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.

Figures

FIG. 1.

FTC [(−)-2′,3′-dideoxy-5-fluoro-3′-thiacytidine].

FIG. 2.

Mean steady-state plasma FTC concentration-versus-time curves. QD, once daily; IC50, 50% inhibitory concentration.

FIG. 3.

Mean ± standard deviation steady-state plasma FTC Cmax and AUC from 0 to 24 h (AUC0-24) versus dose.

FIG. 4.

Change in median HBV DNA (log10) level from the baseline level over time.

FIG. 5.

Dose-response relationship of FTC anti-HBV activity. QD, once daily; C.V., coefficient of variation.

FIG. 6.

Percentage of patients with normal ALT levels over time (all doses).