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Viramidine May Not Lead to Ribavirin Associated Anemia: "Clinical Study of Viramidine in Treatment of Hepatitis C Supports RBC-Sparing Mechanisms of Action"
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"CLINICAL STUDY OF VIRAMIDINE IN TREATMENT OF HEPATITIS C SUPPORTS RBC-SPARING MECHANISM OF ACTION" abstract 84
Reported by Jules Levin
Digestive Disease Week
May 15-20, 2004
New Orleans, LA.
Summary: Ribavirin is associated with anemia in HCV+ receiving interferon/ribavirin therapy for HCV. Studies reported at this conference show preliminary results that Viramidine may not cause anemia. The study results only report viral load (HCV RNA) results for 24 weeks therapy. Phase III studies will show if viral load responses are equal for Viramidine compared to ribavirin. Viramidine is a pro-drug for ribavirin.
Sanjeev Arora (University of New Mexico) reported on these study results at the Digestive Disease Week (DDW) Conference May 15-20, 2004 in New Orleans, LA. Pegylated interferon plus ribavirin (RBV) is the standard of care for therapy for the hepatitis C virus. Ribavirin are pills taken twice daily and is associated with anemia. During the first 4 weeks of combination therapy for HCV hemoglobin (Hb) levels decrease an average of 2 to 3 g/dL. 10% to 13% of patients experience a decrease in Hb to <10 g/dL. About 25% of patients need to reduce dose of RBV due to anemia. It's difficult to predict who gets anemia. Dose reduction of RBV may lead to decrease in sustained viral response, particularly during the first 12 weeks after initiating Peginterferon/RBV therapy.
RBV concentrates in RBCs at a 100-fold higher concentration than in plasma. Uptake occurs via a NBTI-sensitive "es" nucleotide transporter. RBV is trapped in RBCs where it undergoes irreversible intracellular phosphorylation to RBV-triphosphate. Accumulation continues due to insufficient purine 5'-nucleosidase (phosphatase) activity in anucleated RBC.
High levels of RBV compete for phosphorylation enzymes resulting in depletion of intracellular ATP. Low levels of ATP in RBC lead to impaired anti-oxidant defense mechanisms, reduced red cell survival and anemia. Administration of antioxidants may not prevent RBV-induced anemia.
Pre-clinical studies have suggested viramidine, a pro-drug of ribavirin, yields higher liver drug levels than ribavirin, with a corresponding reduction in plasma and red blood cell (RBC) drug concentrations. To test the hypothesis that viramidine is associated with less hemolytic anemia than ribavirin, we looked at hemoglobin reductions and ribavirin levels in RBCs in an ongoing dose ranging clinical study of viramidine as a part of combination therapy for hepatitis C.
Studies in monkeys of 10 mg/kg daily oral dosing found Viramidine had 50% lower levels in RBCs compared to RBV and 3 times greater levels in the liver than RBV.
The study randomized 180 treatment-naive patients in a 1:1 ratio to receive (Pegasys) peginterferon alfa-2a 180 ug/wk SC plus viramidine 400 (N=47), 600 (N=43), or 800 (N=45) mg BID or ribavirin 1000/1200 mg daily (N=45).
HCV RNA reductions were similar in the two groups at week 24 of therapy. So Viramidine did not appear to result in less reductions in HCV viral load than RBV after 24 weeks of therapy but 48 weeks and 72 weeks sustained viral load results are awaited to confirm efficacy of Viramidine.
Blood samples obtained during the study were evaluated for ribavirin Cmin concentrations in RBCs at Weeks 4 and 12. Cmin is the levels of ribavirin seen at the end of the dosing period.
The mean ribavirin Cmin concentration in RBCs following 4 weeks of treatment with viramidine 1200 mg/day was 126 ug/mL compared with 246 ug/mL for the ribavirin treated group.
After 12 weeks of treatment, the mean RBC ribavirin Cmin was 159 ug/mL in patients who received viramidine 1200 mg/day compared to 235 ug/mL in ribavirin-treated patients. After 4 weeks RBV Cmin was 250 ng/ml for RBV compared to 135 ng/ml for Viramidine.
In phase 2 trials anemia (Hb <10 g/dL) incidence was 7% in patients receiving 800 mg Viramidine BID and 0% for patients receiving 400 or 600 mg BID Viramidine compared to 24% for patients receiving 1000/1200 mg RBV. Mean Hb declined by about 4 g/dL for patients taking RBV compared to --2.5 to 3 g/dL for patients taking the 3 doses of Viramidine over 24 week period following initiation of HCV therapy. Investigators reported a smaller proportion of patients who received viramidine 800-1200 mg/day had hemoglobin >= 2.5 g/dL decrease from baseline (48% versus 82%) when compared with ribavirin-treated patients. At EASL Conference in April 2004 study investigators reported 67% of patients receiving 800 mg BID Viramidine had >=2.5 g/dL Hb drop and/or <10 g/dL during 24 weeks compared to 82% receiving RBV 1000/1200 mg daily (P>0.05), 51% for Viramidine 600 mg BID and 45% for Viramidine 400 mg BID. Of note at EASL investigators reported incidence of patient-reported adverse events and 33% reported fatigue for patients receiving 800 mg Viramidine, 33% by patients receiving 600 mg Viramidine compared to 31% for patients receiving RBV 1000/1200 mg BID. Depression rates were 18% for 800mg Viramidine, 9% for 600 mg dose of Viramidine vs 22% for RBV. Other commonly reported side effects were reported at similar rates of incidence as well. The percentages of patients reporting rigors and irritability were less at the 600 mg Viramidine dose than the RBV dose 1000/1200mg/daily.
The study investigators concluded that the cascade of events that leads to hemolysis begins with the preferential uptake of RBV into RBCs. Viramidine is a liver targeting, pro-drug of RBV that does not significantly accumulate in the RBC. The lower concentration of Viramidine-derived RBV in plasma correlates with significantly less decline in Hb. In phase II clinical study, Viramidine at doses of 400 mg BID and 600 mg BID at 24 weeks resulted in: no instances of anemia (Hb <10 g/dL) and no dose reductions due to anemia. Based on 24 week interim data, Viramidine decreases RBC exposure to RBV, resulting in less anemia and comparable antiviral response.
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