Chemical formula: C₂₇H₄₅N₅O₅ Molecular mass: 519.677 g/mol PubChem compound: 10324367
Boceprevir is an inhibitor of the HCV NS3 protease. Boceprevir covalently, yet reversibly, binds to the NS3 protease active site serine (Ser139) through a (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells.
The antiviral activity of boceprevir was evaluated in a biochemical assay for slow binding inhibitors of NS3 protease and in the genotype 1a and 1b HCV replicon system. The IC50 and IC90 values for boceprevir against different genotype 1b replicons ranged from 200 to 600 nM and 400 to 900 nM, respectively, in a 72-hour cell culture assay. Loss of replicon RNA appears to be first-order with respect to time of treatment. Treatment at IC90 for 72 hours resulted in a 1-log10 drop in replicon RNA. Prolonged exposure resulted in a 2-log decrease in RNA levels by Day 15. In a genotype 1a replicon, the IC50 and IC90 values for boceprevir were 900 nM and 1,400 nM, respectively.
Evaluation of varying combinations of boceprevir and interferon alfa-2b that produced 90% suppression of replicon RNA showed additivity of effect; no evidence of synergy or antagonism was detected.
Boceprevir was absorbed following oral administration with a median T max of 2 hours. Steady state AUC, Cmax and Cmin increased in a less-than dose-proportional manner and individual exposures overlapped substantially at 800 mg and 1,200 mg, suggesting diminished absorption at higher doses. Accumulation is minimal and pharmacokinetic steady state is achieved after approximately 1 day of three times daily dosing.
In healthy subjects who received 800 mg three times daily alone, boceprevir medicine exposure was characterized by AUC of 6,147 ng.hr/mL, Cmax of 1,913 ng/mL, and Cmin of 90 ng/mL. Pharmacokinetic results were similar between healthy subjects and HCV-infected subjects.
The absolute bioavailability of boceprevir has not been studied.
Boceprevir should be administered with food. Food enhanced the exposure of boceprevir by up to 60% at the 800 mg three times daily dose when administered with a meal relative to the fasting state. The bioavailability of boceprevir is regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal.
Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 l at steady state. Human plasma protein binding is approximately 75% following a single dose of boceprevir 800 mg. Boceprevir is administered as an approximately equal mixture of two diastereomers which rapidly interconvert in plasma. At steady-state, the exposure ratio for the two diastereomers is approximately 2:1, with the predominant diastereomer being pharmacologically active.
Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo-ketoreductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single 800 mg oral dose of 14C-boceprevir, the most abundant circulating metabolites were a diasteriomeric mixture of ketone-reduced metabolites with a mean exposure approximately 4fold greater than that of boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5.
Boceprevir is eliminated with a mean plasma half-life (t1⁄2) of approximately 3.4 hours. Boceprevir has a mean total body clearance (CL/F) of approximately 161 l/hr. Following a single 800 mg oral dose of 14C-boceprevir, approximately 79% and 9% of the dose was excreted in faeces and urine, respectively, with approximately 8% and 3% of the dosed radiocarbon eliminated as boceprevir in faeces and urine. The data indicate that boceprevir is eliminated primarily by the liver.
In a study of patients with varying degrees of stable chronic liver impairment (mild, moderate and severe), no clinically significant differences in pharmacokinetic parameters were found, and no dose adjustment is recommended.
No clinically significant differences in pharmacokinetic parameters were observed between patients with end-stage renal disease (ESRD) and healthy subjects. Boceprevir is not eliminated by dialysis. No dose adjustment is required in these patients and in patients with any degree of renal impairment.
No gender-related pharmacokinetic differences in the phase III studies have been observed in adult patients.
Population pharmacokinetic analysis of boceprevir indicated that race had no apparent effect on exposure.
Population pharmacokinetic analysis of boceprevir indicated that age had no apparent effect on exposure.
In an in vitro dog Purkinje fiber study, boceprevir prolonged the action potential duration with inverse frequency dependence; the clinical relevance remains uncertain.
In repeat-dose toxicity studies boceprevir showed testicular degeneration in rats at systemic exposures lower than those in humans at the recommended human therapeutic dose. This is not observed in mice or monkeys.
Boceprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, human peripheral blood lymphocyte and mouse micronucleus assays.
In 2-year carcinogenicity studies, no carcinogenicity was observed, but there was an increased ncidence of hepatocellular adenomas in mice, which was not statistically significant, at systemic exposures 5.7-fold higher than those in humans at the recommended therapeutic dose. No carcinomas or adenomas were observed in rats. The hepatocellular tumours are considered due to enzyme induction and therefore not relevant for humans.
Boceprevir/medicine derived material was shown to be transferred into the milk of lactating rats. Exposure to boceprevir in nursing human infants is estimated to be less than 1% of the dose.
In rats, boceprevir induced reversible effects on fertility and early embryonic development in female rats at exposures 1.2-fold the human exposure at the recommended therapeutic dose. Decreased fertility was also observed in male rats, most likely as a consequence of testicular degeneration (no testicular degeneration has been observed in mice or monkeys). Boceprevir was shown to be devoid of embryonic or teratogenic potential in both rats and rabbits at maternotoxic dose levels.
Data obtained in juvenile rats suggest that the pharmacokinetic profile of boceprevir may be different than in adult rats, possibly due to immaturity of some metabolic pathways. No clinical paediatric exposure data is available.
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