Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin.

OBJECTIVES Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia. PATIENTS AND METHODS Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations. RESULTS Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir <10 g/dL relative to patients with haemoglobin nadir ≥10 g/dL (6.54 versus 4.48 pmol/10(6) cells; P = 0.02). Additionally, day 14 RBV-MP average concentrations trended towards being higher in subjects that achieved sustained virological response (SVR) as compared with patients who relapsed (4.97 versus 4.09 pmol/10(6) cells; P = 0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/10(6) cells for SVR (P = 0.06) and 6.1 pmol/10(6) cells for haemoglobin nadir <10 versus ≥10 g/dL (P = 0.02), with sensitivity and specificity ≥60%. Dosing simulations showed that 800 mg of ribavirin once daily produced day 14 RBV-MP concentrations within the 4.4-6.1 pmol/10(6) cells range. CONCLUSIONS RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens.

[1]  G. Everson,et al.  Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection , 2015, Antimicrobial Agents and Chemotherapy.

[2]  P. Anderson,et al.  Measurement of intracellular ribavirin mono-, di- and triphosphate using solid phase extraction and LC-MS/MS quantification. , 2015, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[3]  Brian L. Pearlman,et al.  Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study , 2014, The Lancet.

[4]  L. Prokunina-Olsson,et al.  IFNL4-ΔG genotype is associated with slower viral clearance in hepatitis C, genotype-1 patients treated with sofosbuvir and ribavirin. , 2014, The Journal of infectious diseases.

[5]  X. Forns,et al.  ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. , 2014, The New England journal of medicine.

[6]  O. Weiland,et al.  Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. , 2014, The New England journal of medicine.

[7]  Sanjeev Arora,et al.  Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. , 2014, The New England journal of medicine.

[8]  Brian L. Pearlman,et al.  O10 SAFETY AND EFFICACY OF THE ALL-ORAL REGIMEN OF MK-5172/MK-8742 ± RIBAVIRIN IN TREATMENT-NAIVE, NON-CIRRHOTIC, PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 1 INFECTION: THE C-WORTHY STUDY , 2014 .

[9]  P. Marcellin,et al.  Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. , 2014, Gastroenterology.

[10]  Brad J. Wood,et al.  Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. , 2013, JAMA.

[11]  John McNally,et al.  Sofosbuvir for previously untreated chronic hepatitis C infection. , 2013, The New England journal of medicine.

[12]  C. Howell,et al.  Optimum Ribavirin Exposure Overcomes Racial Disparity in Efficacy of Peginterferon and Ribavirin Treatment for Hepatitis C Genotype 1 , 2012, The American Journal of Gastroenterology.

[13]  G. di Perri,et al.  Development and validation of a useful HPLC-UV method for quantification of total and phosphorylated-ribavirin in blood and erythrocytes of HCV+ patients. , 2012, Journal of pharmaceutical and biomedical analysis.

[14]  C. Howell,et al.  Population Pharmacokinetics and Pharmacodynamics of Ribavirin in Patients with Chronic Hepatitis C Genotype 1 Infection , 2012, The AAPS Journal.

[15]  M. Rizzetto,et al.  Inosine Triphosphatase Polymorphisms and Ribavirin Pharmacokinetics as Determinants of Ribavirin-Associate Anemia in Patients Receiving Standard Anti-HCV Treatment , 2012, Therapeutic drug monitoring.

[16]  Samir K. Gupta,et al.  Pharmacokinetics, safety, and tolerability of ribavirin in hemodialysis-dependent patients , 2011, European Journal of Clinical Pharmacology.

[17]  E. Roda,et al.  Ribavirin for chronic hepatitis C: and the mystery goes on. , 2011, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[18]  K. Shianna,et al.  Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function. , 2011, Gastroenterology.

[19]  K. Shianna,et al.  Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction. , 2010, Gastroenterology.

[20]  Jacques Fellay,et al.  ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C , 2010, Nature.

[21]  Y. Hasegawa,et al.  Blood ribavirin concentration in high‐dose ribavirin for adenovirus‐induced haemorrhagic cystitis – a case report , 2008, Journal of clinical pharmacy and therapeutics.

[22]  E. Snoeck,et al.  Pharmacokinetics of ribavirin in patients with hepatitis C virus. , 2006, British journal of clinical pharmacology.

[23]  J. Hoofnagle,et al.  Mechanism of action of interferon and ribavirin in treatment of hepatitis C , 2005, Nature.

[24]  N. Tanaka,et al.  Marked elevation of erythrocyte ribavirin levels in interferon and ribavirin-induced anemia. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[25]  A. Bruchfeld,et al.  Dosage of Ribavirin in Patients With Hepatitis C Should Be Based on Renal Function: A Population Pharmacokinetic Analysis , 2002, Therapeutic drug monitoring.

[26]  Z. Hong,et al.  Mechanism of action of ribavirin in the combination treatment of chronic HCV infection , 2002, Hepatology.

[27]  P. McNamara,et al.  Pharmacokinetics and Absolute Bioavailability of Ribavirin in Healthy Volunteers as Determined by Stable-Isotope Methodology , 1999, Antimicrobial Agents and Chemotherapy.

[28]  A. Levey,et al.  A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation , 1999, Annals of Internal Medicine.

[29]  E. Schiff,et al.  Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. , 2015, Gastroenterology.

[30]  P. Anderson,et al.  Development and validation of a dried blood spot assay for the quantification of ribavirin using liquid chromatography coupled to mass spectrometry. , 2014, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[31]  L. Rostaing,et al.  Ribavirin pharmacokinetics in renal and liver transplant patients: evidence that it depends on renal function. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[32]  J. Connor,et al.  The metabolism of ribavirin in erythrocytes and nucleated cells. , 1990, The International journal of biochemistry.