Bioequivalence of the Co-formulation of Efavirenz/ Emtricitabine/Tenofovir (Atripla)

Atripla Tablets

Efavirenz (EFV; 600 mg), emtricitabine (FTC; 200 mg) and tenofovir DF (TDF; 300 mg) are preferred agents for use in the treatment of HIV infection. This study evaluated the pharmacokinetics (PK) and bioequivalence of the co-formulation of EFV/FTC/TDF (Test) to their commercially available individual dosage forms (EFV+FTC+TDF, Reference) in a single-dose study in healthy subjects.

Subjects were randomized to two treatment sequences in an open-label cross-over study design. Study drugs were administered under fasted conditions. Serial blood samples were obtained over 504 hours after oral administration of each treatment and PK parameters calculated using noncompartmental methods.

Formulation bioequivalence was assessed by 90% confidence intervals (CI) for the ratio of geometric least square means (GMR) for Cmax, AUC0-t, and AUCinf for the Test versus Reference treatment.

Results

48 subjects were enrolled and 45 completed the study. Headache and dizziness was reported as the most frequent drug-related adverse events in 24.4% (Test) to 29.2 % (Reference) of subjects.

Arithmetic mean (CV %) and the GMR (90%CI) of the PK parameters for EFV, FTC and tenofovir (TFV) are presented below:

 

EFV

FTC

TFV

PK Parameter

Test

Reference

%GMR (90%CI)

Test

Reference

%GMR (90%CI)

Test

Reference

%GMR (90%CI)

Cmax (g/mL)

2.28 (26.7)

2.30 (30.6)

99.9 (93.4,107)

2.13 (25.3)

2.38 (20.4)

88.8 (84.0,93.9)

0.325 (34.2)

0.353 (29.6)

91.5 (84.6,98.8)

AUC0-t (g.hr/mL)

125 (25.9)

133 (27.3)

95.7 (90.5,101)

10.7 (18.1)

10.9 (14.9)

98.0 (94.9,101)

1.95 (32.9)

1.97 (32.8)

99.3 (91.0,108)

AUCinf (g.hr/mL)

144 (32.0)

155 (35.1)

95.2 (88.9,102)

10.9 (17.9)

11.1 (14.9)

98.0 (94.9,101)

2.31 (29.2)

2.32 (30.3)

100 (93.2,108)

These findings show that the co-formulation of EFV/FTC/TDF is bioequivalent to administration of its individual components and represents the first one pill, once-daily complete antiretroviral regimen for the treatment of HIV 1 infection.

Gilead Sciences, Foster City, United States.

08/22/06

Reference
A Mathias, A Plummer, J Skillington, and others. Bioequivalence of the co-formulation of efavirenz /emtricitabine/tenofovir DF. 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract TUPE0098.