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Ospedale Amedeo di Savoia

FARMACOLOGIA CLINICA DELLA TERAPIA ANTIRETROVIRALE. Giovanni Di Perri CLINICA DI MALATTIE INFETTIVE Università degli Studi di Torino. Ospedale Amedeo di Savoia. Antiretroviral Drug Approval: 1987-2009. NRTI, Nucleoside reverse transcriptase inhibitor;

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Ospedale Amedeo di Savoia

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  1. FARMACOLOGIA CLINICA DELLA TERAPIA ANTIRETROVIRALE Giovanni Di Perri CLINICA DI MALATTIE INFETTIVE Università degli Studi di Torino Ospedale Amedeo di Savoia

  2. Antiretroviral Drug Approval: 1987-2009 • NRTI, Nucleoside reverse transcriptase inhibitor; • NNRTI, Non-nucleoside reverse transcriptase inhibitor; • PI, protease inhibitor • Integrase Inhibitor • CCR5 Antagonist/Entry Inhibitor Darunavir Enfuvirtide Atazanavir Emtricitabine Fosamprenavir Maraviroc Raltegravir Etravirine Tipranavir Tenofovir Nelfinavir Delavirdine Lopinavir/r Ritonavir Indinavir Nevirapine Amprenavir Efavirenz Abacavir 3TC Saquinavir d4T ddC ddl AZT

  3. HIV CYCLE Fusion inhibitors co-receptors inhibitors BINDING CD4 BUDDING CXCR4 CCR5 ASSEMBLY cellmembrane integrase inhibitors UNCOATING genomic RNA PROTEASE double strandedDNA genomic RNA viral proteins Protease Inhibitors INTEGRATION TRANSLATION REVERSETRANSCRIPTION proviral RNA viral mRNA RT Inhibitors N/tRTIs NNRTIs TRANSCRIPTION cell nucleus

  4. N/NtRTIs: basic pharmacologic features

  5. N/NtRTIs: New drugs under development • Abacavir ABC • Didanosine DDI • Emtricitabine FTC • Lamivudine 3TC • Stavudine D4T • Zidovudine ZDV • Zalcitabine DDC • Tenofovir TDF • apricitabine • Amdoxovir • GS 9131 (9148) • Racivir • Elvucitabine (?)

  6. NNRTIs: caratteristiche farmacologiche

  7. NNRTIs: New drugs under development • Delavirdine DLV • Efavirenz EFV • Nevirapine NVP • Etravirine ETR • TMC 278 (rilpivirine) • UK- 453,061 (Lersivirine) • IDX 899 • RDEA 806

  8. Reference Concentrations (Cmin) for Efficacy & Toxicity Cmin(ng/mL) Toxicity ** 4000 6000 - Drug Efavirenz Nevirapine Etravirine Cmin (ng/mL) Efficacy ** 1000-2200-3000* 3400-4300 - * * after NVP failure * pending results in nive patients with the 100 mg tablet

  9. 154 HIV-infected patients All taking 3-drug ART HIV RNA in blood <50 c/mL HIV RNA measured using a more sensitive assay (2.5 c/mL) NVP: 60% <2.5 c/mL EFV: 42% <2.5 c/mL LPV/r: 29% <2.5 c/mL NVP was the only factor associated with undetectable HIV RNA on multivariate analysis Ultrasensitive AssessmentofResidualHIV Viraemia in HAART-Treated Patients With PersistentlyUndetectable Plasma HIV-RNA: A Cross-SectionalEvaluation p<0.05 50 p<0.05 40 30 HIV RNA (copies/mL) 20 10 0 NVP EFV LPV/r n 48 57 49 Bonora et al. J Med Virol 2009;81:400–405

  10. PIs: caratteristiche farmacologiche

  11. PIs: New drugs under development • Amprenavir APV • Indinavir IDV • Lopinavir LPV • Nelfinavir NFV • Ritonavir RTV • Saquinavir SQV • Atazanavir ATV • FosAmprenavir fAPV • Tipranavir TPV • Darunavir DRV • GS 8374 • GRL 98065

  12. Reference Concentrations (Cmin) for Efficacy & Toxicity Drug Amprenavir Indinavir Lopinavir/Ritonavir Nelfinavir Ritonavir Saquinavir Atazanavir Tipranavir Cmin (ng/mL) Efficacy 400 100 1000 *800 2100 100-250 150 15000 - 20000 # Cmin (ng/mL) Toxicity - 8000-10000 - - 2100 - 850 35000 * M8; ** Measured 8-20 hours post-dose # in case of triple drug failure

  13. Keq DRUG + TARGET DRUG/TARGET In case of reduced target affinity (by selection of mutations in the PI genome coding for PI-resistance), the same effect may be obtained by increasing drug exposure Keq DRUG + TARGET DRUG/TARGET

  14. Rn MEC R6 MEC R5 MEC R4 MEC R3 MEC Median [c] R2 MEC R1 MEC WT MEC Rn How far the proportionality between the n. of PI resistance mutations and the value of MEC is maintained? ? [c] ng/mL 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 1 2 3 4 5 6 n. PI mutations

  15. Antiretrovirals disposition is complex Intracellualr and plasma concentrations of antiretrovirals are influenced by many processes that are mediated by different transporters and enzymes.

  16. ATP ATP ADP + Pi ADP + Pi Pregnane X receptor CYP3A PXR ABCB1 Drug Drug ABCC1

  17. Favourable genotypes

  18. Number of favourable genotypes rho = 0.517, p = 0.0001 n = 13 n = 15 n = 24 n = 3

  19. Unboosted – Atazanavir (ATV) (3) Bonora S, et al. Abstr O 17 ATV ng/mL [Ctrough] gm 1200 1000 Intracellular (PBMCs) plasma 850 800 745 600 465 400 200 150 0 ATV 200 bid ATV 400 QD ATV 200 bid ATV 400 QD

  20. gag gag env luc pol pol EIs: caratteristiche farmacologiche CD4 CCR5 Luciferase expression vector gag gag env luc pol pol Infection Env expressionvector library Transfection Entry inhibitors added for confirmation of tropism call R5 X4 R5/X4 (dual) CD4 CXCR4

  21. Entry Inhibitors: New drugs under development • Enfuvirtide T-20 • Maraviroc MVC • Vicriviroc • PRO 140 • INCB009471 • AMD 070 • TNX-355

  22. CD4 Binding Co-receptor Binding Virus–Cell Fusion CCR5 antagonistse.g. maraviroc,vicriviroc, PRO 140 Fusion inhibitorse.g. enfuvirtide CD4 bindinginhibitorse.g. TNX-355 gp41 gp120 V3 loop CD4 Cell membrane CCR5/CXCR4 (R5/X4) HIV Attachment, Co-receptor Binding, and Fusion Targets for Inhibition Adapted from Moore JP, et al. Proc Natl Acad Sci USA 2003;100:10598–10602

  23. Reference Concentrations (Cmin) for Efficacy & Toxicity Drug Enfuvirtide Maraviroc Cmin (ng/mL) Efficacy 1500-1900 100 Cmin (ng/mL) Toxicity - 400 • Analysis of MERIT study[1] Δ CD4+ Percentage + 8.1% 150 151 P = .004 for the difference over time + 9.5% 122 100 Median CD4+ Cell Count ΔFrom Baseline (cells/mm3) MVC + ZDV/3TC (n = 360) 50 EFV + ZDV/3TC (n = 360) Bonora S, et al. ICAAC 2009 0 0 2 4 8 12 16 20 24 32 40 48 Weeks

  24. Maraviroc PK is influenced by OATP1B1 OATP1B1 is a major hepatic influx transporter and its substrate specificity for MVC has been investigated. Siccardi M, et al. CROI 2010 OATP1B1 521CT correlates with higher MVC plasma concentrations, confirming the role of OATP1B1 in the disposition of MVC. Siccardi M, et al. IWCPHT 2009

  25. IIs: caratteristiche farmacologiche

  26. Integrase Inhibitors: • Raltegravir • New drugs under development • elvitegravir • GSK 1349572

  27. GM Observed C12hr <33 nM RAL efficacy is not driven by Cmin • 16 out of 332 patients had GM observed C12hr values <33 nM (~in vitro IC95) • These patients had a similar rate of treatment success compared to patients with other GM observed C12hr values Wenning et al HIV Clin Pharm Workshop 2008

  28. Outcomes at Week 48 Virologic Efficacy Raltegravir CD4+ count increases similar between arms: 144-221 cells/mm3 Markowitz 2007

  29. S/GSK1349572: Potent Virologic Suppression in 10-Day Monotherapy Study • 10-day monotherapy study in HIV-infected patients evaluated efficacy of varying doses of S/GSK1349572[1] • Mean maximal reduction in HIV-1 RNA during study period • -2.5 log10 copies/mL in 50-mg dose arm • Resistance profile distinct from that of RAL and ELV[2] • 12-hr half-life allows QD dosing[3] • Activity not dependent on boosting[3] Dosing period Follow-up period 0.5 0.0 -0.5 -1.0 Mean Change From Baseline in HIV-1 RNA (log10 c/mL) -1.5 -2.0 2 mg 10 mg -2.5 50 mg PBO 1(BL) 2 3 4 7 8 9 10 11 14 21(FU) Day 1. Lalezari J, et al. IAS 2009. Abstract TUAB105. Reproduced with permission. 2. Underwood M, et al. IAS 2009. Abstract WEPEA098. 3. Min S, et al. IAS 2009. Abstract WEPEA099.

  30. Persistent RAL inhibitory effect Mapping the RAL inhibition window RAL Inhibition Window: ~4h – 12h post-infection

  31. Raltegravir Exhibits a Long Off-Rate on Complexes Assembled in vitro 1.0 T1/2 = 27 hrs at room temp 0.8 0.6 Fraction bound 0.4 0.2 0.0 0 500 1000 1500 2000 2500 Time (min) WT - ral N155H - ral

  32. LPV Ctrough = 5500 ng/mL IQ = WT MEC for LPV = 1000 ng/mL = 5,5 Letter Nature Medicine14, 762 - 766 (2008) Published online: 15 June 2008 Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs Lin Shen, Susan Peterson, Ahmad R Sedaghat, Moira A McMahon, Marc Callender, Haili Zhang, Yan Zhou, Eleanor Pitt, Karen S Anderson, Edward P Acosta & Robert F Siliciano In ARVs pharmacology it is common to refer to drug potency in terms of Inhibitory quotient (IQ) However, the time required to exert the effect is not considered in the IQ equation The slope of the curve (steepness) can be incorporated in the IQ equation as m : LPV [c] ng/mL WT MEC for LPV [c] ng/mL 0 12 24 Time (hours) Log (fa/fu) = m log(D/IC50) m1 m2 m3

  33. Log (fa/fu) = m log(D/IC50) Fraction of the viral population affected by the drug Drug concentration Drug concentration inhibiting the 50% of viral growth Fraction of the viral population unaffected by the drug 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

  34. A new index is thus termed: Instantaneous Inhibitory Potential (IIP) IIPCmin = log (1/fuCmin) = log [1+ (Cmin/IC50)m]

  35. But……. 100 * 83% 80 84% RAL 100 mg BID. RAL 200 mg BID. 60 Patients With HIV-1 RNA < 50 copies/mL (%) RAL 400 mg BID. RAL 600 mg BID. EFV 600 mg QD 40 Using observed failure approach: RAL 92%and EFV 91% 20 EFV RAL 0 0 4 8 16 24 32 40 48 60 72 84 96 Week These are the facts…….

  36. Thus….. • This is an in vitro assay…… • Data from phase I-II monotherapy trials in humans are available….. • Clinically determined PK/PD findings generally show a reasonable degree of consistency across all drug development phases….. • Humans remain the best model of human disease…..

  37. CNS-Penetration Effectiveness (CPE) Ranks 0 0.5 1 Letendre S, et al. Arch Neurol 2008; 65: 65-70 Varatharajan L, Thomas SA. Antivir Res 2009; 82: A99-A109

  38. Subjects who had lower central nervous system Penetration-Effectiveness (CPE) ranks were more likely to have detectable cerebrospinal fluid (CSF) viral load when CPE rank was analyzed as a continuous variable (A) or as a categorical variable (B) Letendre, S. et al. Arch Neurol 2008;65:65-70.

  39. Male genital tract exposure APV (20%) LPV (5%) EFV (3%) ZDV (200%) TDF (500%) IDV (100%) RAL (645%) 3TC (600%) ABC (150%) NVP (70%) 0% 100% 200% 300% 400% 500% EFV (0.6%) 3TC (400%) FTC (600%) IDV (200%) ATV (30%) TDF (400%) ZDV (200%) LPV (30%) Female genital tract exposure ABC (150%) ABC (40%) APV (50%) NVP (80%) Nucleoside Reverse Transcriptase Inhibitors Nonnucleoside Reverse Transcriptase Inhibitors Protease Inhibitors By courtesy of A. Kashuba

  40. Greater CYP450 enzyme inhibition specificity Less induction of drug metabolizing enzymes and transporters Keys to Pharmacoenhancement hPXR Activation Induction of Hepatocyte CYP3A4 mRNA 100 120 100 80 80 60 RTV Response (%Emax) % Maximum 60 GS-9350 40 40 20 20 0 0 1 µM 3 µM 10 µM 30 µM Rifampicin 1 10 GS-9350 Concentration (µM) mean ± SD, n=3 mean + SD, n=3 * midazolam 1’-hydroxylase (no preincubation) mean of 3 experiments conducted in duplicate

  41. THE UNIVERSITY of LIVERPOOL Acknowledgments TORINO: Stefano Bonora Antonio D’Avolio Mauro Sciandra Marco Siccardi Daniel Gonzalez de Requena Alessandro Sinicco Sabrina Audagnotto Cristina Tettoni Laura Trentini Andrea Calcagno Anna Lucchini Agostino Maiello Ivan Dal Conte LIVERPOOL: David Back Saye Khoo Andy Owen LONDON: Marta Boffito Anton Pozniak ROMA: Andrea Antinori Emanuele Nicastri Giuseppe Ippolito

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