Aspetti di Farmacocinetica e Farmacodinamica nei STR s (Single Tablet Regimens) per il Trattamento dell’Infezione da HIV-1 Gianni Di Perri Clinica di Malattie Infettive Università degli Studi di Torino Ospedale Amedeo di Savoia

L’evoluzione della Farmaceutica, ovvero delle modalità di elaborazione di preparati per uso medico, è in necessario parallelismo con: L’evoluzione Farmacoterapica, ovvero degli avanzamenti in tema di disponibilità di nuovi principi attivi efficaci, sicuri e tollerati L’evoluzione della comprensione dei principi della Farmacodinamica e dell’applicazione degli stessi (come perseguire il miglior possibile risultato con le risorse disponibili) L’evoluzione del paziente, nel senso dell’aumento della potenzialità di cura e controllo di numerosi disordini acuti e cronici, e quindi dell’aumento della durata della vita L’aumento della pretesa di risultato

In the FDC and/or STR conception one assumption and two main reasons are recognizable for pursuing co-formulation: The two main reasons: 1.More than 1 drug is required to treat the disease, and co-formulation might ensure that 2/3 or the entire therapy is taken; 1.A reduced n. of pills has the potential to improve adherence The assumption: For whatever reason (synergy, genetic barrier, …), more than one drug is required for treating the disease

In the FDC and/or STR conception one assumption and two main reasons are recognizable for pursuing co-formulation: The two main reasons: 1.More than 1 drug is required to treat the disease, and co-formulation might ensure that 2/2 or the entire therapy is taken; 1.A reduced n. of pills has the potential to improve adherence The assumption: For whatever reason (synergy, genetic barrier, …), more than one drug is required for treating the disease

NRTI monotherapy P24 Antigen NRTI dual therapy HIV-RNA/mL Log HIV-RNA/mL Log 10 HAART 2NRTIs + NNRTI or PI/r or II now HAART 2NRTIs + PI (single) /1 HIV RNA copies/mL

Malattie da Infezione: Polichemioterapia Virus HIV HBV HCV CMV Micobatteri M.tuberculosis M.leprae MAC & other atypical Parassiti P.falciparum P.vivax P.ovale E.histolytica W.bancrofti Batteri convenzionali P.aeruginosa ES  L producers (e.g. KPC) Endocardite Infezioni polimicrobiche Terapia empirica/razionale H.pylori Funghi Cryptococcus sp. Aspergillus spp. Candida sp.

Motivi del ricorso a più farmaci Modifica di 1 o più parametri di efficacia Barriera genetica Copertura di spettro Copertura compartimentale Controllo epidemiologico / ambientale (“altruista”) Sinergico / Additivo Antagonista / Indifferente Potenziante / Riduttivo Coalistico

Suppression Antagonism The shape of equal inhibition lines in the dose-dose space defines the interaction between the drugs Growth rate [A] [B] MIC Synergy Additivity Minimal Inhibitory Concentration

Michel,Yeh, et al. – PNAS 2008 “Coalistic” Interaction

In the FDC and/or STR conception one assumption and two main reasons are recognizable for pursuing co-formulation: The two main reasons: 1.More than 1 drug is required to treat the disease, and co-formulation might ensure that 2/3 or the entire therapy is taken; 1.A reduced n. of pills has the potential to improve adherence The assumption: For whatever reason (synergy, genetic barrier, …), more than one drug is required for treating the disease

Combivir Atripla Stribild September 1997 July 2006 August 2012 AZT/3TC TDF/FTC/EFV EVG/COBI/TDF/FTC Trizivir Eviplera November 2000 August 2011 AZT/3TC/ABV TDF/FTC/RPV Truvada Triomune August 2006 June 2001 TDF/FTC d4T/3TC/NVP Kivexa Duovir-N August 2004 July 2003 ABV/3TC AZT/3TC/NVP Kaletra September 2000 (Meltrex 2005) LPV/RTV N/NtRTIs N/NtRTIs // NNRTIs N/NtRTIs // IIs Triumeq August-Sept 2014 DGV/ABV/3TC

Darunavir without ritonavir is 37% bioavailable Primary resistance to darunavir leads to significant in class resistance Darunavir package insert

SQV/RTV simultaneously RTV – 4 hs - SQV SQV – 4 hs - RTV

In the FDC and/or STR conception one assumption and two main reasons are recognizable for pursuing co-formulation: The two main reasons: 1.More than 1 drug is required to treat the disease, and co-formulation might ensure that 2/3 or the entire therapy is taken; 1.A reduced n. of pills has the potential to improve adherence The assumption: For whatever reason (synergy, genetic barrier, …), more than one drug is required for treating the disease

Adherence: on-time pharmacy refills by number of tablets per day Patients, % Adherence to antiretroviral therapy Single-tablet regimen P < N 11% more pts with ≥80% adherence to STR vs. MTR: 70% vs. 59% 11% more pts with ≥80% adherence to STR vs. MTR: 70% vs. 59% Cohen C, et al. EACS Belgrade, Serbia. Poster PE7.5/7. <60%60%–79%80%–94%95%–100% Multi-tablet regimen 15

Caratteristiche e Proprietà delle Singole Componenti di un Regime STR

Raltegravir (RAL) BENCHMRK SWITCHMRK STARTMRK ARDENT (ACTG 5257) QDMRK (QD vs bid) Elvitegravir (ELV) Study 102 (vs EFV/FTC/TDF [atripla]) Study 103 (vs ATV/r) STRATEGY - PI STRATEGY - NNRTI Dolutegravir (DGV) SPRING 1, 2 (vs RAL & EFV) SINGLE (vs EFV/FTC/TDF [atripla]) VIKING I, II, III (RAL-R) SAILING (vs RAL, IIs- naïve pts) FLAMINGO (vs DRV/r) Integrase Inhibitors (IIs): main clinical trials * Superiority: at week 48; * At week 156 Treatment-naïve pts Treatment-experienced patients Switch studies (not for failure)

PHARMACODYNAMICS IC 50 : 2.7 nM, IC 50 in PBMC: 0.51 nM RAL IC 50 : 3.3 nM EVG IC 50 : 6.0 nM Dissociation from integrase-DNA complexes: mean dissociation rate constant ((k off ) [s -1 x ] DrugWild-Type HIVQ148 mutation DTG2.737 RAL EVG EVG, elvitegravir; IC 50, 50% inhibitory concentration; PBMC, peripheral blood mononuclear cells; RAL, raltegravir Kobayashi M, et al. Antimicrob Agent Chemother 2011; 55: Hightower KE, et al. Antimicrob Agent Chemother 2011; 55:

RELATIONSHIP BETWEEN DTG TROUGH CONCENTRATION AND VIRAL LOAD REDUCTION DTG is associated with a well characterised, predictable exposure-response relationship Phase IIa, dose-ranging, placebo-controlled, 10-day monotherapy study Placebo 2 mg QD 10 mg QD 50 mg QD Model fit: E max = –2.6, IC 50 – µg/mL C  (µg/mL) Day 11 log 10 viral load change from baseline –3.5 –3.0 –2.5 –2.0 –1.5 –1.0 – c/mL, copies/mL; E max, maximum effect; RNA, ribonucleic acid Subjects with HIV-1 RNA <50 c/mL are represented by orange-bordered circles Open circles with lines denote mean standard deviation Adapted from Min S, et al. AIDS 2011; 25:1737–

DTG: 90% DRV/r: 83% Week BL Proportion (%) Raltegravir 400 mg BID* Efavirenz 600 mg QHS* Weeks Percent of Patients With HIV RNA < 50 Copies/mL % Non-Inferiority P Value < % A favorable finding associated to the therapeutic use of IIs in treatment-naïve patients is a much quicker viral fall then comparators (both NNRTIs and PIs/r Does it matter? My answer is probably yes, I would say for two reasons: a.Greater genetic barrier b.Pharmacodynamic T/2 likely to be longer than pharmacokinetic T/2

Infections with a high bacterial density at the initiation of antibiotic therapy may present a therapeutic problem, including a higher risk for the emergence of resistance due to the larger number of bacteria present and the higher probability of having at least one resistant bacterial cell within a large initial inoculum (CFUo) Johnson, C. C., L. Livornese, M. J. Gold, P. G. Pitsakis, S. Taylor, and M. E. Levison Activity of cefepime against ceftazidime-resistant gram-negative bacilli using low and high inocula. J. Antimicrob. Chemother. 35: in in in in 10 9

Log (f a /f u ) = m log(D/IC 50 ) Fraction of the viral population affected by the drug Fraction of the viral population unaffected by the drug Drug concentration Drug concentration inhibiting the 50% of viral growth The effect of the virus is measured in a single- round infectivity assay in vitro as infected cells (%) rather than as HIV-RNA fall per time unit (clinical studies) Steepness of the curve m1 m2 m3 The parameter m determines the sigmoidicity of the concentration-response curve Shen l, et al. Letter Nature Medicine 14, (2008) Published online: 15 June 2008

These are the facts……. EFV RAL RAL 100 mg BID. RAL 200 mg BID. RAL 400 mg BID. RAL 600 mg BID. EFV 600 mg QD DTG: 90% DRV/r: 83% Week BL Proportion (%) Raltegravir 400 mg BID* Efavirenz 600 mg QHS* Weeks Percent of Patients With HIV RNA < 50 Copies/mL % Non-Inferiority P Value < % Weeks Shen l, et al. Letter Nature Medicine 14, (2008) Published online: 15 June 2008

Experimentally measured antiretroviral IC50s are determined by three factors: 1. intrinsic drug properties (e.g. drug-target binding) how well it is taken up, complexes with, inhibits its target, how easily the reverse process takes place 2. kinetics of the HIV life cycle the longer the drug-susceptible state exists the lower the IC50, because there is more time for the drug to act and affect target cells 3. kinetics of drug-inhibited infected cells These parameters may also depend on the virus-producing cell type. Previously reported IC50s of five RT inhibitors in macrophages are on average 3 fold lower than IC50s measured using a similar and compar- able single round infection assay in CD4+ T cells Enhancing ARV activity through pharmacologic interventions that prolong the drug-susceptible state; eg additional antiretroviral drugs (synergy) Resistance mutations often come at a fitness cost, for example through slowing HIV enzyme kinetics; e.g. 184V & 3TC use

HIV requires an average of 52 h between two sequential generations; Most of this time is taken by reverse transcription (RT, 33 h)

Overall analysis: RAL + DRV/r non inferior to TDF/FTC + DRV/r Primary endpoint at W96 by baseline characteristics n = 805 n = 530 n = 275 n = 123 n = 682 Overall < 100,000 c/ml > 100,000 c/ml < 200/mm 3 > 200/mm 3 Baseline HIV-1 RNA Baseline CD % 7 % 36 % 39.0 % 13.6 % 13.7 % 7 % 27 % 21.3 % 12.2 % RAL + DRV/rTDF/FTC + DRV/r Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted * Test for homogeneity p = 0.09* p = 0.02* NEAT 001/ANRS 143 RAL + DRV/rTDF/FTC + DRV/r

Virological Efficacy at W24 Proportion of patients with HIV RNA <50 cp/mL 28 pts 25/28 VL <50 cp/mL All <50 cp/mL All <20 cp/ml except 37 cp/mL (1) 1 blip W4 (52 cp/mL) 3 virological failures W12: 1 pt – VL 138/469 cp/mL W24: 2 pts – VL: 2220 cp/mL – VL: 291 cp/mL MonoDTG 100% CI 95%: 85–100 96% CI 95%: 82–99 89% CI 95%: 72–98 Katlama C, et al. EACS 2015, Oral PS4/4

Viral suppression at week 24 #SCRBSL DAY 2 DAY 4 DAY 7 DAY 10 W.2W.3W.4W.6W.8W.12W < < < < < < < Not done268105< Not done516202< < < < < < < < 50 Not done< < < < < < 50 From week 8 onwards all patients had pVL <50 copies/mL Dolutegravir-Lamivudine as initial therapy in HIV-infected ARV naïve patients First results of the PADDLE trial ClinicalTrials.gov : # NCT

Days Total Parasite Burden detection limit (50/  L) Parasite Clearance according to the PRR 48h Artesunates Chl, Amod, Halof Quin, Mefl, SP

Differenziazione e Replicazione asessuata del Plasmodium falciparum Le forme inibite dagli inibitori della DHFR, da chinino, chinidina e meflochina

Differenziazione e Replicazione asessuata del Plasmodium falciparum Le forme inibite dagli artesunati

ELIMINATION HALF-LIFE (T/2) EFAVIRENZ RILPIVIRINE ELVITEGRAVIR/COBI DOLUTEGRAVIR h EFV: 45 h TDF (ic): 150 h FTC (ic): 39 h h RPV: 50 h TDF (ic): 150 h FTC (ic): 39 h h EVG: 12.9 h TDF (ic): 150 h FTC (ic): 39 h h DGV: 14 h ABV (ic): 20 h 3TC (ic): 25 h

Acknowledgments THE UNIVERSITY of LIVERPOOL TORINO: Stefano Bonora Antonio D’Avolio Mauro Sciandra Marco Siccardi Lorena Baietto Cristina Tettoni Sabrina Audagnotto Letizia Marinaro Jessica Cusato Margherita Bracchi Laura Trentini Andrea Calcagno Marco Simiele Amedeo De Nicolò Anna Lucchini Filippo Lipani Roberto Bertucci Agostino Maiello Bernardino Salassa Francesco G. De Rosa Chiara Montrucchio Chiara Alcantarini Chiara Cardellino LIVERPOOL: David Back Saye Khoo Andy Owen Marco Siccardi Anna Maria Geretti LONDON: Marta Boffito Margherita Bracchi Nicole Pagani ROMA: Andrea Antinori Emanuele Nicastri Giuseppe Ippolito Alessandra Arialdo Micol Ferrara Alice Trentalange Nicole Pagani Lucio Boglione Sarah Allegra Alessandro Turchi Debora Pensi Pino Cariti Paolo Bigliano Ilaria Motta Silvia Corcione Maria Laura Stella Giancarlo Orofino Valeria Ghisetti