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

Rower, Joseph E.; Meissner, Eric G.; Jimmerson, Leah C.; Osinusi, Anu; Sims, Zayani; Petersen, Tess; Bushman, Lane R.; Wolfe, Pamela; McHutchison, John G.; Kottilil, Shyamasundaran; Kiser, Jennifer J.

doi:10.1093/jac/dkv122

Cited by 23 publications

(27 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In combination with PEG, higher RBV concentrations are associated with a higher likelihood of SVR . This association has also been observed in interferon‐free regimens – . Thus, reductions in RBV dose due to hemolytic anemia could potentially compromise SVR …”

Section: Itpa Genotype Groups With Number and Percentage Of Patients mentioning

confidence: 82%

“…For the PAXgene ® sample, whole blood was drawn into PAXgene ® RNA tubes (Qiagen, Valencia, California) followed by immediate storage at –20°C followed by long‐term storage at –70°C. The sample was then diluted 1:50 in 1 mL of 70% methanol and stored at –70°C until bioanalytical processing …”

Section: Methodsmentioning

confidence: 99%

“…However, ITPA‐deficient individuals appear to have a similar rate of SVR as nondeficient individuals despite this potential decrease in RBV‐TP . There are limited data on the association between ITPA genetics and RBV pharmacokinetics – . Because RBV is an analogue for adenosine and guanosine and is phosphorylated to active RBV‐TP in the cell, it is likely that ITPA activity will have an effect on its intracellular pharmacology.…”

Section: Itpa Genotype Groups With Number and Percentage Of Patients mentioning

confidence: 99%

See 2 more Smart Citations

Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels

Jimmerson

Truesdale

Baouchi-Mokrane

et al. 2016

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Individuals with lower inosine triphosphatase (ITPA) enzyme activity have a reduced likelihood of experiencing hemolytic anemia during hepatitis C virus (HCV) treatment containing ribavirin (RBV). Because ITPA degrades purines and RBV is a purine analogue, it is conceivable that ITPA activity may affect intracellular RBV concentrations. Here we assessed the association between ITPA activity phenotype and concentrations of RBV triphosphate (RBV-TP) in red blood cells (RBCs) during HCV treatment. RBV-TP was quantified in the RBCs of 177 HCV-infected individuals at a median (range) of 84 (19 to 336) days into HCV treatment that included RBV. Mean (SD) RBV-TP concentrations were 92.8 (51.6), 101.3 (53.5), 184.8 (84.5), and 197.7 (64.6) pmol/10 cells for 100%, 60%, 30%, and ≤10% ITPA activity groups, respectively. Overall, RBV-TP was approximately 2-fold higher in patients with ≤30% ITPA activity compared to 100% activity (P < .0001). Despite higher RBV-TP levels, individuals with variant ITPA phenotypes had less anemia. The 100% activity group had, on average, a -2.20 g/dL drop in hemoglobin vs -1.43 g/dL (P = .04) for 60% activity, -1.14 g/dL (P = .008) for 30% activity, and -0.70 g/dL (P = .06) for ≤10% activity. This finding of higher RBV-TP concentrations in RBCs in ITPA variants was unexpected given that ITPA activity-deficient individuals have a reduced likelihood of RBV-induced anemia. It also refutes the hypothesis that the mechanism by which ITPA variants are protected against anemia is due to lower RBV-TP levels in RBCs.

show abstract

Section: Itpa Genotype Groups With Number and Percentage Of Patients mentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Itpa Genotype Groups With Number and Percentage Of Patients mentioning

confidence: 99%

See 1 more Smart Citation

Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels

Jimmerson

Truesdale

Baouchi-Mokrane

et al. 2016

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the NIAID SPARE trial, Rower et al [46] , showed that ribavirin-monophosphate concentrations in red blood cells at day 14 were related to anaemia and SVR. A therapeutic range was identified for ribavirinmonophosphate in persons with HCV G1 disease receiving 24 wk of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in this interferon-free regimen.…”

Section: There Is Probably No More Place For Ribavirin Dose Adjustmenmentioning

confidence: 99%

Ribavirin: Past, present and future

Loustaud‐Ratti¹

2016

WJH

View full text Add to dashboard Cite

Before the advent of direct acting antiviral agents (DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-totreat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs. Author contributions: Loustaud-Ratti V and Carrier P wrote the manuscript; Debette-Gratien M, Jacques J, Alain S, Marquet P, Sautereau D and Rousseau A read the manuscript and conducted a critical analysis. Conflict-of-interest statement:The authors have no conflict of interest concerning this work.Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ INTRODUCTIONBefore the advent of direct acting antiviral agents (DAAs) ribavirin played a crucial role in the treatment of chronic hepatitis C associated to pegylated interferon [1] . This combination is still relevant in many parts of the world which do not have access to new therapies because of cost issues [2] . Although the role of ribavirin in the era of DAAs will probably decrease in the future with the arrival of second generation drugs, it remains essential in strategies decreasing treatment duration or in some difficult situations. The goal of this review is to briefly recall the recent past of ribavirin and consider its present and potential future. RIbavIRIN: meChaNIsms Of aCTIONSo far, multiple mechanisms of action of ribavirin have been described. The antiviral mechanism is probably the best documented, the erroneous incorporation of ribavirin triphosphate into replicating RNA strands inhibiting chain elongation [3] ...

show abstract

“…Ribavirin (RBV; l‐ß‐D‐ribofuranosyl‐l,2,4‐triazole‐3‐carboxamide) is a purine nucleoside analog with broad‐spectrum antiviral activity against a variety of viruses (Fernandez et al ., ; Maag et al ., ; Lin et al ., ; K. Gupta et al ., ). In humans, oral ribavirin therapy is regarded as a major antiviral prescription to treat hepatitis C virus (HCV) infections, in combination with interferons (Maag et al ., ; Rower et al ., ). Ribavirin has various antiviral mechanisms such as the inhibition of inosine monophosphate dehydrogenase (IMPDH), inhibition of RNA‐dependent RNA polymerase (RdRp), and mutagenesis of viral replication (Fernandez et al ., ; Crotty et al ., ; Maag et al ., ).…”

Section: Introductionmentioning

confidence: 98%

Hematological adverse effects and pharmacokinetics of ribavirin in pigs following intramuscular administration

Lee

Yoo

et al. 2017

Vet Pharm & Therapeutics

View full text Add to dashboard Cite

Ribavirin (RBV) is a synthetic guanosine analog that is used as a drug against various viral diseases in humans. The in vitro antiviral effects of ribavirin against porcine viruses were demonstrated in several studies. The purposes of this study were to evaluate the adverse effects and pharmacokinetics of ribavirin following its intramuscular (IM) injection in pigs. Ribavirin was formulated as a double-oil emulsion (RBV-DOE) and gel (RBV-Gel), which were injected into the pigs as single-dose IM injections. After injection of RBV, all of the pigs were monitored. The collected serum and whole blood samples were analyzed by liquid chromatography-tandem mass spectrometry and complete blood count analysis, respectively. All of the ribavirin-treated pigs showed significant decreases in body weight compared to the control groups. Severe clinical signs including dyspnea, anorexia, weakness, and depression were present in ribavirin-treated pigs until 5 days postinjection (dpi). The ribavirin-treated groups showed significant decrease in the number of red blood cells and hemoglobin concentration until 8 dpi. The mean half-life of the RBV-DOE and RBV-Gel was 27.949 ± 2.783 h and 37.374 ± 3.502 h, respectively. The mean peak serum concentration (C ) and area under the serum concentration-time curve from time zero to infinity (AUC ) of RBV-DOE were 8340.000 ± 2562.577 ng/mL and 16 0095.430 ± 61 253.400 h·ng/mL, respectively. The C and AUC of RBV-Gel were 15 300.000 ± 3764.306 ng/mL and 207526.260 ± 63656.390 h·ng/mL, respectively. The results of this study provided the index of side effect and pharmacokinetics of ribavirin in pigs, which should be considered before clinical application.

show abstract

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

Cited by 23 publications

References 33 publications

Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels

Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels

Ribavirin: Past, present and future

Hematological adverse effects and pharmacokinetics of ribavirin in pigs following intramuscular administration

Contact Info

Product

Resources

About