2.4 NONCLINICAL OVERVIEW EMTRICITABINE/TENOFOVIR ALAFENAMIDE FIXED-DOSE COMBINATION (FTC/TAF [F/TAF] FDC) Gilead Sciences 20 CONFIDENTIAL AND PROPRIETARY INFORMATION Emtricitabine/Tenofovir alafenamide Section 2.4 Nonclinical Overview Final TABLE OF CONTENTS TABLE OF CONTENTS ..............................................................................................................................................2 LIST OF IN-TEXT TABLES........................................................................................................................................4 LIST OF IN-TEXT FIGURES ......................................................................................................................................4 LIST OF ABBREVIATIONS........................................................................................................................................5 1. NONCLINICAL OVERVIEW .............................................................................................................................8 1.1. Overview of the Nonclinical Testing Strategy .........................................................................................9 1.1.1. FTC ........................................................................................................................................9 1.1.2. TAF ......................................................................................................................................10 1.1.3. F/TAF...................................................................................................................................11 2. PHARMACOLOGY/VIROLOGY .....................................................................................................................12 2.1. Primary Pharmacodynamics...................................................................................................................12 2.2. Secondary Pharmacodynamics...............................................................................................................13 2.2.1. In Vitro Cytotoxicity ............................................................................................................13 2.2.2. Mitochondrial Toxicity.........................................................................................................14 2.2.3. Off Target Activity...............................................................................................................15 2.3. Safety Pharmacology .............................................................................................................................15 2.3.1. FTC ......................................................................................................................................15 2.3.2. TAF ......................................................................................................................................16 2.3.3. F/TAF...................................................................................................................................16 2.4. Pharmacodynamic Drug Interactions .....................................................................................................16 2.5. Summary of Pharmacology....................................................................................................................16 3. PHARMACOKINETICS....................................................................................................................................18 3.1. Analytical Methods ................................................................................................................................18 3.2. In Vitro Absorption and Single Dose Pharmacokinetics........................................................................18 3.2.1. FTC ......................................................................................................................................18 3.2.2. TAF ......................................................................................................................................18 3.2.3. F/TAF...................................................................................................................................19 3.3. Repeat Dose Pharmacokinetics ..............................................................................................................19 3.3.1. FTC ......................................................................................................................................19 3.3.2. TAF ......................................................................................................................................19 3.3.3. F/TAF...................................................................................................................................20 3.4. Distribution ............................................................................................................................................20 3.4.1. Protein Binding ....................................................................................................................20 3.4.2. Tissue Distribution ...............................................................................................................20 3.4.3. Distribution in Pregnant Animals.........................................................................................21 3.4.4. F/TAF Distribution...............................................................................................................21 3.5. Metabolism.............................................................................................................................................21 3.5.1. Intracellular Metabolism ......................................................................................................21 3.5.2. Routes of Metabolism ..........................................................................................................22 3.5.3. In Vitro Metabolism.............................................................................................................24 3.5.4. In Vivo Metabolism .............................................................................................................24 3.6. Excretion ................................................................................................................................................25 3.6.1. Recovery in Excreta .............................................................................................................25 3.6.2. Excretion into Breast Milk ...................................................................................................26 3.7. Pharmacokinetic Drug Interactions........................................................................................................26 3.7.1. Metabolic Drug Interactions.................................................................................................27 3.7.2. Induction Liability................................................................................................................28 3.7.3. Transporter Drug Interactions ..............................................................................................29 CONFIDENTIAL Page 2 20 Emtricitabine/Tenofovir alafenamide Section 2.4 Nonclinical Overview Final 3.7.4. F/TAF Pharmacokinetic Drug Interactions ..........................................................................32 3.8. Summary of Pharmacokinetics...............................................................................................................33 4. TOXICOLOGY ..................................................................................................................................................35 4.1. Single Dose Toxicity..............................................................................................................................35 4.2. Repeat Dose Toxicity.............................................................................................................................35 4.2.1. FTC ......................................................................................................................................35 4.2.2. TAF ......................................................................................................................................35 4.2.3. FTC/TDF..............................................................................................................................38 4.2.4. F/TAF...................................................................................................................................38 4.3. Genotoxicity...........................................................................................................................................39 4.3.1. FTC ......................................................................................................................................39 4.3.2. TAF ......................................................................................................................................39 4.3.3. FTC/TDF..............................................................................................................................39 4.3.4. F/TAF...................................................................................................................................39 4.4. Carcinogenicity ......................................................................................................................................39 4.4.1. FTC ......................................................................................................................................40