Pharmacokinetics and enhanced PKR response in patients with chronic hepatitis C treated with pegylated interferon alpha-2b and ribavirin.
This study investigated the molecular and pharmacokinetic mechanisms of the enhanced antiviral efficacy associated with pegylated interferon (PEG-IFN) alpha-2b and ribavirin. The study involved comparing the expression of serial double-stranded RNA-activated protein kinase (PKR) before and during treatment in 26 PEG-IFN alpha-2b and 26 conventional IFN alpha-2b recipients matched for age, body weight and dose of ribavirin. The pharmacokinetics of PEG-IFN alpha-2b and ribavirin was analysed in 15 of the 26 PEG-IFN recipients. There was a rapid increase in PKR expression in both treatment groups, although expression from day 2 onwards was maintained at a significantly higher level in the PEG-IFN recipients (P < 0.05). C(max) of PEG-IFN occurred 12-48 h after the initial administration, with t(1/2) and C(min) being 49 h and 190 pg/mL, respectively. In contrast to ribavirin, accumulation of PEG-IFN was minimal. There was no association between serum PEG-IFN and ribavirin levels and virological response. Although baseline expression of PKR before treatment was marginally higher in nonresponders (NRs), from day 2 onwards, sequential PKR expression in response to PEG-IFN was higher in sustained viral responders compared with the NRs (P < 0.05). Significant correlations were found between kinetics of PKR expression and viral decline rates in each phase of hepatitis C virus dynamics (first phase, r = 0.67, P = 0.0006; second phase, r = 0.67, P = 0.001). In conclusion, improvement in pharmacokinetics following pegylation led to higher intracellular PKR expression, which was associated with enhanced virological efficacy of PEG-IFN-based combination therapy. The concentrations of both ribavirin and PEG-IFN alpha-2b were not associated with viral response and PKR expression.
Asahina
Y
Y
Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
Izumi
N
N
Umeda
N
N
Hosokawa
T
T
Ueda
K
K
Doi
F
F
Tsuchiya
K
K
Nakanishi
H
H
Matsunaga
K
K
Kitamura
T
T
Kurosaki
M
M
Uchihara
M
M
Higaki
M
M
Miyake
S
S
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D019892:eIF-2 Kinase; C417083:peginterferon alfa-2b