1216 Disposition and metabolic profile in monkey liver following single and multiple oral dosing of [14C]ribavirin and [14C]viramidine

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AASLD ABSTRACTS

1216 DISPOSITION AND METABOLIC PROFILE IN MONKEY LIVER FOLLOWING SINGLE AND MULTIPLE ORAL DOSING OF [14C]RIBAVIRIN AND [14C]VIRAMIDINE. Li-

HEPATOLOGY, October 2003

Disclosures: Chin-Chung Lin - No relationships to disclose David Lourenco - No relationships to disclose Li-Tain Yeh - No relationships to disclose

Tain Yeh, David Lourenco, Chin-Chung Lin, Ribapharm, Inc., Costa Mesa, CA Background Ribavirin forms part of current combination therapy for chronic hepatitis C, but its RBC toxicity represents a challenge in clinical management. Viramidine, a prodrug of ribavirin can readily convert to ribavirin and exert antiviral activity. Oral dosing of [3H]ribavirin in portal vein-cannulated monkey gave 2X RBC radioactivity, but 1/3 the amount of radioactivity retained in the liver than oral dosing of [3H]viramidine, indicating that viramidine may have better efficacy with reduced RBC toxicity as compared to ribavirin. Aim: To compare disposition and metabolic profile in monkey liver after single and multiple oral dosing of [~4C]viramidine or [~4C]ribavirin. Methods: Cynomolgus monkeys received oral dose (10 mg/kg) of [~4C]viramidine or [~4C]ribavirin once daily for 10 days. At 24 hours after single dose or the 10th dose, liver samples were collected, immediately extracted with 0.5 M EDTA/methanol and centrifuged. Radioactivity in the liver was determined using liquid scintillation spectrometry. The metabolic profile in the liver was analyzed by HPLC equipped with radioactivity flow detection. Results: Liver radioactivity concentration was 8.3 and 16.6 /xg.equivalent/g, respectively, after single and multiple dosing of [~4C]ribavirin. The concentration was 25.9 and 50.7/xg.equivalent/g, respectively after single and multiple dosing of [~4C]viramidine. Metabolic profiles (expressed as % of total radioactivity) in the monkey liver are summarized below: After oral dosing of ribavirin, ribavirin monophosphate (RMP) is the predominant metabolite, followed by ribavirin (R), ribavirin diphosphate (RDP), ribavirin triphosphate(RTP) and triazole carboxamide (TCONH2). After oral dosing of viramidine, viramidine monophosphate (VMP) is the predominant metabolite, followed by RMP, TCONH2, R, RDP, RTP, viramidine, viramidine monophosphate (VMP), viramidine diphosphate (VDP) and viramidine triphosphate (VTP). The total R (R+RMP+RDT+RTP) accounted for 21.5 % of the liver radioactivity after single dosing and 43.8 % after multiple dosing of viramidine. B>Conclusions: (1) Multiple dosing of [~4C]viramidine or [~4C]ribavirin once daily for 10 days resulted in 2X accumulation in liver radioactivity. (2) Viramidine dosing gave 2X higher liver radioactivity than ribavirin dosing after either single or multiple administration. (3) After oral dosing, viramidine in the liver was either phosphorylated or slowly converted to ribavirin and its phosphorylated metabolites. (4) Following prolonged administration, viramidine in the liver may mostly convert to ribavirin and its phosphorylated metabolites with time and the total R may account for majority of drug in the liver. Ribavi~io

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1217 COMBINATION THERAPY FOR HCV AFFECTS THE HIV VIRAL LOAD IN PATIENTS RECEIVING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY(HAART). Joel Kertznus, ~ nrique

G Molina, Arie Regev, ~ ugene R Schiff, University of Miami, Miami, FL Background:. Approximately 25% of HIV-infected persons in the United States are coinfected with HCV. Ribavirin may inhibit in v/tro intracellular phosphorylation of reverse trancriptase inhibitors of HIV-1 such as Stavudine (d4t), Zidovudine (ZDV) ,Lamivudine (3TC) and Didanosine (DDI). Recently the use of DDI and Ribavirin has b e e n associated with increased mitochondrial toxicity. Nevertheless, several small case series of HCV/HIV-coinfected patients have failed to detect clinically significant interactions. Aim: To asses the effect of Ribavirin in combination with standard or Pegilated Interferon (IFN/Riba or Peg-IFN/Riba) on the efficacy of highly active antiretroviral therapy (HAART) in vivo, by measuring changes in HIV viral load. Patients and Methods: We retrospectively reviewed the medical records of 16 patients co-infected with HIV/HCV and treated with HAART. All 16 patients had an HIV viral load undetectable or < 10,000 copies at the beginning of therapy with IFN/Riba or PegIFN/Riba. All were followed in an outpatient Hepatology Clinic of a County Hospital between January 2000 and May 2003. We measured plasma HIV RNA levels, CD4 cell count, and HCV RNA before, during, and after the use of combination therapy. Results: 12 patients (pts) were males, 4 females, the mean ages were 49 and 43 respectively. Three pts had a history of depression and I was coinfected with Hepatitis B. Seven pts admitted prior alcohol use (> 20 g/day), 5 were former WDA, and 4 had snorted cocaine. Thirteen of 16 pts received HAART(ZDV 5 pts, DDI 2 pts, D4t 5 pts, 3TC 11 pts). Nine pts were treated with IFN/Riba and 7 with Peg-IFN/Riba with a mean duration of treatment of 7.7 months (range 3-12). Treatment was discontinued due to adverse events in 3, non-response in 9, and end of treatment response in 4. Forteen pts had HCV Genotype 1(10 pts l a and 4 pts lb) and 2 pts had 3a. Nine of 16 pts exhibited a decrease of greater than 5%in the CD4 cell count after 6 months of therapy. Twelve of 16 pts had an undetectable HIV viral load at the beginning of therapy, 6 of t h e m became detectable, 4 having a viral load < 10000 copies and 2 > 100000 copies. Four of 6 pts with a detectable baseline HIV viral load became undetectable: 2 while receiving therapy and 2 within 12 months after discontinuation of therapy. Sustained virogical response was achieved in I out of 16 pts. Conclussion: Our data suggest that in up to 50% of patients receiving HAART the HIV viral load may become detectable after the initiation of combination therapy for HCV. Sustained virological response is low due to adverse events and possibly drug -drug interaction between Ribavirin and HAART. Close monitoring of HIV viral load in patients receiving HAART and IFN or Peg-IFN with Ribavirin is recommended. Disclosures: Joel Kertznus - No relationships to disclose Enrique G Molina - No relationships to disclose Arie Regev - No relationships to disclose Eugene R Schiff - No relationships to disclose