1. 22nd International AIDS Conference (AIDS 2018)
Single-Dose Fed Bioequivalence Study of Lamivudine, Tenofovir Disoproxil Fumarate and Dolutegravir Tablets (300mg/300mg/50mg) versus EPIVIR® (300mg; ViiV Healthcare), VIREAD® (300mg; Gilead Sciences) and TIVICAY® (50mg; ViiV Healthcare) Tablets in Healthy Adult Volunteers
D. Abhijit1, C Santanu1, R. Chetan1, S. Gahoi1, R. Bangaru2, A. K. Datla2, P. Deshpande3, A. Kanda3, E. Patras3
1 Mylan Laboratories Limited, R&D, Hyderabad, India, 2 Mylan Laboratories Limited, Clinical Research Center, Hyderabad, India, 3 Mylan Laboratories Limited, Business Development, Hyderabad, India
22nd International AIDS Conference (AIDS 2018)
Amsterdam, Netherlands, July 2018

2. 300 mg Epivir, 300 mg Viread, 50 mg Tivicay (R)
Objective and Design
Primary Objective:
Compare the relative bioequivalence and safety profile of Mylan’s lamivudine, tenofovir disoproxil fumarate and dolutegravir tablet, 300 mg/300 mg/50 mg FDC tablets (T) with the reference combination (R) of EPIVIR® (300 mg, ViiV Healthcare), VIREAD® (300 mg, Gilead Sciences) and TIVICAY® (50 mg, ViiV Healthcare)
Design:
Open label, randomized, two-period, two-treatment, cross-over, single dose evaluation in 36 healthy adult human subjects under fed conditions
In each period, each subject received a single, oral dose of T (Mylan’s 3TC/TDF/DTG tablet, “TLD”) or R (300 mg 3TC [Epivir®], 300 mg TDF [Viread®] and 50 mg [Tivicay®])
Serial blood samples (1 x 6 mL) were collected at pre-dose (within 120 minutes prior to dosing), 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4, 5, 6, 8, 10,12, 24, 36, 48 and 72 hours post-dose
High fat FDA standardized breakfast
TLD Mylan (300/300/50 mg)
(T)
300 mg Epivir, 300 mg Viread, 50 mg Tivicay (R)
30 min
10 h
Fasting
Sampling
pre-dose 0 – post-dose 72 h
Wash-Out Period
7 days
Abhijit D et al., 22nd IAC (AIDS 2018) Amsterdam 2018; #WEPDB0204

3. Methods Analytical Methods:
Drug concentrations in plasma were quantified by using a validated method for the test product (T) and reference combination (R)
All analyses were performed using 96-well liquid-liquid extraction and high performance liquid chromatography with tandem mass spectroscopy
Limits of quantification were 40 ng/mL for DTG, 25 ng/mL for 3TC and 3 ng/mL for tenofovir
Criteria for Bioequivalence Evaluation:
The 90% confidence interval for the LSMeans ratio of CPEAK, AUCL, and AUCINF for the T and R products should be between 80% and 125%.
Statistical Methods:
Single-dose pharmacokinetic parameters for 3TC/TDF/DTG were calculated using non-compartmental techniques. Statistical analyses were performed on the pharmacokinetic parameters using the General Linear Models Procedure (PROC GLM) of SAS Software (SAS Institute, Cary, NC).
Abhijit D et al., 22nd IAC (AIDS 2018) Amsterdam 2018; #WEPDB0204

4. Pharmacokinetic Results (n=34)
Tenofovir
Lamivudine
Dolutegravir
All statistical analyses of these data reveal that the 90% confidence intervals are within the acceptable bioequivalent range of 80% and 125% for the natural log transformed parameters AUCL, AUCINF, and CPEAK.
Abhijit D et al., 22nd IAC (AIDS 2018) Amsterdam 2018; #WEPDB0204

5. Conclusions
This study demonstrates that Mylan’s 3TC/TDF/DTG 300 mg/300 mg/50 mg tablet is 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.
Abhijit D et al., 22nd IAC (AIDS 2018) Amsterdam 2018; #WEPDB0204

6. Back-Up

7. Results: Safety
34 subjects completed the study, one subject withdrew consent due to personal reasons; one discontinued due to an adverse event (loose stool)
25 post-dose adverse events (AEs) were experienced by 15 subjects over the course of this study.
Mylan product (TLD):
9 AEs were considered probably related: diarrhea (n=2), dizziness, feeling hot, nausea (n=2) somnolence (n=3)
3 AEs were considered possibly related: dizziness, somnolence (n=2)
Reference combination (Viread ®, Epivir® and Tivicay ®):
1 definitely related AE (upper abdominal pain)
7 AEs were considered probably related: upper abdominal pain, diarrhea, headache, nausea (n=2), somnolence (n=2)
4 AEs were considered possibly related: fatigue, headache, nausea, somnolence
1 AE was considered unrelated: catheter site hematoma
All AEs were mild in severity.
No deaths, serious adverse events (SAE) or other significant AEs were reported.
Abhijit D et al., 22nd IAC (AIDS 2018) Amsterdam 2018; #WEPDB0204