Safety and Pharmacokinetics of IDX184, a Liver-Targeted Nucleotide Polymerase Inhibitor of Hepatitis C Virus, in Healthy Subjects

Abstract

IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the active triphosphate of 2-methylguanosine (2-MeG), a potent and specific polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. Plasma and urine pharmacokinetic sampling was performed over a period of 120 h after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a mean half-life (t 1/2 ) of approximately 1 h, while plasma concentrations of 2-MeG gradually increased. Consistent with a liver-targeting approach, plasma exposure of IDX184 and 2-MeG was low and was also dose related: the mean maximum concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 2-MeG, and the respective mean total area under the curve ranged from 1.2 to 22.7 and 17.3 to 334 ng ⅐ h/ml. Mean 2-MeG plasma concentrations 24 h after dosing were 0.6 to 3 ng/ml for the 25-to 100-mg doses. Mean 2-MeG t 1/2 values ranged from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2-MeG, respectively. IDX184 was safe and well tolerated; no serious adverse events (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were observed. The incidence of AEs and laboratory abnormalities was low and was similar among subjects receiving IDX184 or a placebo. All AEs were mild to moderate and resolved at the end of study. The favorable safety and pharmacokinetic profiles support further clinical evaluation of IDX184 in HCV-infected patients.Hepatitis C virus (HCV) infection is a global public health problem. The global prevalence of hepatitis C infection is estimated to average 3%, resulting in approximately 170 million HCV-infected persons worldwide (8).The current standard of care for patients with chronic hepatitis C and compensated liver disease is the combination of parenterally administered pegylated interferon and orally administered ribavirin. However, sustained virologic response rates are less than 50% in treatment-naive patients with genotype 1 infection (2, 4). In addition, many patients are not good candidates for treatment with these agents due to advanced liver disease or concurrent medical conditions, and many patients show poor tolerance of these treatments. Therefore, there is a need for new anti-HCV therapies, particularly for patients with genotype 1 HCV or those who have failed to respond to the available treatment options.While nucleoside HCV polymerase inhibitors have a higher genetic barrier to resistance and have demonstrated clinical anti-HCV activity, early nucleoside analogs have wide systemic exposure and inefficient phosphorylation of their 5Ј-monophosphate (MP) metabolite, resulting in limited formation of the active 5Ј-triphosphate (TP) in the liver, the site of HCV replication (1,3,5). In that context, IDX184 (Fig. 1) ...

Short-Term Monotherapy with IDX184, a Liver-Targeted Nucleotide Polymerase Inhibitor, in Patients with Chronic Hepatitis C Virus Infection

“…This is likely due to a food effect recently characterized (data on file). Because of the differences in sampling schedules, which were shorter and less frequent in patients than in healthy subjects, the true terminal phase for 2=-MeG was not observed, resulting in a shorter estimated half-life (19). Nevertheless, the roughly 2-fold-higher trough concentration seen after repeat dosing implies that the elimination process responsible for achieving the steady state is associated with an effective or functional half-life of around 24 h. This was similar to the terminal half-life reported in healthy subjects and recently confirmed in a subsequent phase II clinical study in HCV-infected patients receiving IDX184 for 14 days (data on file).…”

“…Intensive plasma pharmacokinetic assessments were performed over a period of 8 h after the first and third doses, with predose sampling for trough level monitoring. Plasma concentrations of IDX184 and 2=-MeG were measured using a validated liquid chromatography-mass spectrometry-mass spectrometry methodology as previously described (19). This assay has lower limits of quantification of 0.1 and 0.2 ng/ml for IDX184 and 2=-MeG, respectively.…”

“…Human plasma IDX184 and 2=-MeG concentrations were low, consistent with IDX184 being a liver-targeted prodrug. The overall pharmacokinetic profile of IDX184 supported once-daily dosing in HCVinfected patients (19).…”

Genotype and Subtype Profiling of PSI-7977 as a Nucleotide Inhibitor of Hepatitis C Virus

“…PSI-7977 (prodrug of 2=-F-2=-C-methyluridine monophosphate) (38), PSI-352938 (prodrug of 2=-F-2=-C-methylguanosine monophosphate) (34), PSI-6130 (2=-F-2=-C-methylcytidine) (40), R1479 (4=-azidocytidine) (13), IDX-184 and INX-189 (prodrugs of 2=-C-meth-ylguanosine monophosphate) (43,48), NS5B nonnucleoside inhibitors NNI-1 (an indole analog), NNI-2 (a thiophene analog), NNI-3 (a benzothiadiazine analog), and HCV-796 (a benzofuran analog or NNI-4) (39), NS3 protease inhibitors telaprevir and RG7227 (ITMN-191) (21,22), NS3/4a inhibitor ACH-806 (46), and NS5A inhibitor BMS-790052 (8) were synthesized at Pharmasset and shown to be Ͼ95 to 99% pure by proton nuclear magnetic resonance, mass spectroscopy, and highperformance liquid chromatography analysis. Ribavirin was obtained from Sigma-Aldrich.…”

Overcoming Stability Challenges in the Quantification of Tissue Nucleotides: Determination of 2′-<i>C</i>-Methylguanosine Triphosphate Concentration in Mouse Liver

“…1) is a liver-targeted prodrug that is metabolized to 2′-C-methylguanosine monophosphate (2′-MeGMP) and subsequently converted to the active triphosphate (2′-MeGTP) by cellular kinases following uptake by hepatocytes. 15) For the purpose of pharmacokinetic assessments in drug development, it was crucial to develop a rapid, selective and accurate method for quantifying 2′-MeGTP in liver samples. Previously a method for analyzing 2′-MeGTP in mouse liver was reported using a chelating reagent to stabilize the triphosphate homogenization step, which lacks sufficient detailed descriptions, and included a laborious pulverizing step on dry ice.…”