1. 10 th International Workshop on Clinical Pharmacology of HIV Therapy Pierre Giguere, B.Pharm., M.Sc. The Ottawa Hospital

2. Selection of the Abstracts  Scientifically sound  High rigorous methods…  Criteria: What made a good impression to the speaker What made a good impression to the speaker

3. Agenda  Raltegravir PK-PD relationship PK-PD relationship Interactions Interactions  DRVr Simplification using vIQ Simplification using vIQ PK, safety, efficacy 900/100mg qd PK, safety, efficacy 900/100mg qd Interaction with EFV Interaction with EFV  Effect of Smoking EFV EFV  ATV PK/PD from CASTLE PK/PD from CASTLE ATV unboosted + TDF ATV unboosted + TDF Another FAM – ATVr – TDF study ! Another FAM – ATVr – TDF study !  Pregnancy  Malaria

4. Raltegravir  MOA: irreversible binding to the Integrase preventing strand transfer into host genome  Metabolized UGT1A1  1 study (P_11)failed to show an association due to extreme interpatient variability (CV 92%)

5. PK-PD of RAL  Cmin poor predictor. AUC ?  Model : HOSCD4R5 cells and HIV-1 cell modified to express fluorescence.  Infected cells using bead cells x 30min then wash out.  Counted fluorescence, which reflects occupency at the integrase site. 

6. Dissociation of RAL from INT  Window of 4-12 hrs, time after which integration cannot occur  Residency time RA = 5-6 hrs  Impact of N155H: increase dissociation by 10-fold  This parameter would be potentially the best marker of activity  Analogous to One shot Kill

7. RAL Interaction in HIV+  Atazanavir 400mg OD + RAL 800mg OD  N=15 HIV-infected  ATV 400mg po x 14 days Then + RAL 800mg qd Then + RAL 800mg qd Molto, IWCPHT2009; Abst 0_13.

8. RAL Interaction in HIV+ Molto, IWCPHT2009; Abst 0_13. No discontinuation due to AE

9. RAL Interaction in HIV+  Atazanavir 200mg BID + RAL 400mg BID Ripamonti, IWCPHT2009;Abst 0_14.

10. RAL Interaction in HIV+ Ripamonti, IWCPHT2009;Abst 0_14.

11. RAL Interaction in HIV+ Ripamonti, IWCPHT2009;Abst 0_14.

12. RAL Interaction in HIV+ Ripamonti, IWCPHT2009;Abst 0_14.

13. RAL Interaction in HIV+ Ripamonti, IWCPHT2009;Abst 0_14.

14. RAL interaction  Ezetimibe 10 mg qd N=20 N=20

15. Results

16. Results The variability in raltegravir Cmax and AUC was higher in the presence of ezetimibe. Six (30%) of the volunteers had Ctrough Which were lower than the reported IC95 of 15 ng/mL.

17. Darunavir 900/100mg  Simplification using vIQ 30 pts with VL 12 weeks 30 pts with VL 12 weeks vIQ (Ctrough / 0.55 x FC IC50) > 2 vIQ (Ctrough / 0.55 x FC IC50) > 2 Ranodmized to continue DRV/r 600/100 mg BID or switch to 900/100mg qd Ranodmized to continue DRV/r 600/100 mg BID or switch to 900/100mg qd If vIQ < 1.5 x 2 values, then switched back If vIQ < 1.5 x 2 values, then switched back PTs had a medium exposure of 5 PI, and a median number protease mutations = 11 PTs had a medium exposure of 5 PI, and a median number protease mutations = 11

18. Results  3 patients switched back to BID due to low vIQ  All maintained VL<50 copies/mL  DRV Cmin lower in qd group (GMR 0.72 [0.49-1.06])  TC no different between groups  TG 159  140 mg/dL (p=0.031)

19. Darunavir 900/100mg qd  25 pts (48% HCV co-infected)  47% had VL<50 at baseline, the remainder median 4.2 log  Results Ctrough= 1.62 [1.06, 1.46] Ctrough= 1.62 [1.06, 1.46] 24/25 had level > 0.55 ug/mL 24/25 had level > 0.55 ug/mL All VL<50 at week 24 All VL<50 at week 24 No effect of gender, HCV, other ART No effect of gender, HCV, other ART Curran et al. IWCPHIVT 2009, Amsterdam, P_14

20. DRVr-EFV  Attractive once daily first-line regimen  PK DRVr 900/100mg + EFV 600mg  12 Healthy volunteers DRVr 900mg/100mg Day 0day10 PK DRVr 900mg/100mg + EFV 600mg Day 11Day 25 EFV 600mg Day 26Day 40 PK Period 1Period 2Period 3 Lee et al. IWCPHIVT 2009, Amsterdam, P_29

21. Darunavir/r + EFV DRV Period #2 EFV (Period #3) (2) AUCGMR=0.86 [0.75, 0.97] GM = 0.91 [0.75, 1.11] CmaxGMR=0.92 [0.82, 1.03] GMR=0.80[0.63,1.02] Cmin 1180ng/mL (1) GMR=0.43 [0.32, 0.57] GMR 1.01 [0.81, 1.25] 1.All were > 0.55 ng/mL 2.Half-life higher by 66% Lee et al. IWCPHIVT 2009, Amsterdam, P_29

22. Smoking  Known interaction with Theophyllin Mediated through induction of the CYP1A2 Mediated through induction of the CYP1A2  1 abstract showing effect of smoking on EFV levels Cortes (P_04) Cortes (P_04) 219 pts from Chile 219 pts from Chile  Also shown to have an inducing effect on constitutive androstane receptor (CAR) known to regulate 2B6

23. EFV plasma concentrations grouped by CYP2B6 G516T polymorphism 2.21 3.13 5.23 Cortes et al. IWCPHIVT 2009, Amsterdam, P_04

24. EFV plasma concentrations grouped by smoking status 2.81 3.32 Cortes et al. IWCPHIVT 2009, Amsterdam, P_04

25. Atazanavir: PK-PD CASTLE  883 treatment naïve patients  Samples at day 1, week 4,12,24,36,48  Correlation between Ctrough and efficacy or toxicity Zhu. IWCPHIVT 2009, P_19

26. PK PD CASTLE  No correlation could be found between Decline in viral load Decline in viral load VL<50 VL<50  For both ATVr and LPVr Zhu. IWCPHIVT 2009, P_19

27. PK PD CASTLE  Bilirubin was associated with higher trough of ATVr Zhu. IWCPHIVT 2009, P_19

28. PK PD CASTLE Nausea was associated with trough but not diarrhea nor TC & TG( not shown) Zhu. IWCPHIVT 2009, P_19

29. ATV + TDF Harris. IWCPHIVT 2009, P_21

30. ATV + TDF Harris. IWCPHIVT 2009, P_21

31. ATV + TDF Harris. IWCPHIVT 2009, P_21

32. ATV + TDF CONCLUSIONS Despite low atazanavir trough levels, selected patients may be virologically controlled on regimens including unboosted atazanavir with tenofovir. Harris. IWCPHIVT 2009, P_21

33. ATVr +FAM: Saga Continues !  Assess ATVr 300/100mg is affected by FAM 20mg BID FAM 20mg BID FAM 40mg BID FAM 40mg BID 2hrs apart or at same time 2hrs apart or at same time With or without TDF With or without TDF  In HIV-Infected patients Wang. IWCPHIVT 2009, P_30

34. ATVr +FAM: With NO TDF  Fam 20 BID did not decrease Cmin  Fam 40 BID decreased Cmin by 20% Wang. IWCPHIVT 2009, P_30

35. ATVr +FAM: With TDF  Fam 20 BID decreased Cmin by 19%  Fam 40 BID decreased Cmin by 25% Wang. IWCPHIVT 2009, P_30

36. ATVr +FAM: Temporal Separation  Separation of the dose does not change ATV Cmin.  10 hr separation between doses is still required Wang. IWCPHIVT 2009, P_30

37. Pregnancy  Several studies reported decrease exposure of PIs in 3 rd trimester.  Some advocate increase dose  60 pregnant women on LPVr, ATV and NVP Sample each trimester, at delivery, in the cord and post partum (1-2 months) Sample each trimester, at delivery, in the cord and post partum (1-2 months) Total and free plasma concentration Total and free plasma concentration Interim analysis (42 pregnancies) Interim analysis (42 pregnancies) Fayet. IWCPHIVT 2009, P_57

38. Pregnancy  LPV: Fu, free and total AUC, Cmin not affected  ATV: Total AUC and Cmin decreased by 36%, while total CL increased. BUT free Cmin and AUC not affected (Fu tends to increase)  NVP: Total AUC and Cmin decreased by 32% while total CL tended to increase. Free AUC and Cmin decreased in parallel  Cord to mother ratio (C/M) LPV and ATV: free C/M ratio were 2-fold; free fraction higher than in mothers plasma LPV and ATV: free C/M ratio were 2-fold; free fraction higher than in mothers plasma NVP: free fractions similar NVP: free fractions similar Fayet. IWCPHIVT 2009, P_57

39. Malarone PIs - EFV  Malarone = atovaquone + proguanil  Proguanil is metabolized by 2C19 to cycloguanil (active moiety)  Atovaquone: likely metabolized through glucoronidation  PIs and NNRTIS can induce 2C19 (1)  LPVr or RTV can induce glucuronidation  However, Proguanil (not cycloguanil) is the synergistic compound to atovaquone (2) ATV/r LPV/r EFV Health volunteers HIV + 1 month Single dose Malarone Also looked at 2C19*2 and -*3 van Lui. IWCPHIVT 2009, O_19 1.JAIDS 006, 42:52-60 2.AAC 1999. 43:1334-9

40. Baseline Characteristics van Lui. IWCPHIVT 2009, O_19