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MODULE 2.6.4. PHARMACOKINETICS WRITTEN SUMMARY CONFIDENTIAL M2.6.4

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MODULE 2.6.4. PHARMACOKINETICS WRITTEN SUMMARY CONFIDENTIAL M2.6.4 MODULE 2.6.4. PHARMACOKINETICS WRITTEN SUMMARY CONFIDENTIAL m2.6.4. Pharmacokinetics Written Summary 2012N154235_00 TABLE OF CONTENTS PAGE 1. BRIEF SUMMARY .............................................................................................7 1.1. Test Substance.............................................................................................7 2. METHODS OF ANALYSIS...............................................................................10 3. ABSORPTION..................................................................................................11 3.1. Mouse.........................................................................................................11 3.1.1. Oral administration.......................................................................11 3.1.1.1. Pharmacokinetics/Toxicokinetics after repeated administration.............................................................11 3.2. Rat..............................................................................................................12 3.2.1. Intravenous administration...........................................................12 3.2.1.1. Pharmacokinetics/Toxicokinetics after single doses .........................................................................12 3.2.2. Oral administration.......................................................................13 3.2.2.1. Pharmacokinetics/Toxicokinetics after single doses .........................................................................13 3.2.2.2. Pharmacokinetics/Toxicokinetics after repeated administration.............................................................13 3.2.3. Subcutaneous and intramuscular administration..........................16 3.3. Rabbit .........................................................................................................18 3.3.1. Oral administration.......................................................................18 3.3.1.1. Pharmacokinetics/Toxicokinetics after repeated administration.............................................................18 3.4. Dog.............................................................................................................18 3.4.1. Intravenous administration...........................................................18 3.4.1.1. Pharmacokinetics/Toxicokinetics after single doses .........................................................................18 3.4.2. Oral administration.......................................................................19 3.4.2.1. Pharmacokinetics/Toxicokinetics after single doses .........................................................................19 3.4.2.2. Evaluation of Pediatric Formulation...............19 3.5. Monkey.......................................................................................................20 3.5.1. Intravenous administration...........................................................20 3.5.1.1. Pharmacokinetics/Toxicokinetics after single doses .........................................................................20 3.5.2. Oral administration.......................................................................20 3.5.2.1. Pharmacokinetics/Toxicokinetics after single doses .........................................................................20 3.5.2.2. Pharmacokinetics/Toxicokinetics after repeated administration.............................................................21 3.5.3. Subcutaneous and intramuscular administration..........................22 4. DISTRIBUTION................................................................................................28 4.1. In Vitro Distribution Studies.........................................................................28 4.1.1. Serum and plasma protein binding studies ..................................28 4.1.2. P-glycoprotein transport and membrane permeability ..................29 1 CONFIDENTIAL m2.6.4. Pharmacokinetics Written Summary 2012N154235_00 4.1.3. Inhibition of P-glycoprotein...........................................................29 4.1.4. Human breast cancer resistance protein-mediated transport ......................................................................................30 4.1.5. Inhibition of BCRP transport.........................................................30 4.1.6. Inhibition of multidrug resistance associated protein-2 transporter ...................................................................................30 4.1.7. Inhibition of OATP1B1 and OATP1B3..........................................31 4.1.8. Inhibition of OCT1 and OCT2 mediated transport ........................31 4.2. In Vivo Distribution Studies .........................................................................32 4.2.1. Mouse..........................................................................................32 4.2.1.1. Blood:plasma and liver:blood ratios ............................32 4.2.2. Rat...............................................................................................33 4.2.2.1. Whole body distribution ..............................................33 4.2.2.2. Blood:plasma and liver:blood ratios ............................33 4.2.2.3. Placental transfer .......................................................33 4.2.2.4. Lacteal secretion ........................................................34 4.2.3. Monkey........................................................................................35 4.2.3.1. Blood:plasma ratio......................................................35 5. METABOLISM..................................................................................................39 5.1. In Vitro Studies ...........................................................................................39 5.1.1. Metabolism studies with microsomes, hepatocytes or recombinant enzymes derived from animals and humans............39 5.1.1.1. Metabolic stability in liver S9 and in hepatocytes................................................................39 5.1.1.2. Formation of glutathione adducts................................39 5.1.1.3. Metabolic microsomal binding ....................................39 5.1.1.4. Metabolism by hepatocytes ........................................40 5.1.1.5. Recombinant CYP enzymes and liver microsomes................................................................40 5.1.1.6. Recombinant UGT enzymes and liver microsomes................................................................41 5.1.1.7. Potential metabolic formation of stereoisomers ..........41 5.1.2. In vitro inhibition and induction potential in animals and humans........................................................................................42 5.1.2.1. Induction of rat PXR ...................................................42 5.1.2.2. Induction of human PXR.............................................42 5.1.2.3. Inductive potential in human hepatocytes ...................43 5.1.2.4. Inhibition of CYP enzymes..........................................43 5.1.2.5. Inhibition of UDP-glucuronosyltransferase..................44 5.1.2.6. Isolated perfused rat liver ...........................................44 5.2. In Vivo Studies............................................................................................49 5.2.1. Mouse..........................................................................................49 5.2.1.1. Metabolic profile following oral administration.............49 5.2.2. Rat...............................................................................................50 5.2.2.1. Metabolic profile following oral administration.............50 5.2.2.2. Potential epimerization in juvenile rats........................50 5.2.2.3. Metabolites in milk from lactating rats.........................51 5.2.2.4. Cytochrome P450 induction........................................51 5.2.3. Monkey........................................................................................51 5.2.3.1. Metabolic profile following oral administration.............51 5.2.3.2. Cytochrome P450 induction........................................52 2 CONFIDENTIAL m2.6.4. Pharmacokinetics Written Summary 2012N154235_00 6. EXCRETION ....................................................................................................53 6.1. Mouse.........................................................................................................53 6.1.1. Excretion following oral administration .........................................53 6.2. Rat..............................................................................................................53 6.2.1. Excretion following oral administration .........................................53 6.3. Monkey.......................................................................................................54 6.3.1. Excretion following oral administration .........................................54 7. PHARMACOKINETIC DRUG INTERACTIONS................................................56 8. OTHER PHARMACOKINETIC STUDIES.........................................................57 9. DISCUSSION AND CONCLUSIONS TO PHARMACOKINETICS....................58 APPENDIX 1 ANALYTICAL METHODS USED FOR THE DETERMINATION OF DOLUTEGRAVIR IN BIOLOGICAL FLUIDS...............................................63 APPENDIX 2 ADDITIONAL INFORMATION.............................................................70 3 CONFIDENTIAL m2.6.4. Pharmacokinetics Written Summary 2012N154235_00 LIST OF TABLES PAGE Table 3.1
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