Clinical Pharmacology Related Considerations. David Back University of Liverpool David Back UK University of Liverpool Disclosures • Honoraria received for advisory boards and lectures from AbbVie, BMS, Gilead, Merck, ViiV, Janssen, Teva • Educational grants for www.hep-druginteractions.org and www.hiv-druginteractions.org from AbbVie, BMS, Gilead, Janssen, Merck, ViiV Overview 1 The changing face of treatment. 2 3 Antiretroviral Therapy: Past, Present & Future 1. New Drugs The Integrase 2. 2 Drug Regimens era (2DR) Single 3. Long acting Triple drug tablet agents? therapy regimens ZDV monotherapy HIV-1 discovered 1983 1987 1996 2006 2012/13 2018ff Overview of Clinical Guidelines and First-Line Antiretroviral Treatment Options DRV/r RAL RPV TDF/FTC DRV/c DTG EFV TAF/FTC EVG/c ABC/3TC Overview of Clinical Guidelines and First-Line Antiretroviral Treatment Options DRV/r RAL RPV TDF/FTC DRV/c DTG EFV TAF/FTC EVG/c ABC/3TC Raltegravir (RAL) 1200 mg once daily (QD) versus RAL 400 mg twice daily (BID), in combination with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), in previously untreated HIV-1 infection through week 96 P. Cahn for the ONCEMRK Study Group IAS 2017: TULBPEB20 First-Line ART Regimens for Adults WHO Guidelines June 2016 C EFV at lower dose of 400 mg e Safety and efficacy data on the use of EFV400 in pregnant women, people with HIV/TB coinfection and adolescents younger than 12 years of age are not yet available. Pharmacokinetics, pharmacodynamics and pharmacogenomics of efavirenz 400mg once-daily during pregnancy and postpartum Marta Boffito, Chelsea and Westminster Hospital, Curr Opin HIV AIDS 2017; 12: 339-342 United Kingdom. IAS 2017: TUPDB0203LB Newer ART Agents (partial list) NRTI NNRTI PI EI II MI Phase 3 Doravirine Albuviritide Bictegravir Fostemsavir Cabotegravir Ibalizumab Phase 2 Apricitabine BILR 355 Cenicriviroc Festinavir Elsulfavirine PF-232798 Dexelvucitabine Phase TMC HGS004 1/2 310911 UB-421 Phase I MK-8591 RDEA 806 CTP-298 BMS-986197 BI 224436 GSK- CTP-518 SCH532706 2838232 PPL-100 VIR-576 SPI-256 Adapted from Gulick R, HIV Therapy, Glasgow 2016 Bictegravir Disposition and PK BIC/FTC/TAF 50/200/25 mg STR under evaluation in Phase 3 studies Well absorbed (>70%) Metabolized by CYP3A4 and UGT1A1 Inhibition of both CYP3A4 & UGT1A1 needed for marked increase in exposure Minimal renal clearance (~1% of parent drug excreted in urine) Potent induction reduces exposure to a clinically significant extent. Zhang et al. CROI 2017, Oral 40 Bictegravir: DDIs via CYP3A4, UGT1A1 and P-gp Zhang et al. CROI 2017, Oral 40 Cabotegravir Disposition and PK CAB under evaluation in Phase 3 studies as: – Oral 30 mg tablet (t½, ~40 hours) – LA nanosuspension 200 mg/mL (t½, ~20-40 days) CAB is primarily metabolised by UGT1A1 (minor involvement of UGT1A9) CAB is a substrate of P-gp and BCRP Potent induction (by rifampicin) reduces exposure by a clinically significant extent (~60%) CAB inhibits sensitive OAT substrates (eg methotrexate) BUT overall low risk of DDIs as perpetrator. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB; Ford S et al IWCP HIV & HEP 2016; Slide modified from Viiv Healthcare. Overview 1 The changing face of treatment. 2 2 Drug Regimens (2DR) 3 Why consider 2DR? Why take 3 (or 4) drugs, when 2 can do? Potential preservation of future treatment options Cost? Why 2DR? Reduce impact of long-term exposure Establish new treatment paradigms to multiple ARVs and evolve the SoC. Less potential for AEs? Fewer drugs - Potential to reduce DDIs Important with Aging patients and Comorbidities AE, adverse event; ARV, antiretroviral; DDI, drug-drug interaction; HCP, healthcare professional; SoC, standard of care; 2DR, two-drug regimen; Slide courtesy of Viiv Healthcare What would make an ideal 2DR? Potent antiviral activity Low cost; Affordable Favourable PK/DDI profile Ideal 2DR Reduced cumulative High barrier to resistance long-term drug exposure Fewer short-term and long-term AEs/toxicities AE, adverse event; DDI, drug–drug interaction; PK, pharmacokinetic Slide modified from Viiv Healthcare Overview of Clinical Guidelines and First-Line Antiretroviral Treatment Options DRV/r RAL RPV TDF/FTC DRV/c DTG EFV TAF/FTC EVG/c ABC/3TC Why consider DTG as a core agent to support 2DRs? Rapid and potent antiviral activity1 2–5 Clinical trial data High barrier to resistance5,7 • Numeous trials in tx-naïve and tx- • In vitro and Phase III data experienced subjects. Long binding to WT INI8 • Dissociation from INI–DNA Dolutegravir complexes slower vs RAL or EVG DDIs Generally well tolerated • Booster-free • Few discontinuations due to AEs in • Relatively few clinically significant DDIs INI-naïve clinical trials2–6 Long half-life; low variability in exposure 9 • DTG exposure 17-fold above IC90 • Long ‘tail’10 ATV; atazanavir; DDI, drug–drug interaction; DRV, darunavir; EFV, efavirenz; EVG, elvitegravir; INI, integrase inhibitor; RAL, raltegravir; tx, treatment; QD, once daily; WT, wild-type 1. Min S et al. AIDS 2011;25:1737–1745; 2. Walmsley S et al. N Engl J Med 2013;369:1807–1818; 3. Clotet B et al. Lancet 2014;383:2222–2231; 4. Orrell C et al. ARIA Study. Int AIDS Conference (IAC), July 2016, Durban, SA. Abstract #10215; 5. Cahn P et al. Lancet 2013;382:700–708; 6. Raffi F et al. Lancet 2013;381:735–743; 7. Kobayashi M et al. AAC 2011;55:813–821; 8. Hightower KE et al. AAC 2011;5:4552–4559; 9. van Lunzen J et al. Lancet Infect Dis 2012;12:111–118; 10. Elliot E et al. IWCPHIV 2015. Abstract 13. Slide modified from Viiv Healthcare Why 3TC or RPV in combination with DTG? 3TC RPV . Present in all major Guidelines1-4 . LATTE & LATTE-2 proof of principle for INH- . Well tolerated; Low number of discontinuations RPV 2-DR for maintenance therapy11,12. due to AEs in pivotal clinical trials5-8 . Long half-life (~50h) and relatively low DDI . Long Intracellular half-life (22h)9 profile9 . Low potential for DDIs9 . Tolerability13. RPV associated with fewer neurological and psychiatric AEs than EFV in tx- . Clinical data emerging10 naïve patients 1. DHHS. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2016; 2. Günthard HF, et al. JAMA 2016;316:191–210; 3. EACS guidelines, Version 8.2 January 2017; 4. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Updated 2016; 5. Eron JJ, et al. AIDS 1996;5:S11–9; 6. Bartlett JA, et al. Ann Intern Med 1996;125:16172; 7. Result summary for NUCB3001, ViiV Healthcare 2005; 8. Result summary for NUCB3002, ViiV Healthcare 2005; 9. www.hiv-druginteractions.org. 10. Cahn P, et al. Lancet Infect Dis 2014;14:572–80; 11. Margolis DA, et al. Lancet Infect Dis 2015;15:1145– 55; 12. Margolis DA, et al. CROI 2016. Abstract 31LB; 13. 13. Gunthard H, et al. JAMA 2016;316:191–210; Slide modified from Viiv Healthcare ; Why Cabotegravir in combination with RPV? – CAB Oral 30 mg (t½, ~40 hours) – CAB LA nanosuspension 200 mg/mL (t½, ~20-40 days) – RPV Oral 25 mg (t½, ~50 hours) – RPV LA nanosuspension 300 mg/mL (t½, ~30-90 days) • Oral 2-drug CAB + RPV proof of efficacy through Week 96 in LATTE-1 • im 2-drug CAB + RPV maintained VL < 50 in LATTE-2* *Safety and efficacy of long-acting CAB and RPV as two drug IM maintenance therapy: LATTE-2 week 96 results J. Eron1, D. Margolis2, J. Gonzalez-Garcia3, H.-J. Stellbrink4, Y. Yazdanpanah5, D. Podzamczer6, T. Lutz7, J.B. Angel8, G.J. Richmond9, B. Clotet10, F. Gutierrez11, L. Sloan12, K.C. Sutton2, D. Dorey13, K.Y. Smith2, P.E. Williams14, W.R. Spreen2 IAS 2017: MOAX0205LB CAB, cabotegravir; LA, long-acting; RPV, rilpivirine; t½, half-life. Margolis et al. Lancet Infect Dis. 2015;15:1145-1155. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB; Slide modified from Viiv Healthcare. Half Lives of 2-Drug Regimens Regimen Half Lives (h) Dolutegravir (DTG) + 3TC DTG ~14h1 3TC (plasma) ~5h1 3TC-TP (cell) ~22h1 Dolutegravir (DTG) + Rilpivirine (RPV) DTG ~14h1 RPV ~50h1 Cabotegravir (CAB) + Rilpivirine (RPV) CAB (oral) ~40h2 RPV (oral ~50h1 CAB(im) ~20-40days2 RPV (im) ~30-90 days2 Note: Bictegravir half life is ~17h3 1. Data from www.hiv-druginteractions.org; 2. Landovitz RJ et al. Curr Opinion HIV AIDS 2016; 11: 122-128; 3 Custodio.J et al, CROI 2017 Dolutegravir and Elvitegravir Plasma Concentrations after stopping drug. Cobicistat Dolutegravir Elvitegravir Elliott E et al. J Antimicrob Chemother. 2015;71(4):1031-1036. PK-PD Characteristics of Integrase Inhibitors Parameter DTG EVG RAL CAB IC50PA ng/ml 16 7.2 NA IC90PA ng/ml 64 NA NA 164 IC95PA ng/ml NA 44.9 14.7 EC50 ng/ml 36 14 NA EC90 ng/ml 324 126 NA Ctrough (ng/ml) 1090 450 120 4100 (30 mg) IQ (Ctrough /IC90/95PA) 17 10 8 25 IC50/90/95PAprotein binding adjusted conc inhibiting viral replication by 50/90/95% Podany AT et al Clin Pharmacokin 2017; 56: 25-40 Genetic Barrier to Resistance for Specific ARVs EVG DTG (IQ 17) DRV/RTV (IQ 76) 3 log RAL ATV/ RTV INSTI 2 log RPV FTC NNRTI ABC NRTI Potency 3TC TDF PI 1 log (Estimated (Estimated log change in VL) 1 2 3 4 Genetic Barrier to Resistance (Approximate # Mutations Needed to Fail) Clutter DS, et al. Infect Genet Evol. 2016; 46: 292-307. Slide credit: clinicaloptions.com Fully Suppressive Therapy • Where fully suppressive concentrations of antiretroviral drug(s) are uniformly achieved at all sites of viral replication. Determinants of Drug Penetration into sites of viral infection • Lipophilicity • Molecular Weight • Plasma Protein Binding • Transporters Fletcher CV.