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Emtricitabine/Tenofovir Alafenamide Fixed-Dose Combination (F/Taf Fdc)

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Emtricitabine/Tenofovir Alafenamide Fixed-Dose Combination (F/Taf Fdc) SECTION 2.7.1—SUMMARY OF BIOPHARMACEUTICAL STUDIES AND ASSOCIATED ANALYTICAL METHODS EMTRICITABINE/TENOFOVIR ALAFENAMIDE FIXED-DOSE COMBINATION (F/TAF FDC) Gilead Sciences 20 CONFIDENTIAL AND PROPRIETARY INFORMATION F/TAF 2.7.1 Summary of Biopharmaceutical Studies Final TABLE OF CONTENTS SECTION 2.7.1—SUMMARY OF BIOPHARMACEUTICAL STUDIES AND ASSOCIATED ANALYTICAL METHODS.................................................................................................................................1 TABLE OF CONTENTS ..............................................................................................................................................2 LIST OF IN-TEXT TABLES........................................................................................................................................3 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................................5 PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS ............................................................................7 1. SUMMARY OF BIOPHARMACEUTICAL STUDIES AND ASSOCIATED ANALYTICAL METHODS ...........................................................................................................................................................8 1.1. Background and Overview.......................................................................................................................8 1.1.1. Formulation Development......................................................................................................9 1.1.2. Dissolution Profile................................................................................................................10 1.1.3. Bioanalytical Methods..........................................................................................................11 1.1.4. Cross-Validations.................................................................................................................17 1.1.5. Long-Term Storage Stability................................................................................................17 2. SUMMARY OF RESULTS OF INDIVIDUAL STUDIES................................................................................19 3. COMPARISON AND ANALYSES OF RESULTS ACROSS STUDIES.........................................................20 3.1. Bioavailability........................................................................................................................................20 3.1.1. Bioavailability of TAF .........................................................................................................20 3.1.2. Bioavailability of FTC..........................................................................................................20 3.2. Bioequivalence of F/TAF Tablet to E/C/F/TAF Tablet .........................................................................21 3.3. Bioequivalence of F/TAF to TAF and FTC Single Agents....................................................................22 3.4. Effect of Food ........................................................................................................................................23 3.4.1. TAF ......................................................................................................................................23 3.4.2. FTC ......................................................................................................................................24 3.5. Conclusions............................................................................................................................................24 4. APPENDICES ....................................................................................................................................................26 4.1. Quantitative Composition of the Proposed Commercial Formulation of F/TAF FDC Tablets..............27 4.2. Summary of In Vitro Dissolution Profiles of FTC and TAF From F/TAF 200/10 mg Tablets (CR 08B) and F/TAF 200/25 mg Tablets (CR 05B) ........................................................................28 4.3. Tabular Summary of Biopharmaceutic Studies......................................................................................29 4.4. Summary of Analytical Methods for Individual Studies........................................................................30 4.5. Summary of Long-Term Storage Stability Data for Individual Studies.................................................39 4.6. Determination of Coadministered Drugs in Human Plasma Supporting F/TAF Studies .......................54 4.6.1. Determination of EVG and COBI in Human Plasma...........................................................54 4.6.2. Determination of Penciclovir in Human Plasma and Urine .................................................55 4.6.3. Determination of ATV and RTV in Human Plasma ............................................................55 4.6.4. Determination of RTV and LPV in Human Plasma .............................................................56 4.6.5. Determination of DTG in Human Plasma ............................................................................56 4.6.6. Determination of EFV in Human Plasma.............................................................................57 4.6.7. Determination of RPV in Human Plasma.............................................................................58 4.6.8. Determination of DRV in Human Plasma............................................................................59 4.6.9. Determination of Iohexol in Human Plasma ........................................................................59 4.6.10. Determination of MDZ and 1-OH MDZ in Human Plasma................................................60 4.6.11. Determination of Sertraline in Human Plasma.....................................................................60 4.6.12. Determination of Tacrolimus in Human Whole Blood ........................................................61 4.6.13. Determination of SOF, GS-566500, and GS-331007 in Human Plasma..............................61 4.6.14. Determination of GS-5816 in Human Plasma......................................................................62 CONFIDENTIAL Page 2 20 F/TAF 2.7.1 Summary of Biopharmaceutical Studies Final 5. REFERENCES ...................................................................................................................................................63 LIST OF IN-TEXT TABLES Table 1. Bioanalytical Method Validation for Determination of TAF in Human Plasma at .........................................................................................................................................11 Table 2. Bioanalytical Method Validation for Determination of TFV in Human Plasma at ( Method 60-1116)..................................................................................................12 Table 3. Bioanalytical Method Validation for Determination of TFV in Human Plasma at ( Method 60-1352)..................................................................................................12 Table 4. Bioanalytical Method Validation for Determination of TFV in Human Plasma at ( Method 60-1368)..................................................................................................13 Table 5. Bioanalytical Method Validation for Determination of TAF and TFV in Human Urine at ...........................................................................................................................13 Table 6. Bioanalytical Method Validation for Determination of TFV and FTC in Human Plasma at Gilead.....................................................................................................................14 Table 7. Bioanalytical Method Validation for Determination of TFV and FTC in Human Plasma at ........................................................................................................................14 Table 8. Bioanalytical Method Validation for Determination of FTC in Human Plasma at Gilead .....................................................................................................................................15 Table 9. Bioanalytical Method Validation for Determination of FTC and Emivirine in Human Plasma at Gilead ........................................................................................................15 Table 10. Bioanalytical Method Validation for Determination of FTC, Zidovudine, and Stavudine in Human Plasma at Gilead ...................................................................................16 Table 11. Bioanalytical Method Validation for Determination of FTC in Human Urine at Gilead ( Method 2638)..............................................................................................16 Table 12. Bioanalytical Method Validation for Determination of FTC in Human Urine at Gilead ( Method 8361)..............................................................................................17 Table 13. Long-Term Storage Stability of TAF, TFV, and FTC............................................................17 Table 14. Combination Stability of TAF, TFV, and FTC ......................................................................18 Table 15. Study GS-US-311-1473: Statistical Comparisons of TAF and FTC PK Parameter Estimates Between Test and Reference Treatments (TAF or FTC PK Analysis Set) ............21 Table 16. Study GS-US-311-1472: Statistical Comparisons of TAF
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