1. DDIs with new DAAs Franco Maggiolo AO Papa Giovanni XXIII Bergamo

3. 3 CYP450 The P450 cytochromes chemically oxidize or reduce drugs > than 25 human cytochrome P450’s They are named by number and letter: 4 major families  indicated by number 6 major sub-families  indicated by letter Individual enzymes within a subfamily  indicated by number For example 3A4, 2D6, 2C19 Badea G. Drug Metabolism. Feb 2007

4. CYP 3A4 activity 300% 200% 100% 0% EFV introductionwithdrawal [c] CYP 3A4 activity 300% 200% 100% 0% RTV introductionwithdrawal [c] 6-10 hours 2-3 weeks

6. Drug transporters

7. 7 P-glycoprotein Transports drugs out of the cell Tissue expression is varied Found in the major absorption, distribution and elimination organs P-gp inducers and inhibitors\ Source: http://www.nature.com/nrc/journal/v2/n6/images/nrc823-f3.gif

8. Paritaprevir kinetics

9. C min < 59% (dose 90 mg) C min > 265% (dose 30 mg) C min > 163% C max > 79% DAAs’ DDIs

10. C min < 48% C min > 4,58 fold C min < 91% expected to decrease C min Exposure 3 fold increase (QT prolungation risk) DAAs’ DDIs

13. DAAs’ DDIs management Choice of DAA combination (protease inhibitors?) Modify cART (NRTI, INI, RPV, [ATV, EFV]) Closely monitor Rx tolerability Modify (eventually) associated Rx Temporarly sospend associated Rx