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

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

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

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

Target Minimal Concentrations ARV Cmin (mg/l) Naïve pts Éfavirenz 1.0 Névirapine Amprénavir 3.4 0.4 Atazanavir 0.15 Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir 0.1 1.0 0.8 2.1 0.1 Cmin (mg/l) PI experienced pts NA NA 1.6 4.0 www.hivpharmacology.com GIQ NA NA 0.3 0.9 0.04

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

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

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.

TPV GIQ Results: Logistic Regressions Wk 24 Parameter OR CI 95% p value Ctrough 1.0 1-1 0.43 # TPV mutations 0.65 0.37-1.12 0.12 TPV GIQ 1.17 1.01-1.35 1.35 0.03 T-20 0.53 0.13-2.09 0.36 Baseline VL 1.09 0.6-1.9 0.76 Bonora et al, 7th PK Workshop, Abstract 83.

TPV GIQ Target > 13 000 ng/ml 60 50 40 30 %Virologic Response 20 10 0 GIQ < 13000 GIQ > 13 000 Bonora et al, 7th PK Workshop, Abstract 83.

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

Logistic binary regressions for viral load < 400 copies/ml at week 48 vs PK / PD parameters PK / PD parameter p value LPV C 12 0.707 SQV C 12 0.702 LPV GIQ 0.049* SQV GIQ 0.241 SQV mgiq 0.382 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

Virologic response as a function of LPV, SQV and GIQ % subjects with viral load < 400 copies/ml 90 80 70 60 50 40 30 20 10 0 LPV GIQ SQV GIQ Sum GIQ GIQ targets > 1.7 > 0.35 > 2.6 Below Target Above Target P value 0.011 0.029 0.003 Fisher s Exact Test

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

% Concentrations Below Adult Targets LPV EFV NVP Infants 16,7-44,4 1 5 years 19,4 25,9 22,2 6 12 years 19,0 19,5 20,9 Adolescents 25,5 26,8 21,4 Gibbons et al, 7th PK Workshop, Abstract 8.

% Concentrations < LOQ Lopinavir Nevirapine Infants 8,3 4,4 1 5 years 15,1 6,1 6 12 years 17 9,3 Adolescents 19,4 10,7 Gibbons et al, 7th PK Workshop, Abstract 8.

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

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

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

TPV & T-20T TPV Pk samples taken 11-13 13 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

Tipranavir PK C trough (ng/ml) With T-20 Without T-20 41069 ± 20174 27261 ± 17516 Vd / F (L) 9.85 6.5 Kel (1/h) 0.07 0.17 T ½ (h) 9.69 5.36 Gonzalez de Requena et al, 7th PK Workshop, Abstract 52

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

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

Tipranavir PK median,, (IQR) PK Parameter C trough 35.3 + T-20T Without T-20 (28.0-43.3) AUC 603.6 (517.3-1003.7) 1003.7) Cmax 96.45 (61.3-137.9) 137.9) 39.5 (27.0-44.5) 695 (420-904) 81.9 (52.2 113.4) p value 0.730 1.0 0.46 Curran et al, 7th PK Workshop, Abstract 53

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

TMC-114 PK & T-20T Median (range) With T-20 Without T-20 AUC (ng*h/ml) 127 141 (68911 298820) 117700 (56127 265 880) C trough (ng/ml) 3920.6 (1429.4-10919) 10919) 3680.4 (1232.8 9960.7) Sekar et al, 7th PK Workshop, Abstract 54

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

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

TAZ PK with TPV GMR, 90% CI PK Parameter % change GMR (90% CI) AUC 0-24 -6868 0.32 (0.29-0.36) 0.36) Cmax -5757 0.43 (0.38-0.5) 0.5) Cmin - 81 0.19 (0.15-0.24) 0.24) Sabo et al, 7th PK Workshop, Abstract 41

TPV PK with TAZ GMR, 90% CI PK Parameter % change GMR (90% CI) AUC 0-24 + 20 1.20 (1.09-1.32) 1.32) Cmax + 8 1.08 (0.98-1.2) Cmin + 75 1.75 (1.39-2.2) Sabo et al, 7th PK Workshop, Abstract 41

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

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

TPV & Methadone GMR, 90% CI, % Change PK Parameter AUC0-24 (ng*h/ml) S- methadone (inactive) 0.37 (0.34-0.41) 0.41) - 63 % R-methadone (active) 0.52 (0.49-0.56) 0.56) - 48 % Cmax (ng/ml) 0.38 (0.35-0.43) 0.43) - 62 % 0.54 (0.5-0.58) 0.58) - 46 % Sabo et al, 7th PK Workshop, Abstract 42

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

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 0 7 14 21 35 50 57 Study Day Luber et al, Poster 36, 7th International Workshop on Clinical Pharmacology of HIV Therapy, Lisbon, 2006

Impact of omeparazole 20 mg on steady-state pharmacokinetics of fosamprenavir and atazanavir Concentrations ( u g 8 6 4 2 0 0 5 10 15 20 25 30 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

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

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

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

Jetter et al, 7th PK Workshop, Abstract 37

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

TNF and MDR2, MDR4 TNF potentially substrate MDR2 and MDR4 N = 27 13 / 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%

MRP4 A3463G Intracell TNF conc. TNF AUC TNF CLr MRP2 C-24T TNF fraction excreted AA 63.5 3.7 13 CC AG / GG 90.9 4.6 10.5 CT 31 % 37% IC TNF conc: fmol/10 6 cells; AUC mcg*h/ml; CLr: L/h

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