| The Optimal Dose of Potent Experimental Anti-HBV Drug Clevudine Appears to Be >10 mg Once Daily
Clevudine (CLV, L-FMAU) is a potent inhibitor of Hepatitis B virus (HBV) replication in vitro. In woodchucks and in a Phase I/II clinical study, CLV produced a potent and sustained viral suppression following a 4-week dosing period.
This was a multicenter, international, randomized, double-blind study comparing 10, 30 and 50 mg CLV once daily (QD) for 12 weeks. Patients were followed post-treatment for at least 24 weeks.
Eligible patients had chronic HBV infection with Baseline serum HBV DNA levels (VL) ≥ 3x106 copies/mL (c/mL) as measured by the Chiron Quantiplex?assay, and were nucleoside treatment-na飗e without HIV, HDV or HCV co-infection.
VL was assayed using Digene Hybrid Capture II (lower limit of detection of 4700 c/mL) and genotypic analysis of Baseline, Week 12 and Week 26 samples was performed using di-deoxy sequencing.
Results
Thirty-one patients were enrolled (10, 11 and 10 in the 10, 30 and 50 mg cohorts, respectively) of whom 55% were male, 84% Asian, and 81% HBeAg positive.
At Baseline, median VL was 8.7, 7.9, and 8.7 log10 c/mL and median alanine aminotransferase (ALT) level was 53, 63, and 80 IU/L in the 10, 30 and 50 mg CLV cohorts, respectively.
After 12 weeks of dosing, the median log10 VL change from Baseline was -3.2, -3.7 and -4.2 log10 c/mL in the 10, 30, and 50 mg cohorts, respectively (P=0.012 for trend). One out of 10, 5/11 and 2/10 patients had VL below the assay LOD at Week 12 in the 10, 30, and 50 mg cohorts, respectively.
Only 2 patients seroconverted to anti-HBe (both in the 30mg cohort). CLV was generally well tolerated without dose related adverse events, and no severe or serious adverse events.
One patient reported a transient Grade 3 increase in ALT and another a transient Grade 3 creatine phosphokinase increase, both while on study drug. The pharmacokinetics of CLV were dose proportional with a mean plasma half-life of 70 hours.
Pharmacodynamic modeling shows that 97% of the maximal treatment effect was reached with a dose of 30 mg QD.
Conclusion
The authors conclude, 揟hese preliminary results confirm the potent antiviral activity of once daily clevudine and further demonstrate the tolerability of the drug over 12 weeks of dosing. Based on these results, the optimal dose of clevudine appears to be >10 mg QD.?/font>
11/05/04
Reference
P Marcellin and others. A PHASE II, RANDOMIZED TRIAL EVALUATING THE SAFETY, PHARMACOKINETICS AND ANTIVIRAL ACTIVITY OF CLEVUDINE FOR 12 WEEKS IN PATIENTS WITH CHRONIC HEPATITIS B. Abstract 1129 (poster). 55th AASLD. | 
发表于 2004-11-6 07:40
