Paper # 605 
Assessment of Bioequivalence of Tenofovir, Emtricitabine, and Efavirenz Fixed-dose Combination Tablet Compared with a Compounded Oral Liquid Formulation Derived from the Tablet
Jennifer King*, M McCall, A Cannella, M Markiewicz, A James, and E Acosta
Univ of Alabama at Birmingham, US
Background: Atripla is a fixed dose combination
(FDC) tablet combining efavirenz (EFV), emtricitabine (FTC), and tenofovir
disoproxil fumarate (TDF). Administration of Atripla is limited to
patients who can swallow tablets, since a liquid formulation is not
commercially available. This study determined the bioequivalence of the FDC
tablet and a compounded liquid formulation derived from the FDC tablet.
Methods: Fourteen healthy subjects (8 female, 6
male) were randomized to receive the FDC tablet of EFV, FTC, and TDF or the FDC
tablet crushed, dissolved in 5 mL of water and titrated to 20 mL with
Ora-Sweet oral vehicle. Subjects took single doses of both formulations on an
empty stomach separated by a 14-day washout period. Plasma concentrations were
measured pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post dose.
Area under the concentration-time curve (AUC∞) and maximum
concentration (Cmax) were determined using noncompartmental methods
(WinNonlin 5.2). Geometric mean ratio (GMR) of liquid to tablet Cmax,
AUC∞, and 90% confidence intervals (CI) were calculated to
determine bioequivalence (90%CI 0.8 to 1.25).
Results: Mean ± standard deviation age and weight
were 33.3 ± 10.9 years and 85.7 ± 18.4 kg, respectively. Geometric mean
(percent coefficient of variation) Cmax and AUC∞ for
each drug in each formulation are listed below. EFV and TDF AUC∞
and Cmax for both formulations were lower compared with steady-state
historical data in HIV-infected patients.
|
Drug
|
Formulation
|
Cmax (mg/L)
|
AUC¥ (mg×h/L)
|
|
GM
(%CV)
|
Ratio of GM
Liquid vs. Tablet (90% CI)
|
GM
(%CV)
|
Ratio of GM
Liquid vs. Tablet
(90% CI)
|
|
EFV
|
Liquid
|
1.3 (28.8)
|
0.86 (0.75-1.04)
|
56.7 (80.0)
|
0.97 (0.82-1.26)
|
|
Tablet
|
1.5 (39.0)
|
58.7 (57.5)
|
|
FTC
|
Liquid
|
2.1 (21.0)
|
1.15 (0.97-1.25)
|
10.8 (15.9)
|
0.99 (0.91-1.05)
|
|
Tablet
|
1.8 (32.3)
|
10.9 (24.7)
|
|
TDF
|
Liquid
|
0.3 (27.7)
|
1.38 (1.12-1.70)
|
2.2 (36.3)
|
1.21 (1.07-1.40)
|
|
Tablet
|
0.2 (47.8)
|
1.8 (29.2)
|
Conclusions: Although exposures were similar between
the formulations, the compounded formulation did not strictly meet
bioequivalence criteria. The 90% CIs for EFV Cmax fell below the
range of bioequivalence while EFV AUC∞ fell slightly above the
range and TDF Cmax and AUC∞ fell well above the
range. TDF Cmax and AUC∞ were approximately 40% and
20% higher, respectively, with the liquid formulation. These data suggest both
formulations are not bioequivalent for 2 of the 3 drugs; the clinical
implications of these data are unknown.
|
