Search

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 6 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., (© 2016, The American College of Clinical Pharmacology.)

Anemia is a well-known RBV-related event in HCV therapy which is exacerbated by the addition of telaprevir and boceprevir. This retrospective study evaluated and compared ribavirin exposure and parameters able to influence hemoglobin decrease in a large population of patients treated with dual or triple therapy. Patients on triple therapy had higher ribavirin concentrations at week 12 of treatment (3460 ng/mL vs. 1843 ng/mL; P < .0001). An association was also observed between week 12 eGFR and ribavirin concentration only for patients on triple therapy (P = .002). The proportion of patients with a  >20 mL/min/1.73 m(2) decrease in eGFR at week 12 was higher among patients on triple therapy: 32%, 14%, and 5% for boceprevir, telaprevir, and dual therapy, respectively (P = .025 and .026). No correlation was observed between boceprevir and telaprevir concentrations and hemoglobin or eGFR decrease. Exacerbation of anemia in patients on triple therapy is related to higher ribavirin concentrations. We provide an explanation for this increase in plasma RBV concentration. Triple therapy with PEG-IFN, RBV, and telaprevir or boceprevir will remain the only HCV treatment option for many patients. Our data show that the RBV dose can be decreased while maintaining adequate plasma concentrations and reducing anemia., (© 2015, The American College of Clinical Pharmacology.)

This was a 36-day, open-label, fixed-sequence, multiple-dose drug interaction study in 23 healthy subjects to evaluate the effects of multiple doses of tenofovir disoproxil fumarate on the single-dose pharmacokinetics of ribavirin. Subjects received a 600-mg once-daily oral dose of ribavirin on days 1 and 22 and 300-mg once-daily oral doses of tenofovir disoproxil fumarate on days 17 through 24. Pharmacokinetic sampling was performed on days 1 through 4 and 22 through 25. Pharmacokinetics of ribavirin was not altered by its coadministration with tenofovir disoproxil fumarate as the point estimates (day 22 [test treatment]/day 1 [reference treatment]), and the 90% confidence interval for maximum observed concentration (0.95; 88.7-101) and area under the plasma concentration-time curve up to time of last measurable concentration (1.12; 106-117) were within the equivalence bounds of 80% to 125%. Tenofovir pharmacokinetics after ribavirin coadministration was similar to that observed in previous studies. These results indicate that coadministration of tenofovir disoproxil fumarate and ribavirin does not result in substantial changes to their individual pharmacokinetic profiles.

The current study was carried out to evaluate pharmacokinetic profiles of viramidine and ribavirin in patients (n = 8 per dose group) with compensated hepatitis C infection following oral dosing of viramidine (400, 600, or 800 mg bid for 4 weeks). Pharmacokinetic parameters were determined on days 1 and 29 based on plasma, red blood cell, and urine concentrations of viramidine and ribavirin. The results indicate rapid absorption and conversion of viramidine to ribavirin after oral administration of viramidine. Viramidine and ribavirin exposure in plasma and RBCs generally increased from the 400- to 600-mg dose level of viramidine. However, no further increase in exposure was noted at the 800-mg dose. Long half-lives for viramidine (66-76 hours in plasma and 200-420 hours in red blood cells) and ribavirin (340-410 hours in plasma and 360-430 hours in red blood cells) were noted. A negligible amount of viramidine (1%-4% of dose) and a small amount of ribavirin (9%-14% of dose) were excreted in the urine. The renal clearance was low for both viramidine (5-8 L/h) and ribavirin (4-7 L/h). Significant accumulation of viramidine was noted in red blood cells (accumulation factor [R] = 5-8) but not in plasma (R = 2). Extensive accumulation of ribavirin was noted in both plasma (R = 9-17) and red blood cells (R = 77-129). Steady-state levels of ribavirin and viramidine in plasma and red blood cells were achieved by day 22. At steady state, there was extensive conversion of viramidine to ribavirin in both plasma and red blood cells. Both viramidine and ribavirin were preferentially distributed into red blood cells than plasma.

Ribavirin, part of the current first-line combination therapy for the treatment of chronic hepatitis C, has side effects-in particular, hemolytic anemia-that is frequently dose limiting. Based on animal studies, viramidine, a prodrug of ribavirin, is converted to ribavirin in the liver. Viramidine dosing yielded 50% higher ribavirin levels in the monkey liver but only half in plasma and red blood cells compared to ribavirin dosing. At the same dose, it also had a safer profile than ribavirin in a 28-day toxicity study in monkeys. The current study was carried out to evaluate the safety, tolerability, and pharmacokinetics of viramidine in healthy male volunteers (n = 8-18 on viramidine vs. 2 on placebo at each dose level) after oral dosing of viramidine at 200, 600, and 1200 mg. There were no serious adverse events, and most adverse events were mild. The percentages of treatment-emergent events judged to be possibly related to the study drug were 50% in the 1200-mg group, 26% in the 600-mg group, and none in the 200-mg group. Viramidine was orally absorbed and rapidly converted to ribavirin with a t(max) of 1.5 to 3.0 hours for both viramidine and ribavirin in plasma. There was dose proportionality in plasma AUC(0-168 h) and C(max) for viramidine and in plasma AUC(0-168 h) for ribavirin. Plasma AUC(0-168 h) for ribavirin was two to four times higher than plasma AUC(0-168 h) for viramidine, indicating that viramidine is extensively metabolized to ribavirin and is a prodrug of ribavirin in man. Amounts of viramidine and ribavirin excreted in the urine were small (2%-5% of dose), indicating that the main route of elimination for both viramidine and ribavirin is metabolism. Both viramidine and ribavirin were excreted into urine through the mechanism of glomerular filtration. In addition, an evaluation of the effect of a high-fat meal on the pharmacokinetics of viramidine and ribavirin after oral dosing of viramidine at 600 mg was conducted in healthy male volunteers (n = 33-34) in a crossover study design. A high-fat meal increased viramidine plasma AUC(0-168 h) by 44% and C(max) by 20%. It also increased ribavirin plasma AUC(0-168 h) by 19% and C(max) by 43%. The clinical relevance of these increases is unknown.

A comparison of different regiments of ribavirin (R), administered either orally or by aerosol, was performed in 16 elderly subjects (13 men, 3 women, mean age 63 +/- 8 years) considered to be in the "high-risk" category for complications from influenza as defined by the Centers for Disease Control. The subjects were divided into four groups. Group O-600 received 600 mg orally R every 8 hours for 48 hours followed by 200 mg every 8 hours for 72 hours for a total dose of 5.4 g (22.1 mmol). Group O-800 received 800 mg oral R every 8 hours for 24 hours followed by 400 mg every 12 hours for 96 hours for a total dose of 4.1 g (22.9 mMoles). Group A-40 received R (40 mg/ml) aerosolized through a small particle aerosol generator for 6 hours every 12 hours for 96 hours, yielding an average delivered dose of 6.2 g (25.4 mMoles) R. Group A-60 received aerosolized R (60 mg/mL) for 2 hours every 8 hours for 96 hours, yielding an average delivered dose of 4.6 g (18.8 mMoles) R. No hematologic or other laboratory abnormalities were associated with any of the regimens. Group O-800 and O-600 reached mean peak plasma R levels of 11.8 microM and 5.3 microM, respectively, after 18 hours of therapy. Subsequent administration of 20 mg R every 8 hours was sufficient to maintain a plasma R level greater than 7 microM. Among the aerosol groups, group A-40 approached steady state plasma R levels (8-10 microM) more quickly than group A-60.(ABSTRACT TRUNCATED AT 250 WORDS)