Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B.
BACKGROUND
Clevudine is a polymerase inhibitor that has the unusual feature of delayed viral rebound after therapy in some patients which may be related to its pharmacokinetics.


OBJECTIVE
To characterize pharmacokinetic and pharmacodynamic profile of clevudine, a potent hepatitis B polymerase inhibitor.


METHODS
A multicenter, randomized study comparing 10, 30 and 50 mg clevudine once daily for 12 weeks with 24 weeks off-treatment follow-up. Patients had chronic HBV infection, were nucleoside-naïve without co-infection. HBV viral load (VL) was assayed using Digene Hybrid Capture II with a lower limit of detection of 4700 copies/mL (940 IU/mL). Clevudine levels were measured using a liquid chromatography/mass spectrometery method.


RESULTS
A total of 31 patients were enrolled into the 10 mg (n = 10), 30 mg (n = 11) and 50 mg (n = 10) groups, respectively. At week 12, the median VL change was -3.2, -3.7 and -4.2 log(10) copies/mL (-0.64, -0.74 and -0.84 log(10) IU/mL) in the 10, 30 and 50 mg groups, respectively (P = 0.012). At week 12, one of 10, five of 11 and two of 10 patients had VL below the assay lower limit of detection. Clevudine was well tolerated with no severe/serious adverse events. The mean plasma half-life of clevudine was 70 h and consequently is not the cause of the delayed viral rebound seen in some patients. Through modelling, 97% of the maximal treatment effect was reached with a 30 mg daily dose. Six patients had genomic changes without viral rebound.


CONCLUSIONS
Clevudine appears to be a potent and tolerable (over 12 weeks) anti-viral and the optimal dosage appears to be 30 mg once daily.
Lim
S G
SG
Department of Gastroenterology and Hepatology, National University Hospital, Yong Yoo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Rd, Singapore 119074. mdclimsg@nus.edu.sg
Leung
N
N
Hann
H W L
HW
Lau
G K K
GK
Trepo
C
C
Mommeja-Marin
H
H
Moxham
C
C
Sorbel
J
J
Snow
A
A
Blum
M R
MR
Rousseau
F
F
Marcellin
P
P
D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000187:drug effects; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D000914:Antibodies, Viral; D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C034935:clevudine