Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic‐pharmacodynamic models

Jen, J.; Laughlin, Mark; Chung, Carol; Heft, Samuel; Affrime, Melton B.; Gupta, Samir K.; Glue, Paul; Hajian, Gerald

doi:10.1067/mcp.2002.127112

Cited by 51 publications

(36 citation statements)

References 3 publications

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“…Whereas much effort has been targeted toward understanding the mechanism of IFN and potential IFN resistance, relatively little effort has been directed toward understanding RBV. RBV has been shown to play an important role in the treatment response (14), and higher RBV serum concentrations correlate with improved treatment outcome (26,34). However, we still do not understand how RBV works synergistically with IFN to improve SVR rates or whether resistance to RBV develops in patients.…”

Section: Discussionmentioning

confidence: 94%

“…Perhaps elevated RBV uptake correlates with overall treatment success. Higher RBV serum concentrations have been associated with SVR (26,34). SVR rates of up to 90% have been achieved by using extremely high doses of RBV (35), albeit with increased toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, genotype 1 infections are more difficult to treat than those of other genotypes. Additionally, male gender, AfricanAmerican race, advanced age, fibrosis, obesity, human immunodeficiency virus coinfection, and low RBV serum concentrations have been negatively correlated with treatment success (3,14,26,27,34,35).Although RBV clearly plays a role in the HCV treatment response, the antiviral mechanism remains controversial. There are many proposed mechanisms of action for RBV (6,10,37,63).…”

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confidence: 99%

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Reduced Ribavirin Antiviral Efficacy via Nucleoside Transporter-Mediated Drug Resistance

Ibarra

Pfeiffer

2009

J Virol

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Treatment for hepatitis C virus infection currently consists of pegylated interferon and ribavirin (RBV), a nucleoside analog. Although RBV clearly plays a role in aiding the treatment response, its antiviral mechanism is unclear. Regardless of the specific mechanism of RBV, we hypothesize that differences in levels of cellular uptake of RBV may affect antiviral efficacy and treatment success and that cells may become RBV resistant through reduced uptake. We monitored RBV uptake in various cell lines and determined the effect of uptake capacity on viral replication. RBV-resistant cells demonstrated reduced RBV uptake and increased growth of a model RNA virus, poliovirus, in the presence of RBV. Overexpression of equilibrative nucleoside transporter 1 (ENT1) or concentrative nucleoside transporter 3 (CNT3) increased RBV uptake in RBV-sensitive cell lines and restored the uptake defect in most RBV-resistant cell lines. However, CNT3 is not expressed in Huh-7 liver cells, and inhibition of concentrative transport did not affect RBV uptake. Blocking equilibrative transport using the inhibitor nitrobenzylmercaptopurine riboside recapitulated the RBV-resistant phenotype in RBVsensitive cell lines, with a reduction in RBV uptake and increased poliovirus growth. Taken together, these results indicate that RBV uptake is restricted primarily to ENT1 in the cell lines examined. Interestingly, some RBV-resistant cell lines may compensate for reduced ENT1-mediated nucleoside uptake by increasing the activity of an alternative nucleoside transporter, ENT2. It is possible that RBV uptake affects the antiviral treatment response, either through natural differences in patients or through acquired resistance.Approximately 170 million people are infected with hepatitis C virus (HCV), with the majority developing chronic infection (1). With no vaccine currently available, the only approved treatment consists of a combination of alpha interferon (IFN-␣) and ribavirin (RBV), a guanosine nucleoside analog. IFN-␣ monotherapy has limited success, with only 16 to 20% of genotype 1-infected patients achieving a sustained virological response (SVR). However, the addition of RBV doubled response rates to 35 to 40%. Current treatment regimens including pegylated IFN and RBV achieve SVR rates of 54 to 56% in genotype 1-infected patients, while SVR rates of 70 to 80% are achieved in genotype 2-or 3-infected patients. The patient response is divided into three categories: SVR, end-of-treatment response and relapse, and nonresponse. Little is known about factors that influence the treatment response, although various host and viral factors have been implicated. For instance, genotype 1 infections are more difficult to treat than those of other genotypes. Additionally, male gender, AfricanAmerican race, advanced age, fibrosis, obesity, human immunodeficiency virus coinfection, and low RBV serum concentrations have been negatively correlated with treatment success (3,14,26,27,34,35).Although RBV clearly plays a role in the HCV treatment response, ...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Reduced Ribavirin Antiviral Efficacy via Nucleoside Transporter-Mediated Drug Resistance

Ibarra

Pfeiffer

2009

J Virol

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“…For the treatment of chronic HCV, ribavirin is currently dosed according to body weight, usually between 800 and 1,200 mg daily. 5 In a recent report by Hadziyannis et al, 3 patients with genotype 1 and a high viral load responded better to a ribavirin dose of 1,000 to 1,200 mg daily than to 800 mg/day combined with peginterferon. 3 In contrast to current recommendations, we have recently shown that renal function is of greater importance than body weight for ribavirin clearance, and we therefore have suggested the use of a pharmacokinetic formula based primarily on renal function as a tool to determine the accurate dose of ribavirin for treatment.…”

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High‐dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C†

et al. 2005

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Improved treatment regimens for patients with chronic hepatitis C, genotype 1 and high viral load are needed. Increasing the dose of ribavirin has increased the response rate, but experience with doses of more than 1,200 mg/day is limited. The aim of this study was to investigate the safety and tolerance to treatment with a high and individualized dose of ribavirin in combination with peginterferon. Ten patients with chronic hepatitis C, genotype 1 and high viral load were treated with peginterferon alfa-2a and ribavirin for 48 weeks in a prospective trial. The initial ribavirin dose was individualized and calculated from a pharmacokinetic formula based mainly on renal function. Ribavirin plasma concentrations were monitored, and the dose was adjusted to reach the target concentration. Hemoglobin was monitored, and patients were treated with erythropoietin and blood transfusions when indicated. After dose adjustments, the mean dose of ribavirin was 2,540 mg/day (range, 1,600-3,600) at week 24. The main side effect was anemia, which was controlled with erythropoietin. Two patients required blood transfusions. One patient was withdrawn at week 24 because of a lack of viral response, and one patient at week 39 because of side effects, primarily interferon associated. A lthough improvements have been made in the antiviral therapy of chronic hepatitis C virus (HCV), patients with genotype 1 infection with a high level of HCV RNA still pose a therapeutic challenge. The standard combination treatment with 12 months of peginterferon combined with ribavirin results in a sustained virological response rate of approximately 40% for this subset of patients. [1][2][3]

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Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C

Hauser

Awad

Brok

et al. 2014

Cochrane Database of Systematic Reviews

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Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic‐pharmacodynamic models

Abstract: This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa-2b) for patients with chronic hepatitis C should be based on body weight.

Cited by 51 publications

References 3 publications

Reduced Ribavirin Antiviral Efficacy via Nucleoside Transporter-Mediated Drug Resistance

Reduced Ribavirin Antiviral Efficacy via Nucleoside Transporter-Mediated Drug Resistance

High‐dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C†

Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C

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