New Drugs New Regimens New Tests

Transkript

1 Slide 1 Some Key Clinical Pharmacology Issues in 2010 David Back University of Liverpool UK David Back BHIVA/BASHH April 2010 New Drugs New Regimens New Tests 1

2 NRTIs Apricitabine Elvucitabine Some Antiretrovirals in Development PIs Combination of ATV and DRV with PK enhancers. Slide 3 NNRTIs Rilpivirine Lersivirine IDX899 RDEA427/640 NVP XR Integrase Inhibitors Elvitegravir Soltegravir (S/GSK ) CCR5 Antagonists Vicriviroc TBR652 PF Antiretrovirals in Development Slide 4 FDCs QUAD ELV/GS9350/TDF/FTC Truvada/Rilpivirine Other Boosters PF (PK enhancer) SPI-452 (PK enhancer) 2

3 NRTIs Apricitabine (Formerly BCH10618, SPD754 and AVX754) Deoxycytidine analogue NRTI Plasma half life ~ 3h Intracellular TP half life ~ 7h Interacts with 3TC Renally eliminated Low potential for cross resistance with current NRTIs Currently in Phase III at a dose of 800 mg BID. 3

4 Slide 7 May provide some benefit to patients with limited options, but... NNRTIs 4

5 Rilpivirine (TMC278) Key PK Characteristics Half-life of 45 hours - supports once-daily dosing (25 mg) Mean TMC278 Plasma Concentration, ng/ml Absorption ph dependent; increased AUC with food ( 60%); Metabolism: mainly CYP3A4; Renal elimination is minor. Expect Rilpivirine to be affected by drugs that: i) alter gastric ph Time, Hour ii) induce or inhibit CYP3A4 Only induces at high doses. ph increase Effect of co-medication on Rilpivirine AUC 24h ph increase CYP3A induction atorvastatin chlorzoxazone darunavir/rtv famotidine 2h before famotidine 4h after famotidine 12h before ketoconazole lopinavir/rtv omeprazole paracetamol rifabutin rifampin TDF sildenafil LSMean ratio (AUC 24h ) CYP3A inhibition CYP3A inhibition no effect boundaries 0.8 to 1.25 TMC278 TMC

6 Lersivirine PK Characteristics Phase II; dose 750 or 1000 mg QD Well absorbed; negligible food effect. T 1/2 ~ 6 7 hours Highly metabolized UGT2B7 CYP3A4 Modest CYP3A4 induction. P-gp inhibition (in vitro) Effect of Co-Medication on Lersivirine AUC Geometric Mean Ratio Antacid (Maalox) Raltegravir Lopinavir/r Darunavir/r Atazanavir/r Atazanavir TDF/FTC Valproic Acid Rifampicin Ketoconazole CYP3A Inhibition Lersivirine No effect boundaries Lersivirine 6

7 PK of NVP Extended Release (XR) vs. Immediate Release (IR) 48 stable patients on NVP IR 200mg BID HIV-RNA < 50 copies/ml Switched to NVP XR Overall, XR showed slower absorption with comparable C min but modestly lower C max and bioavailability Nevirapine Plasma Conc. (ng/ml) [day] 0 IR 400 mg (N=24) XR 400 mg (N=24) Time (hours) Plasma Concentration of NVP XR 400 mg 25% QD vs. NVP IR 200 mg BID Quinson A, et al. 49 th ICAAC; San Francisco, CA; Sept , 2009; Abst. H Protease Inhibitors with novel PK enhancers 7

8 Slide 15 GS-9350 (Cobicistat) Potent inhibitor of CYP3A4 No antiviral activity Less induction potential than RTV Physicochemical properties make it amenable to co-formulation. QUAD pill. 8

9 HIV Highlights From San Francisco clinicaloptions.com/hiv Virologic Efficacy of ATV boosted with GS-9350 and RTV in Naive Pts Phase II study comparing cobicistat (GS-9350) vs ritonavir as boosting agent for atazanavir Treatment-naive pts with CD4+ 50 cells/mm 3, HIV-1 RNA 5000 c/ml, no NRTI, NNRTI, or PI resistance (N = 79) Wk 24 primary endpoint Wk GS-9350 Boosted ATV + FTC/TDF (n = 50) RTV-Boosted ATV + FTC/TDF (n = 29) Cohen C, et al. CROI Abstract 58LB. Reproduced with permission. HIV-1 RNA < 50 c/ml (%) GS-9350 RTV Wk 24 stratum-weighted 20 difference: -1.9% (95% CI: -18.4% to 14.7%) Wk ITT, M = F HIV Highlights From San Francisco clinicaloptions.com/hiv GS-9350 Appears to Alter Estimated GFR, Not Actual GFR Most creatinine excretion occurs by filtration, but 10-15% by active tubular secretion day GS-9350 v placebo in healthy subjects no effect on actual GFR (iohexol CL) but lower estimated GFR. Mechanism: inhibition of tubular secretion? Actual GFR (ml/min; lohexol) BL GS-9350 n = 12 Day 7 Day 14 BL Placebo n = 12 Day 7 Day 14 Cohen C, et al. CROI Abstract 58LB. Reproduced with permission. 9

10 Integrase Inhibitors 10

11 S/GSK PK and Exposure-Response Relationship (Phase IIa) 1 S/GSK Concentration (µg/ml) S/GSK (unboosted; QD dosing) Plasma Concentrations on Day In vitro PA-IC 90 (0.064 µg/ml) Time (hour) 2mg QD 10mg QD 50mg QD Day 11 log 10 VL Change from Baseline Emax model of S/GSK Exposure vs. Response Ctau (µg/ml) Placebo 2mg QD 10mg QD 50mg QD Model Fit, Emax= -2.6, EC 50 = 0.036µg/mL 1. Song I, et al. IAS 2009, Cape Town, Wednesday poster #WEPEB250 Lalezari, et. al. IAS th Conference on HIV Pathogenesis, Treatment and Prevention July 2009, Cape Town South Africa Abstract TUAB105 Shionogi-GlaxoSmithKline Pharmaceuticals, LLC 21 S/GSK Drug Interaction Profile Metabolised by UGT1A1; CYP3A4 minor Drug interaction profile: As Perpetrator limited (ie no effect on Midazolam, a CYP3A4 drug or Tenofovir); Multiple in vitro studies. As Victim care. Simultaneously with antacid, AUC 70% With ATV AUC 90% Lalezari, et. al. IAS th Conference on HIV Pathogenesis, Treatment and Prevention July 2009, Cape Town South Africa Abstract TUAB105 Shionogi-GlaxoSmithKline Pharmaceuticals, LLC 22 11

12 S/GSK Interaction with Etravirine Lalezari, et. al. IAS th Conference on HIV Pathogenesis, Treatment and Prevention July 2009, Cape Town South Africa Abstract TUAB105 Shionogi-GlaxoSmithKline Pharmaceuticals, LLC 23 PK of Raltegravir + Etravirine Healthy subjects (n=19) ETR decreased RAL C12 by 34% and AUC by 10% Conclusions: ETR combined with RAL - no dose adjustment necessary for either drug. Anderson M et al. Antimicrobial Agents and Chemotherapy, 2008; 52: Etravrine Raltegravir: A marked interaction in HIV-1 infected patients Menard A et al. AIDS 2009;23: Raltegravir (RAL) in combination with etravirine (ETV) is there a case for TDM in clinical practice. Leake Date H et al BHIVA?BASHH 2010 P6 12

13 CCR5 Antagonists Slide 26 Gathe J, et al. CROI Abstract 54LB. Limited benefit in experienced cf Placebo Ongoing considerations - Naive Boosted PI increases exposure by 5-fold t1/2 = ~24h 13

14 2. New regimens Slide 28 NEAT 001: RAL (400 mg bid) + DRV/r (800 mg QD) EARNEST: RAL (400 mg bid) + LPV/r (400/100 bid) 14

15 Slide 29 Atazanavir + Raltegravir Slide 30 Numerous PK studies Atazanavir 300 mg BID + Raltegravir 400 mg BID (Zhu et al CROI 2009) Atazanavir 200 mg BID + Raltegravir 400 mg BID (Ripamonti et al. Pharm Workshop 2009) Atazanavir 400 mg QD + Raltegravir 800 mg QD (Molto et al IAS 2009) Atazanavir 400 mg QD + Raltegravir 400 mg QD (Neely et al IAS 2009) ATV Metabolized by CYP3A4 RAL Metabolized by UGT1A1 15

16 Slide 31 Phase IIB. Atazanavir + Raltegravir (SPARTAN) (HIV+ Naïve; >5000 VL) ATV (300 mg BID) + RAL (400 mg BID) v ATV/r (300/100 mg QD) + TDF/FTC (300/200 mg QD) Primary Outcome: < 50 at week 24. Phase III. Atazanavir + Raltegravir (SPARTA) (HIV+; suppressed) ATV (300 mg BID) + RAL (400 mg BID) for 4 weeks then ATV/r (300/100 mg QD) + RAL (800 mg QD) for 4 weeks. ARMS A & B. Atazanavir + Maraviroc 16

17 3. New Tests (PGx) 17

18 Implementation of pharmacogenetic testing Clinical validation Clinical confirmation Mechanistic studies Define mechanisms and identify biologically plausible candidate genes. Exploratory clinical studies Candidate gene association studies to define whether an association exists. Confirmatory clinical studies Genotype directed clinical management to define the clinical benefit. Cost effectiveness studies Risk benefit analyses to assess whether the association is affordable. Exploratory clinical studies Genome Wide association study (GWAS) to discover novel associations. Mechanistic studies Explore the mechanism for the association to ensure biological plausibility. Confirmatory clinical studies Genotype directed clinical management to define the clinical benefit. Cost effectiveness studies Risk benefit analyses to assess whether the association is affordable. Plasma efavirenz concentration (ng / ml) Interindividual variability in Efavirenz plasma concentrations. (n= 300 patients) > ng / ml Higher chance of CNS toxicity? < 1000 ng / ml Higher chance of resistance Time post dose ng / ml 530 ng /ml Wyen et al (2008) J Antimicrob Chemother. 61, Marzolini et al. (2001) AIDS. 15,

19 Implementation of pharmacogenetic testing Clinical validation Clinical confirmation Mechanistic studies Define mechanisms and identify biologically plausible candidate genes. Exploratory clinical studies Candidate gene association studies to define whether an association exists. Confirmatory clinical studies Genotype directed clinical management to define the clinical benefit. Cost effectiveness studies Risk benefit analyses to assess whether the association is affordable. Exploratory clinical studies Genome Wide association study (GWAS) to discover novel associations. Mechanistic studies Explore the mechanism for the association to ensure biological plausibility. Confirmatory clinical studies Genotype directed clinical management to define the clinical benefit. Cost effectiveness studies Risk benefit analyses to assess whether the association is affordable. 19

20 Pharmacogenetics Pyramid: Efavirenz Cost Clinical Course Clinical Variables Marker Association Clinical situation/need Adapted from Zineh and Lesko, Per Med 2009;6(4) Genetic Determinants of Antiretroviral PK and Toxicity Drugs Gene, Allele, Polymorphism Reported Association ABACAVIR HLA-B*5701 Risk of HSR TENOFOVIR ABCC2 (MRP2) Risk of renal proximal tubulopathy Slide 40 NEVIRAPINE HLA-DRB1*0101 HLA-cw8 Risk of HSR and hepatotoxicity Risk of HSR EFAVIRENZ CYP2B6 516G>T, 983T>C; CYP2A6, UGT2B7; CAR Increased plasma exposure ATAZANAVIR UGT1A1*28 Unconjugated hyperbilirubinaemia PIs APOA5, APOC3, APOE, ABCA1 Increased risk of hyperlipidemia LOPINAVIR SLC01B1 521T>C Increased plasma concentrations RALTEGRAVIR UGT1A1*28 Modest increase in plasma levels 20

21 Slide 41 New Drugs New Regimens New Tests New Opportunities Slide 42 21

22 Thanks Slide 43 University of Torino For Slides Colleagues at Merck, GSK, Pfizer, Viiv, Tibotec, Gi lead. 22