Viral dynamics and pharmacokinetics in combined interferon alfa-2b and ribavirin therapy for patients infected with hepatitis C virus of genotype 1b and high pretreatment viral load.
OBJECTIVE
The aim of this study was to clarify the viral dynamics and single- and multiple-dose pharmacokinetics of ribavirin and interferon (IFN) alfa-2b in the virologic response to combination therapy with both compounds in patients infected with hepatitis C virus (HCV) genotype 1b and high viral load.


METHODS
Fourteen patients received high-dose daily induction therapy followed by intermittent maintenance therapy with IFN alfa-2b and daily oral ribavirin for 24 weeks, and followed up for 24 weeks after treatment. Single- and multiple-dose pharmacokinetic studies and viral dynamics were assessed by serial measurements of serum concentrations of both compounds and HCV RNA, respectively, at weeks 1 and 24.


RESULTS
During treatment, all 14 patients showed biochemical response (i.e., normalization of serum alanine transaminase activity), while 11 showed virologic response (i.e., undetectable serum HCV RNA level by qualitative polymerase chain reaction assay). Sustained biochemical and virologic response after cessation of treatment was noted in 8 and 2 patients, respectively. Serum ribavirin concentrations asymptoted by 4 weeks of treatment. Serum ribavirin concentrations in steady state, and maximum concentration and accumulation rate of ribavirin after multiple dosing were significantly higher in the presence of sustained virologic response. HCV-related parameters were not significantly associated with sustained virologic response.


CONCLUSIONS
Continuous exposure and tissue accumulation of ribavirin may be necessary for sustained virologic response to combination therapy in chronic hepatitis C with genotype 1b and high viral load. Pharmacokinetic analysis of ribavirin provides information on its mechanism of action and for developing more rational treatment for IFN-resistant HCV.
Tsubota
Akihito
A
Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan. ZUA05135@nifty.com
Akuta
Norio
N
Suzuki
Fumitaka
F
Suzuki
Yoshiyuki
Y
Someya
Takahi
T
Kobayashi
Masahiro
M
Arase
Yasuji
Y
Saitoh
Satoshi
S
Ikeda
Kenji
K
Kumada
Hiromitsu
H
D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019562:Viral Load
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin