Dose Range Study of Pharmacokinetics, Safety, and Preliminary Antiviral Activity of Emtricitabine in Adults with Hepatitis B Virus Infection

Abstract

A multicenter, open-label study was performed to evaluate the safety, anti-hepatitis B virus (anti-HBV) activity, and pharmacokinetics of emtricitabine therapy administered once daily for 8 weeks to patients infected with HBV. Clinical and virologic evaluations were completed at the baseline; at 7, 14, 28, 42, and 56 days during treatment; and at 24, 48, and 28 days posttreatment. Forty-nine patients were enrolled in five dose cohorts (doses of 25, 50, 100, 200, and 300 mg, all of which were administered once daily [q.d.]). Peak plasma emtricitabine concentrations occurred within 1.5 h following dosing. Plasma emtricitabine concentrations (maximum concentrations of drug in plasma and areas under the concentration-time curves) increased nearly dose proportionally over the 25-to 300-mg dose range, with relatively small intersubject variabilities. The plasma half-life of emtricitabine ranged from 6 to 9 h. HBV DNA levels were measured by the Digene HBV Hybrid Capture II assay. Viral suppression (reduction in log 10 serum HBV DNA levels) occurred in all dose cohorts. All doses demonstrated potent and rapid antiviral activities, with a trend toward a greater suppression with daily doses of 100 mg or greater. At 2 months, the median change in the serum HBV DNA level from the baseline level ranged from ؊1.7 log 10 for the 25-mg dose administered q.d. to ؊3.3 log 10 for the 300 mg dose administered q.d. Emtricitabine was well tolerated over the 2-month dosing period. These results support further clinical development of emtricitabine for the treatment of chronic hepatitis B infection.Chronic hepatitis B virus (HBV) infection is a common and often severe form of liver disease that affects approximately 1 million Americans and 350 million people worldwide (4,8,14). In addition to treatment with alpha interferon, major therapeutic advances have occurred with the discovery of new antiviral compounds that inhibit the reverse transcriptase activity of HBV DNA polymerase. Recently, lamivudine (3TC) has been approved for use in the treatment of chronic HBV infection. However, prolonged monotherapy with 3TC selects for resistance mutations at rates varying from 16 to 32% at 1 year in immune competent patients (4,5,7,12,13). Therefore, there is a need to develop additional anti-HBV drugs that may be used alone or in combination to alleviate the problem of resistance.Emtricitabine (FTC) is a deoxycytidine analog reverse transcriptase inhibitor that has been demonstrated to have potent and selective inhibitory activities against HBV and human immunodeficiency virus (HIV) (the structure of FTC is illustrated in Fig. 1). FTC is readily anabolized by cellular enzymes stepwise to form its monophosphate, diphosphate, and finally, triphosphate forms. The triphosphate form is the active intracellular moiety that completely inhibits HBV DNA polymerase. The anti-HBV activity of FTC has been demonstrated in a chimeric mouse model and against woodchuck hepatitis virus in naturally infected woodchucks (1, 2).In in vitro assays with HIV, FTC is...

Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic Hepatitis B virus infection

“…Emtricitabine was shown to select for the same drug resistant mutants as lamivudine, although at a lower rate in phase II and III trials (9% at one year, and 18% at two years) (Gish et al, 2002). Preliminary data obtained in phase II trials with Telbivudine show the same trend with the selection of a M204I mutation in less than 10% of the patients after one year of treatment.…”

A Bioequivalence Study Comparing Two Formulation of Emtricitabine Capsules

“…Emtricitabine is rapidly and extensively absorbed followed oral administration, with peak plasma concentration occurring within 1.5 hr of dosing and with an oral bioavailability >90% (Wang et al, 2001; Gish et al, 2002). Emtricitabine disposition follows linear kinetics with small intersubject variability and plasma emtricitabine concentrations increased dose propotionally over a wide dose range (100-1200mg) (Wang et al, 1995).…”

Combinations of Adefovir with Nucleoside Analogs Produce Additive Antiviral Effects against Hepatitis B Virus In Vitro

“…FTC is an L-nucleoside with structural similarity to lamivudine that was recently approved for the treatment of human immunodeficiency virus (HIV) and is in phase III development for chronic hepatitis B. In vitro and clinical studies have indicated that FTC has antiviral activity and a resistance profile similar to that of lamivudine (13,14); however, preliminary clinical results suggest that resistance to FTC may occur less frequently than with lamivudine (R. Gish …”