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Single-dose fed bioequivalence study of Lamivudine, TenofovirDisoproxilFumarate and Dolutegravir tablets (300mg/300mg/50mg) versus EPIVIR® tablets (300mg; ViiV-Healthcare), VIREAD® tablets (300mg; Gilead Sciences) and TIVICAY® tablets (50mg; ViiV-Healthcare) in healthy adult volunteers
Abstract Content:
Background: Dolutegravir (DTG) is one of the most frequently used
recommended antiretrovirals for the treatment of HIV in high-income countries.
WHO and several national guidelines recommend DTG/3TC/TDF as an alternative
first- and third-line in low-and middle-income countries. The objective of this
study was to compare the relative bioequivalence and safety profile of Mylan''s lamivudine,
tenofovirdisoproxilfumarate and dolutegravir tablets, 300 mg/300 mg/50 mg FDC
tablets (T) with the reference combination (R) of EPIVIR® (300 mg), VIREAD® (300
mg) and TIVICAY® (50mg).
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 T (Mylan''s 3TC/TDF/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: All 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 lamivudine, tenofovir and dolutegravir. (Table 1).
[Table 1: Pharmacokinetic Results 3TC, TNF and DTG]
The AEs were mild in severity. Overall both R and T were well tolerated administered as a single, oral dose under fed conditions.
Conclusions: This study demonstrates that Mylan''s 3TC/TDF/DTG 300 mg/300 mg/50 mg tablets are bioequivalent to a combination of EPIVIR® (300 mg), VIREAD® (300 mg) and TIVICAY® (50 mg) as separate tablets following administration of a single, oral dose administered under fed conditions.
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 T (Mylan''s 3TC/TDF/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: All 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 lamivudine, tenofovir and dolutegravir. (Table 1).
| Product | Parameter | Arithmetic Mean (%CV) T= Mylan | Arithmetic Mean (%CV) R = Reference | LSMEANS Ratio (T/R) | 90% Confidence Interval |
| 3TC | AUCL (ng?hr/mL) | 11648 (18.64) | 11911 (18.84) | 0.98 | 96.41% - 100.29% |
| 3TC | AUCINF (ng?hr/mL) | 12062 (19.04) | 12206 (18.26) | 0.99 | 96.94% - 101.15% |
| 3TC | CPEAK (ng/mL) | 1960 (27.94) | 2064 (24.37) | 0.94 | 88.17% - 100.59% |
| TNF | AUCL (ng?hr/mL) | 3124 (19.55) | 3107 (19.45) | 1.01 | 98.10% - 103.80% |
| TNF | AUCINF (ng?hr/mL) | 3311 (19.74) | 3269 (19.85) | 1.01 | 98.69% - 104.32% |
| TNF | CPEAK (ng/mL) | 318.7 (24.99) | 278.9 (20.60) | 1.11 | 104.08% - 119.12% |
| DTG | AUCL (ng?hr/mL) | 71099 (24.79) | 70780 (26.25) | 1.00 | 95.64% - 104.78% |
| DTG | AUCINF (ng?hr/mL) | 74636 (25.55) | 73486 (26.72) | 1.01 | 96.51% - 105.45% |
| DTG | CPEAK (ng/mL) | 4025 (18.75 | 3840 (18.14) | 1.03 | 99.05% - 107.71% |
The AEs were mild in severity. Overall both R and T were well tolerated administered as a single, oral dose under fed conditions.
Conclusions: This study demonstrates that Mylan''s 3TC/TDF/DTG 300 mg/300 mg/50 mg tablets are bioequivalent to a combination of EPIVIR® (300 mg), VIREAD® (300 mg) and TIVICAY® (50 mg) as separate tablets following administration of a single, oral dose administered under fed conditions.