.8998, respectively) [12]. The pharmacokinetic parameters of LB80331 and LB80317 following single dose and multiple doses administration are summarized in Table 2 and Table 3, respectively.…”

“…The pharmacokinetics of besifovir in human were illustrated in two phase I studies [11,12]. Since LB80380 is a prodrug and is not detected in plasma, its metabolites namely LB80331 (intermediate metabolite) and LB80317 (the active metabolite) were measured.…”

HBV life cycle and novel drug targets

“…Clinical trials with clevudine, a newer pyrimidine nucleoside that was already approved in some Asian countries, have been stopped in 2009 because myopathy was reported in a number of patients [35][36][37]. Prodrugs that are selectively metabolized and activated in the liver, as for example, LB80380 (similar to adefovir and tenofovir) are currently being tested [38][39][40][41]. Apart from that, an acyclic pyrimidine nucleoside phosphate named PMEO-DAPym represents the prototype compound of a novel class of pyrimidine acyclic nucleoside phosphonates that are recognized as a purine nucleotide [42].…”