Single-dose fed bioequivalence study of Emtricitabine, Tenofovir Alafenamide and Dolutegravir Tablets (200mg/25mg/50mg) versus DESCOVY® tablets (200mg/25mg; Gilead Sciences) and TIVICAY® tablets (50mg; ViiV Healthcare) in healthy adult volunteers
Background: The combination of Dolutegravir (DTG) with the fixed dose
combination (FDC) of emtricitabine (FTC) and tenofovir alafenamide (TAF) is one
of the most frequently used recommended combinations for the treatment of HIV in
high-income countries. WHO and several national guidelines recommend DTG as an
alternative first- and third-line. The use of TAF is currently not recommended
by WHO, also due to open questions on dosing in TB co-infection and pregnancy,
however the positioning of the combination of DTG, TAF and FTC is still
evolving. The objective of this study was to compare the relative bioequivalence
and safety profiles of Mylan''s FTC/TAF/DTG 200mg/25mg/50mg FDC tablets (T) with
the reference combination (R) of DESCOVY® (200/25 mg) and TIVICAY® (50 mg)
tablets.
Methods: In this open label, randomized, two-period, two-treatment,
cross-over, single dose evaluation, the relative oral bioequivalence was tested
in 33 healthy adult human subjects under fed conditions. In each period, each
subject received a single, oral dose of either Mylan''s FTC/TAF/DTG tablets or R.
Serial blood samples were collected pre-dose and at 21 timepoints until 72
hours post dose. Subjects were monitored for safety and tolerability. Single-dose
pharmacokinetic parameters for FTC/TAF/DTG were calculated using
non-compartmental techniques.
Results: Statistical analyses of these data reveal that the 90% confidence intervals are within the acceptable bioequivalent range of 80.00% and 125.00% for the natural log transformed parameters, LNAUCL, LNAUCINF and LNCPEAK for emtricitabine, tenofovir (data not shown), tenofovir alafenamide, and dolutegravir. (Table 1)
| Product | Parameter | Arithmetic Mean (%CV) T= Mylan | Arithmetic Mean (%CV) R = Reference | LSMEANS Ratio (T/R) | 90% Confidence Interval |
| FTC | AUCL (ng?hr/mL) | 10253 (18.23) | 10276 (17.43) | 1.00 | 98.14% - 101.40% |
| FTC | AUCINF (ng?hr/mL) | 10523 (17.84) | 10594 (17.31) | 0.99 | 97.82% - 100.91% |
| FTC | CPEAK (ng/mL) | 1986 (24.99) | 1923 (27.21) | 1.04 | 96.67% - 111.00% |
| TAF | AUCL (ng?hr/mL) | 230.5 (38.42) | 246.7 (46.53) | 0.95 | 88.43% - 101.53% |
| TAF | AUCINF (ng?hr/mL) | 231.7 (39.39) | 249.3 (46.84) | 0.95 | 88.41% - 101.07% |
| TAF | CPEAK (ng/mL) | 173.7 (62.51) | 180.7 (81.94) | 1.00 | 84.47% - 119.20% |
| DTG | AUCL (ng?hr/mL) | 83109 (30.84) | 82440 (27.20) | 1.00 | 95.69% - 104.44% |
| DTG | AUCINF (ng?hr/mL) | 87840 (32.62) | 87330 (29.65) | 1.00 | 95.37% - 104.52% |
| DTG | CPEAK (ng/mL) | 4097 (15.69) | 4121 (17.35) | 1.00 | 96.83% - 102.72% |
The AEs were mild in severity. Overall both R and T were well tolerated when administered as a single, oral dose under fed conditions.
Conclusions: This study demonstrates that Mylan''s FTC/TAF/DTG tablets are bioequivalent to a combination of DESCOVY® (200/25 mg) and TIVICAY® (50 mg) as separate tablets following administration of a single, oral dose administered under fed conditions.
D. Abhijit1, C. Santanu1, R. Chetan1, G. Sachin1, R. Bangaru2, A.K. Datla2, P. Deshpande3, A. Kanda3, E. Patras3
1Mylan Laboratories Limited, R&D, Hyderabad, India, 2Mylan Laboratories Limited, Clinical Research Center, Hyderabad, India, 3Mylan Laboratiories Limited, Business Development, Hyderabad, India