The Utility of Therapeutic Drug Monitoring for Ribavirin in Patients with Chronic Hepatitis C

Abstract

Spanish

French

Objective:

To evaluate the utility of therapeutic drug monitoring (TDM) for ribavirin in chronic hepatitis C.

Data Sources:

Literature searches were conducted through PubMed (1949–June 2009), EMBASE (1980–June 2009), BIOSIS Previews (1969–June 2009), International Pharmaceutical Abstracts (1970–June 2009), Google, and www.clinicaltrials.gov using the terms ribavirin, therapeutic monitoring, hepatitis C, and drug levels. In addition, pertinent reference citations from identified publications were reviewed. Studies were limited to English language, adult age, and human subjects.

Study Selection and Data Extraction:

All articles identified from the data sources were evaluated. Studies that measured ribavirin concentrations or dose and treatment response were included in the review.

Data Synthesis:

While monitoring of ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C has been described in the literature, the utility of TDM for ribavirin in this group of patients has not been systematically studied. Thus, a previously published 9-step decision-making algorithm was employed to help determine whether TDM is warranted, based on currently available evidence. Thirty articles involving patients with chronic hepatitis C mono-infection, 12 for hepatitis C–HIV coinfection, 5 for renal dysfunction, and 5 for post–liver transplant patients were reviewed. In all subpopulations, studies exist that either support or refute the usefulness of ribavirin TDM. Additionally, the majority of the included studies had methodologic limitations, such as small sample size, retrospective analyses, and lack of p value adjustment for multiple analyses. Large randomized controlled trials would help to definitively answer this question.

Conclusions:

There is conflicting evidence about the existence of a correlation between ribavirin concentrations and virologic response or development of toxicity. This inconsistent evidence, coupled with the currently employed effective strategies that maximize sustained virologic response and minimize development of anemia, precludes the utility of TDM for ribavirin.

Keywords

clinical pharmacokinetic monitoring drug levels hepatitis C ribavirin therapeutic monitoring

Get full access to this article

View all access options for this article.

References

Wasley

, Grytdal

, Gallagher

, Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis—United States, 2006. MMWR Surveill Summ 2008;57:1–24.

Hepatitis

Ottawa, ON: Public Health Agency of Canada, www.phacaspc.gc.ca/hepc/index_e.html (accessed 2008 Mar 30).

Davis

, Lau

. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 1997;26(suppl 1):122S–7S.

Strader

, Wright

, Thomas

, Seeff

, American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147–71.

Wong

, Lee

Hepatitis C: a review for primary care physicians. CMAJ 2006;174:649–59.

Khakoo

, Glue

, Grellicr

. Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions. Br J Clin Pharmacol 1998;46:563–70.

Keating

, Curran

. Peginterferon-alpha-2a (40kD) plus ribavirin: a review of its use in the management of chronic hepatitis C. Drugs 2003;63:701–30.

Chang

, Chen

, Lai

, Chan

. Meta-analysis: ribavirin-induced haemolytic anaemia in patients with chronic hepatitis C. Aliment Pharmacol Ther 2002;16:1623–32.

De Franceschi

, Fattovich

, Turrini

. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997–1004.

10.

Manns

, McHutchison

, Gordon

. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65.

11.

Hadziyannis

, Sette

Jr , Morgan

. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346–55.

12.

Jacobson

, Brown

Jr , Freilich

. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007;46:971–81.

13.

Reddy

, Shiffman

, Morgan

. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastro Hepatol 2007;5:124–9.

14.

Reddy

, Dieterich

, Hadziyannis

, Messinger

, Fried

. Multiple logistic regression analysis identifies ribavirin as a modifiable and independent predictor of relapse amongst chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin (poster 1283). Presented at: The Liver Meeting 2008: 59th Annual Meeting of the American Association for the Study of Liver Disease (AASLD), San Francisco, CA, October 31–November 4, 2008.

15.

Oze

, Hiramatsu

, Yakushijin

. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with chronic hepatitis C responding to pegylated interferon alfa-2b plus ribavirin (poster 1238). Presented at: The Liver Meeting 2008: 59th Annual Meeting of the American Association for the Study of Liver Disease (AASLD), San Francisco, CA, October 31–November 4, 2008.

16.

Morello

, Rodriguez-Novoa

, Jimenez-Nacher

, Soriano

Usefulness of monitoring ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C. J Antimicrob Chemother 2008;62:1174–80.

17.

Ensom

, Davis

, Cropp

, Ensom

. Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes? Clin Pharmacokinet 1998;34:265–79.

18.

Sherman

, Shafran

, Burak

. Management of chronic hepatitis C: consensus guidelines. Can J Gastroenterol 2007;21 (suppl C):25C-34C.

19.

Gish

, Arora

, Rajender Reddy

. Virological response and safety outcomes in therapy-naive patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alfa-2a: a randomized, phase 2 study. J Hepatol 2007;47:51–9.

20.

Benhamou

, Pockros

, Rodrieuez-Torres

. The safety and efficacy of viramidine plus pegylated interferon alpha-2B versus ribavirin plus pegylated interferon alpha-2B in therapy-naïve patients infected with HCV: Phase 3 results (abstract 751). J Hepatol 2006;44(suppl 2):S273.

21.

Marcellin

, Lurie

, Rodrigues-Torres

, Chasen

, Xu

, Murphy

The safety and efficacy of taribavirin plus pegylated interferon alfa-2a versus ribavirin plus pegylated interferon alfa-2a in therapy-naive patients infected with HCV: Phase 3 results (abstract 10). J Hepatol 2007;46(suppl 1):S7.

22.

Austin

, Trefts

, Hintz

, Connor

, Kagnoff

. Sensitive radioimmunoassay for the broad-spectrum antiviral agent ribavirin. Antimicrob Agents Chemother 1983;24:696–701.

23.

Larrat

, Stanke-Labesque

, Plages

, Zarski

, Bessard

, Souvignet

Ribavirin quantification in combination treatment of chronic hepatitis C. Antimicrob Agents Chemother 2003;47:124–9.

24.

Svensson

, Bruchfeld

, Schvarcz

, Stahle

Determination of ribavirin in serum using highly selective solid-phase extraction and high-performance liquid chromatography. Ther Drug Monit 2000;22:215–8.

25.

Shou

, Bu

, Addison

, Jiang

, Naidong

Development and validation of a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the determination of ribavirin in human plasma and serum. J Pharm Biomed Anal 2002;29:83–94.

26.

Inoue

, Homma

, Matsuzaki

. Liquid chromatography assay for routine monitoring of cellular ribavirin levels in blood. Antimicrob Agents Chemother 2004;48:3813–6.

27.

Breadmore

, Theurillat

, Thormann

Determination of ribavirin in human serum and plasma by capillary electrophoresis. Electrophoresis 2004;25:1615–22.

28.

Morello

, Rodriguez-Novoa

, Cantillano

, Gonzalez-Pardo

, Jimenez

, Soriano

Measurement of ribavirin plasma concentrations by high-performance liquid chromatography using a novel solid-phase extraction method in patients treated for chronic hepatitis C. Ther Drug Monit 2007;29:802–6.

29.

Homma

, Jayewardene

, Gambertoglio

, Aweeka

High-performance liquid chromatographic determination of ribavirin in whole blood to assess disposition in erythrocytes. Antimicrob Agents Chemother 1999;43:2716–9.

30.

Paroni

, Sirtori

, Borghi

, Kienle

. High-performance liquid chromatographic determination of ribavirin in serum and urine and of its urinary metabolite 1,2,4-triazole-3-carboxamide. J Chromatogr 1987;420:189–96.

31.

Yeh

, Nguyen

, Lin

. A sensitive and specific method for the determination of total ribavirin in human red blood cells by chromatographytandem mass spectrometry. J Chromato Sci 2003;41:255–60.

32.

Granich

, Krogstad

, Connor

, Desrochers

, Sherwood

High-performance liquid chromatography (HPLC) assay for ribavirin and comparison of the HPLC assay with radioimmunoassay. Antimicrob Agents Chemother 1989;33:311–5.

33.

Alsio

, Westin

, Hellstrand

, Norkrans

, Lagging

Non-responder HCV genotype 2/3 patients: is it simply a question of suboptimal interferon and ribavirin concentrations (poster 1878). Presented at The Liver Meeting 2008:59th Annual Meeting of the American Association for the Study of Liver Disease (AASLD), San Francisco, CA, October 31-November 4, 2008.

34.

Arase

, Ikeda

, Suzuki

. Adequate timing of ribavirin reduction in patients with hemolysis during combination therapy of interferon and ribavirin for chronic hepatitis C. J Gastroenterol 2004;39:1090–4.

35.

Arase

, Ikeda

, Tsubota

. Significance of serum ribavirin concentration in combination therapy of interferon and ribavirin for chronic hepatitis C. Intervirology 2005;48:138–44.

36.

Asahina

, Izumi

, Umeda

. Pharmacokinetics and enhanced PKR response in patients with chronic hepatitis C treated with pegylated interferon alpha-2b and ribavirin. J Viral Hepat 2007;14:396–403.

37.

Christensen

, Alsio

, Buhl

. Ribavirin concentration at week four is an independent predictor for sustained virological response after treatment of hepatitis C genotype 2/3 (NORDynamic trial). J Hepatol 2008;48(suppl 2):S6–7.

38.

Donnerer

, Grahovac

, Stelzl

. Ribavirin levels and haemoglobin decline in early virological responders and non-responders to hepatitis C virus combination therapy. Pharmacology 2006;76:136- 40.

39.

Inoue

, Homma

, Matsuzaki

. Erythrocyte ribavirin concentration for assessing hemoglobin reduction in interferon and ribavirin combination therapy. Hepatol Res 2006;34:23–7.

40.

Jen

, Glue

, Gupta

, Zambas

, Hajian

Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000;22:555–65.

41.

Jen

, Laughlin

, Chung

. Ribavirin dosing in chronic hepatitis C: application of population pharmacokinetic-pharmacodynamic models. Clin Pharmacol Ther 2002;72:349–61.

42.

Lindahl

, Schvarcz

, Bruchfeld

, Stahle

Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin-induced anaemia. J Viral Hepat 2004;11:84–7.

43.

Lindahl

, Stahle

, Bruchfeld

, Schvarcz

High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology 2005;41:275–9.

44.

Loustaud-Ratti

, Alain

, Rousseau

. Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C. Hepatology 2008;47:1453–61.

45.

Maeda

, Kiribayashi

, Moriya

. Dosage adjustment of ribavirin based on renal function in Japanese patients with chronic hepatitis C. Ther Drug Monit 2004;26:9–15.

46.

Mangia

, Dalgard

, Minerva

. Ribavirin (RBV) dosage as independent predictor of RVR in HCV genotype 2 (HCV-2) and 3 (HCV-3) patients undergoing combined treatment with peg interferon (pegIFN) alpha-2b (abstract 630). J Hepatol 2009;50(suppl 1):S232.

47.

Maynard

, Pradat

, Gagnieu

, Souvignet

, Trepo

Prediction of sustained virological response by ribavirin plasma concentration at week 4 of therapy in hepatitis C virus genotype 1 patients. Antivir Ther 2008;13:607–11.

48.

Nunez

, Miralles

, Berdun

. Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: the PRESCO trial. AIDS Res Hum Retroviruses 2007;23:972–82.

49.

Saito

, Tada

, Ebinuma

. Role of erythrocytes as a reservoir for ribavirin and relationship with adverse reactions in the early phase of interferon combination therapy for chronic hepatitis C virus infections. J Clin Microbiol 2006;44:3562–8.

50.

Shirakawa

, Matsumoto

, Joshita

. Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors. Hepatology 2008;48:1753–60.

51.

Snoeck

, Wade

, Duff

, Lamb

, Jorga

Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin. Br J Clin Pharmacol 2006;62:699–709.

52.

Souvignet

, Stanke-Labesque

, Bronowicki

, Larrat

, Quesada

, Zarsld

. Evidence that serum ribavirin steady-state concentrations do not correlate with early virological response during peginterferon alpha-2a plus ribavirin combination therapy for chronic hepatitis C (abstract 604). J Hepatol 2005;42(suppl 2):S221.

53.

Tsubota

, Akuta

, Suzuki

. Viral dynamics and pharmacokinetics in combined interferon alfa-2b and ribavirin therapy for patients infected with hepatitis C virus of genotype lb and high pretreatment viral load. Intervirology 2002;45:33–42.

54.

Tsubota

, Hirose

, Izumi

, Kumada

Pharmacokinetics of ribavirin in combined interferon-alpha 2b and ribavirin therapy for chronic hepatitis C virus infection. Br J Clin Pharmacol 2003;55:360–7.

55.

Uchida

, Hamada

, Yamasaki

, Fujiyama

, Sasaki

, Saito

Assessment of adverse reactions and pharmacokinetics of ribavirin in combination with interferon alpha-2b in patients with chronic hepatitis C. Drug Metab Pharmacokinet 2004;19:438–43.

56.

Poordad

, Reddy

, Martin

Rapid virologic response: a new milestone in the management of chronic hepatitis C. Clin Infect Dis 2008;46:78–84.

57.

Hospices Civils de

Lyon

. RIBAJUSTE Clinical Trial Investigating the Efficacy and Safety of Dose Adaptation of Ribavirin. In: www.ClinicalTrials.gov. Bethesda, MD: National Library of Medicine (US). 2000-(cited 2009 Oct 31). Available from: http://clinicaltrials.gov/ct2/show/NCT00485342?term=RIBAJUSTE&rank=1.NLM Identifier: NCT 00485342.

58.

Aguilar Marucco

, Gonzalez

Requena

, Bonora

. The use of trough ribavirin concentration to predict sustained virological response and haematological toxicity in HIV/HCV-co-infected patients treated with ribavirin and pegylated interferon. J Antimicrob Chemother 2008;61:919–24.

59.

Barreiro

, Rodriguez-Novoa

, Ruiz-Sancho

. Comparison of hepatitis C virus early kinetics in HIV/HCV coinfected patients treated with weight-based ribavirin plus either pegIFN alpha-2a or pegIFN alpha 2b (poster 901). Presented at: 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, February 25–28, 2007.

60.

Crespo

, Pou

, Esteban

. Early monitoring of ribavirin serum concentration is not useful to optimize hepatitis C virus treatment in HIV-coinfected patients. Antivir Ther 2007;12:1217–23.

61.

Dahari

, Markatou

, Zeremski

. Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin. J Hepatol 2007;47:23–30.

62.

Dominguez

, Cassard

, Duvivier

. Early therapeutic drug monitoring of ribavirin predicts anemia and early virological response in HIV-HCV-co-infected patients (poster 893). Presented at 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, February 25–28, 2007.

63.

Labarga

, Vispo

, Barreiro

. Rescue therapy with optimized peg-interferon plus ribavirin in HIV/HCV coinfected patients: critical role of ribavirin plasma levels in the pilot-NR trial (abstract 801). J Hepatol 2008;48(suppl 2):S299.

64.

Nicot

, Legrand-Abravanel

, Lafont

. Serum concentrations of ribavirin and pegylated interferon and viral responses in patients infected with HIV and HCV. J Med Virol 2008;80:1523–9.

65.

Nunez

, Camino

, Ramos

. Impact of ribavirin exposure on early virological response to hepatitis C therapy in HIV-infected patients with chronic hepatitis C. Antivir Ther 2005;10:657–62.

66.

Quioc

, Julien

, Mallet

, Nalpas

, Pol

Antiretroviral drugs reduce ribavirin levels in HIV-HCV-coinfected patients (poster 1269). Presented at: The Liver Meeting 2008: 59th Annual Meeting of the American Association for the Study of Liver Disease (AASLD), San Francisco, CA, October 31-November 4, 2008.

67.

Rendon

, Nunez

, Romero

. Early monitoring of ribavirin plasma concentrations may predict anemia and early virologic response in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2005;39:401–5.

68.

Bruchfeld

, Stahle

, Andersson

, Schvarcz

Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection—a pilot study. J Viral Hepat 2001;8:287–92.

69.

Bruchfeld

, Lindahl

, Stahle

, Soderberg

, Schvarcz

Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant 2003;18:1573–80.

70.

Bruchfeld

, Lindahl

, Reichard

, Carlsson

, Schvarcz

Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Hepat 2006;13:316–21.

71.

Rendina

, Schena

, Castellimeta

. The treatment of chronic hepatitis C with peginterferon alfa-2a (40 kDa) plus ribavirin in haemodialysed patients awaiting renal transplant. J Hepatol 2007;46:768–74.

72.

van Leusen

, Adang

, de Vries

. Pegylated interferon alfa-2a (40 kD) and ribavirin in haemodialysis patients with chronic hepatitis C. Nephrol Dial Transplant 2008;23:721–5.

73.

Dumortier

, Ducos

, Scoazec

, Chevallier

, Boillot

, Gagnieu

. Plasma ribavirin concentrations during treatment of recurrent hepatitis C with peginterferon alpha-2b and ribavirin combination after liver transplantation. J Viral Hepat 2006;13:538–43.

74.

Jain

, Vekatramanan

, Yelochan

, Kashyap

, Marcos

, Fung

Ribavirin levels in post liver transplant patients treated for recurrent hepatitis C viral infection. Transplant Proc 2005;37:3190–6.

75.

Saab

, Oh

, Ibrahim

. Anemia in liver transplant recipients undergoing antiviral treatment for recurrent hepatitis C. Liver Transpl 2007;13:1032–8.

76.

Sharma

, Marrero

, Fontana

. Sustained virologie response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence. Liver Transpl 2007;13:1100–8.

77.

Sterneck

, Benten

, Stoehr

, Rogers

, Renders

, Fischer

Ribavirin therapeutic drug monitoring in HCV reinfected liver transplant recipients treated with IFN/ribavirin (abstract 683). Am J Transplant 2006;6(suppl 2):298.

78.

Lopez-Cortes

, Valera-Bestard

, Gutierrez-Valencia

. Role of pegylated interferon-alpha-2a and ribavirin concentrations in sustained viral response in HCV/HIV-coinfected patients. Clin Pharmacol Ther 2008;84:573–80.

79.

Bruno

, Puoti

, Verucchi

. Higher ribavirin doses are associated with a better RVR in HIV infected patients treated with pegylated interferon in combination with ribavirin for chronic hepatitis C (abstract 773). J Hepatol 2008;48(suppl 2):S288.

80.

Bruchfeld

, Lindahl

, Schvarcz

, Stahle

Dosage of ribavirin in patients with hepatitis C should be based on renal function: a population pharmacokinetic analysis. Ther Drug Monit 2002;24:701–8.

81.

Kamar

, Chatelut

, Manolis

, Lafont

, Izopet

, Rostaing

Ribavirin pharmacokinetics in renal and liver transplant patients: evidence that it depends on renal function. Am J Kidney Dis 2004;43:140–6.

82.

Wade

, Snoeck

, Duff

, Lamb

, Jorga

Pharmacokinetics of ribavirin in patients with hepatitis C virus. Br J Clin Pharmacol 2006;62:710–4.

83.

Sherman

, Bain

, Villeneuve

. The management of chronic viral hepatitis: a Canadian consensus conference 2004. Can J Infect Dis Med Microbiol 2004;15:313–26.

84.

Jensen

, Marcellin

Rationale and design of the REPEAT study: a phase III, randomized, clinical trial of peginterferon alfa-2a (40 kDa) plus ribavirin in non-responders to peginterferon alfa-2b (12 kDa) plus ribavirin. Eur J Gastroenterol Hepatol 2005;17:899–904.

85.

Afdhal

, Dieterich

, Pockros

. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004;126:1302–11.

86.

Pockros

, Shiffman

, Schiff

. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology 2004;40:1450–8.

87.

Fried

, Shiffman

, Reddy

. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82.

The Utility of Therapeutic Drug Monitoring for Ribavirin in Patients with Chronic Hepatitis C—A Critical Review

Abstract

Objective:

Data Sources:

Study Selection and Data Extraction:

Data Synthesis:

Conclusions:

Keywords

Get full access to this article

References