IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C.

BACKGROUND: IDX184 is a liver-targeted nucleotide prodrug that selectively inhibits HCV NS5B polymerase. METHODS: This randomized, double-blind, placebo-controlled, ascending-dose study investigated the antiviral activity, safety and pharmacokinetics of IDX184 plus pegylated interferon-α2a and ribavirin (P/R) in treatment-naive patients with genotype-1 HCV. A total of 81 patients with baseline HCV RNA≥5 log10 IU/ml, alanine aminotransferase ≤3× upper limit of normal and compensated liver disease were dosed. Sequential cohorts of 20 patients, randomized 16:4 (active:placebo), received IDX184 for 14 days at rising daily doses of 50, 100, 150 or 200 mg in combination with P/R for 14 days. RESULTS: At the end of triple dosing, HCV RNA changes from baseline (mean ±sd log10) and proportion of patients achieving undetectable viral load (<15 IU/ml) based on the efficacy-evaluable population were -2.7 ±1.3 (13%), -4.0 ±1.7 (50%), -4.2 ±1.9 (50%), -4.1 ±1.2 (40%), -4.3 ±1.5 (29%) and -3.7 ±1.2 (25%) for the 50 mg once daily, 50 mg twice daily, 100 mg once daily, 150 mg once daily, 100 mg twice daily and 200 mg once daily IDX184 doses, respectively. P/R alone resulted in a reduction of -1.5 ±1.3 log10 with only 6% of patients with undetectable viral load. Patients with genotypes-1a or -1b responded similarly. No viral breakthrough or resistance associated with IDX184 was observed. Anti-HCV activity of IDX184 correlated with plasma exposure of its nucleoside metabolite 2'-methylguanosine. Most adverse events were mild or moderate in severity and were consistent with those associated with P/R. The most common adverse events were fatigue and headache. CONCLUSIONS: IDX184 in combination with P/R for 14 days was well tolerated and demonstrated greater antiviral activity with more patients achieving undetectable viral load than P/R.

Short-term monotherapy with IDX184, a liver-targeted nucleotide polymerase inhibitor, in patients with chronic hepatitis C virus infection.

IDX184 is a liver-targeted prodrug of 2'-methylguanosine (2'-MeG) monophosphate. This study investigated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184 as a single agent in treatment-naïve patients with genotype-1 chronic hepatitis C virus (HCV) infection. Forty-one patients with baseline HCV RNA ≥ 5 log(10) IU/ml, alanine aminotransferase (ALT) ≤ 2.5× the upper limit of normal, and compensated liver disease were dosed. Sequential cohorts of 10 patients, randomized 8:2 (active:placebo), received 25, 50, 75, and 100 mg of IDX184 once daily for 3 days, with a 14-day follow-up. There were no safety-related treatment discontinuations or serious adverse events. The adverse events and laboratory abnormalities observed for IDX184- and placebo-treated patients were similar. At the end of the 3-day treatment period, changes from baseline in HCV RNA levels (means ± standard deviations) were -0.5 ± 0.6, -0.7 ± 0.2, -0.6 ± 0.3, and -0.7 ± 0.5 log(10) for the 25-, 50-, 75-, and 100-mg doses, respectively, while viral load remained unchanged for the pooled placebo patients (-0.05 ± 0.3 log(10)). Patients with genotype-1a and patients with genotype-1b responded similarly. Serum ALT levels decreased, especially at daily doses ≥ 75 mg. During the posttreatment period, plasma viremia and serum aminotransferase levels returned to near pretreatment levels. No resistance mutations associated with IDX184 were detected. Plasma exposure of IDX184 and its nucleoside metabolite 2'-MeG was dose related and low. Changes in plasma viral load correlated with plasma exposure of 2'-MeG. In conclusion, the results from this proof-of-concept study show that small doses of the liver-targeted prodrug IDX184 were able to deliver significant antiviral activity and support further clinical evaluation of the drug candidate.

Pharmacokinetics of telbivudine in subjects with various degrees of renal impairment.

This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CL(CR)), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CL(R)), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CL(R) and CL(CR). In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of approximately 45%, representing a approximately 23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.

Pharmacokinetics of telbivudine in subjects with various degrees of hepatic impairment.

This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.