7th International Workshop on Clinical Pharmacology of HIV Therapy Lisbon,, Portugal April 20-22, 22, 2006

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1 7th International Workshop on Clinical Pharmacology of HIV Therapy Lisbon,, Portugal April 20-22, 22, 2006 Nancy Sheehan, B.Pharm, M.Sc Immunodeficiency Service, Montréal Chest Institute Faculté de Pharmacie, Université de Montréal

3 Conference Content Clinical Pharmacology in Developing Countries Therapeutic Drug Monitoring PK in special populations Pharmacogenetics CNS & Genital Tract Penetration Drug-Drug interactions PK / PD of existing and new drugs FDA roundtable: Antiretroviral Drug Labelling and Drug Interaction

4 Angela Kashuba, 7th PK workshop, Lisbon, April 21, 2006

5 Angela Kashuba, 7th PK workshop, Lisbon, April 21, 2006

6 Target Minimal Concentrations ARV Cmin (mg/l) Naïve pts Éfavirenz 1.0 Névirapine Amprénavir Atazanavir 0.15 Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Cmin (mg/l) PI experienced pts NA NA GIQ NA NA

7 Poster and Oral Abstracts Inhibitory Quotients PK in special populations: Pediatrics Drug drug interactions Enfuvirtide interactions Tipranavir interactions Acid-modifying agent interactions Interactions via P-glycoproteinP

9 Poster and Oral Abstracts Inhibitory Quotients PK in special populations: Pediatrics Drug drug interactions Enfuvirtide interactions Tipranavir interactions Acid-modifying agent interactions Interactions via P-glycoprotein

10 Tipranavir Genotypic Inhibitory Quotient Predicts Virological Response at 24 weeks to TPV-based Salvage Regimens S Bonora,, D Gonzalez de Requena,, A Calcagno,, M Milia, A D AvolioD Avolio,, M Sciandra,, S Garazzino,, M Siccardi,, A. Sinicco,, G Di Perri Abstract 83

11 TPV GIQ Methods 24 week PK/PD study 2 NRTIs + TPV/RTV ± T-20 Ctrough wk 2,4,8,12, 24 GIQ = mean Ctrough # TPV mutations (Valdez et al, 3rd IAS) Virologic Response: Viral load < 50 copies / ml and/or > 1 log drop Bonora et al, 7th PK Workshop, Abstract 83.

12 TPV GIQ Results: Logistic Regressions Wk 24 Parameter OR CI 95% p value Ctrough # TPV mutations TPV GIQ T Baseline VL Bonora et al, 7th PK Workshop, Abstract 83.

13 TPV GIQ Target > ng/ml %Virologic Response GIQ < GIQ > Bonora et al, 7th PK Workshop, Abstract 83.

14 Genotypic Inhibitory Quotient as Best PK/PD Predictor of Virologic Response to a LPV/SQV dual RTV- boosted regimen in patients with multiresistant HIV-1 S Lam, MS Delisle, L Labbé,, GHR Smith, CJL la Porte, DM Burger, RG Lalonde, NL Sheehan Abstract 81

15 Logistic binary regressions for viral load < 400 copies/ml at week 48 vs PK / PD parameters PK / PD parameter p value LPV C SQV C LPV GIQ 0.049* SQV GIQ SQV mgiq GIQ 0.044* Multivariate analysis: age, gender, baseline CD4 and viral load, weight, and # ARV in regimen had no impact on significance of LPV GIQ and GIQ

16 Virologic response as a function of LPV, SQV and GIQ % subjects with viral load < 400 copies/ml LPV GIQ SQV GIQ Sum GIQ GIQ targets > 1.7 > 0.35 > 2.6 Below Target Above Target P value Fisher s Exact Test

17 Poster and Oral Abstracts Inhibitory Quotients PK in special populations: Pediatrics Drug drug interactions Enfuvirtide interactions Tipranavir interactions Acid-modifying agent interactions Interactions via P-glycoprotein

18 An audit of TDM in paediatric subjects from the UK and Ireland S Gibbons, D Back, S Khoo Abstract 8

19 % Concentrations Below Adult Targets LPV EFV NVP Infants 16,7-44,4 1 5 years 19,4 25,9 22, years 19,0 19,5 20,9 Adolescents 25,5 26,8 21,4 Gibbons et al, 7th PK Workshop, Abstract 8.

20 % Concentrations < LOQ Lopinavir Nevirapine Infants 8,3 4,4 1 5 years 15,1 6, years 17 9,3 Adolescents 19,4 10,7 Gibbons et al, 7th PK Workshop, Abstract 8.

21 Age-dependent PK of 3TC in HIV-infected children DM Burger, G Verweel,, C Verwey-Van Van Wissen,, CJL la Porte, A, Bergshoeff,, H. Lyall, N. Hartwig,, H. Green, D. Gibb,, R. De Groot Abstract 20

22 PK variability with age of 3TC dosed 4 mg/kg PK Parameter Pts 6 years vs > 6 AUC 42 % Cmax 51 % CL 74% VD 109 % T 1/2 Comparable Burger et al, 7th PK Workshop, Abstract 20

23 Poster and Oral Abstracts Inhibitory Quotients PK in special populations: Pediatrics Drug drug interactions Enfuvirtide interactions Tipranavir interactions Acid-modifying agent interactions Interactions via P-glycoprotein

24 Unexpected drug-drug interaction between TPV/rtv and enfuvirtide D Gonzalez de Requena,, A Calagno,, S. Bonora,, L. Ladetto,, A. D AvolioD Avolio,, M. Sciandra, M. Siccardi,, O. Bargiacchi,, A. Sinicco,, G. Di Perri Abstract 52

25 TPV & T-20T TPV Pk samples taken hours post- dose N = 55 with 463 random samples PK model: 1st order absorption and elimination, monocompartmental Gonzalez de Requena et al, 7th PK Workshop, Abstract 52

26 Tipranavir PK C trough (ng/ml) With T-20 Without T ± ± Vd / F (L) Kel (1/h) T ½ (h) Gonzalez de Requena et al, 7th PK Workshop, Abstract 52

27 PK evaluation of potential interaction between tipranavir and enfuvirtide A Curran,, R Lopez, L Pou, C Azuaje,, E Ribera, A Pahissa Abstract 53

28 Tipranavir & T-20T Intensive PK study (12 hours) N = 8 with TPV & T-20 T vs 4 without T-20 Total: 44 C troughs Curran et al, 7th PK Workshop, Abstract 53

29 Tipranavir PK median,, (IQR) PK Parameter C trough T-20T Without T-20 ( ) AUC ( ) ) Cmax ( ) 137.9) 39.5 ( ) 695 ( ) 81.9 ( ) p value Curran et al, 7th PK Workshop, Abstract 53

30 Absence of an interaction between the potent HIV PI TMC114 and the FI enfuvirtide in the Power 3 analysis V Sekar,, E De Paepe, T Vangeneugden,, R Falcon, E Lefebvre, R Hoetelmans Abstract 54

31 TMC-114 PK & T-20T Median (range) With T-20 Without T-20 AUC (ng*h/ml) ( ) ( ) C trough (ng/ml) ( ) 10919) ( ) Sekar et al, 7th PK Workshop, Abstract 54

32 Poster and Oral Abstracts Inhibitory Quotients PK in special populations: Pediatrics Drug drug interactions Enfuvirtide interactions Tipranavir interactions Acid-modifying agent interactions Interactions via P-glycoproteinP

33 The PK Interaction Between ATZ/r and TPV/r in healthy volunteers JP Sabo,, M Elgadi,, J Wruck,, W Cameron, TR MacGregor,, M Kraft, H Valdez, D Mayers Abstract 41

34 TAZ & TPV Methods Day 1 Day9 Day 16 Day 24 Day 33 TPV TAZ PK PK TAZ PK PK Steady-state intensive PK study in healthy volunteers N = 21 TPV 500 / rtv 200 BID; TAZ 300 / rtv 100 QD Sabo et al, 7th PK Workshop, Abstract 41

35 TAZ PK with TPV GMR, 90% CI PK Parameter % change GMR (90% CI) AUC ( ) 0.36) Cmax ( ) 0.5) Cmin ( ) 0.24) Sabo et al, 7th PK Workshop, Abstract 41

36 TPV PK with TAZ GMR, 90% CI PK Parameter % change GMR (90% CI) AUC ( ) 1.32) Cmax ( ) Cmin ( ) Sabo et al, 7th PK Workshop, Abstract 41

37 Stereoselective PK of methadone after coadministration with steady- state TPV/rtv in healthy volunteers JP Sabo,, S Macha, C Oksala,, C Edwards, P Jones, TR MacGregor,, H Valdez, D Mayers

38 TPV & Methadone Methods Day 1 Day 9 TPV PK M 5 mg M 5 mg PK Steady-state intensive PK study in healthy volunteers N = 15 healthy volunteers TPV 500 / rtv 200 BID; 2 single doses of methadone 5 mg (Day 1 and 9) Sabo et al, 7th PK Workshop, Abstract 42

39 TPV & Methadone GMR, 90% CI, % Change PK Parameter AUC0-24 (ng*h/ml) S- methadone (inactive) 0.37 ( ) 0.41) - 63 % R-methadone (active) 0.52 ( ) 0.56) - 48 % Cmax (ng/ml) 0.38 ( ) 0.43) - 62 % 0.54 ( ) 0.58) - 46 % Sabo et al, 7th PK Workshop, Abstract 42

40 Poster and Oral Abstracts Inhibitory Quotients PK in special populations: Pediatrics Drug drug interactions Enfuvirtide interactions Tipranavir interactions Acid-modifying agent interactions Interactions via P-glycoproteinP

41 Steady-state PK of QD fosamprenavir / ritonavir and atazanavir / ritonavir alone and in combination with 20 mg QD of omeprazole in healthy volunteers A Luber,, R Brower, C Peloquin,, I Frank Abstract 36

42 Steady-state PK of fapv/rtv 1400 / 200 QD and TAZ/rtv 300/100 with Omeprazole 20 mg Open-label cross-over over interaction study PK PK PK PK Regimen 1 + OMP WASHOUT Regimen 2 + OMP Study Day Luber et al, Poster 36, 7th International Workshop on Clinical Pharmacology of HIV Therapy, Lisbon, 2006

43 Impact of omeparazole 20 mg on steady-state pharmacokinetics of fosamprenavir and atazanavir Concentrations ( u g FAPV / RTV FAPV / RTV + OMP TAZ / RTV TAZ /RTV + OMP Hours post - dose Atazanavir Cmin and AUC decreased by 27% Luber et al, Poster 36, 7th International Workshop on Clinical Pharmacology of HIV Therapy, Lisbon, 2006

44 Poster and Oral Abstracts Inhibitory Quotients PK in special populations: Pediatrics Drug drug interactions Enfuvirtide interactions Tipranavir interactions Acid-modifying agent interactions Interactions via P-glycoproteinP

47 The ABC transporter P-P glycoprotein is inhibited by LPV and low-dose ritonavir both in HIV-infected patients and healthy volunteers A Jetter,, U Fuhr,, R Aarnoutse,, A Lazar,, F Abdulrazik,, N Schmeisser,, E Schomig,, D Burger, G Fatkenheuer,, C Wyen Abstract 37

48 LPV/rtv & p-glycoproteinp Methods N = 30, HIV positive ARV naive patients Intensive PK before LPV / rtv and 14 days post LPV/rtv 400 BID Probes: 0.5 mg digoxin Dextromethorphan Midazolam Jetter et al, 7th PK Workshop, Abstract 37

49 In patients: Digoxine AUC 0-24 : 81 % (90%CI: 56% - 109%) Jetter et al, 7th PK Workshop, Abstract 37

50 Jetter et al, 7th PK Workshop, Abstract 37

51 Effect of MDR proteins 2 and 4 polymorphisms on TNF PK in HIV-infected patients J Kiser,, C Aquilante, P Anderson, P Wolfe, M Carten,, C Fletcher Abstract 34

52 TNF and MDR2, MDR4 TNF potentially substrate MDR2 and MDR4 N = / 27 + LPV/ rtv 6 / 37 black Genotype MRP2 SNPs (G1249A, C-24T) C MRP4 SNPs (A3463G, T4131G) Frequency G1249A: 22.2 % C-24T: 16.7 % A3463G: 20.4 % T4131G: 40.7%

53 MRP4 A3463G Intracell TNF conc. TNF AUC TNF CLr MRP2 C-24T TNF fraction excreted AA CC AG / GG CT 31 % 37% IC TNF conc: fmol/10 6 cells; AUC mcg*h/ml; CLr: L/h

54 Questions?

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