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Workshop 2: Il paziente con problematiche neuropsichiatriche e neurocognitive Moderatori: E. Sagnelli, F. Suter Discussant: F.v. Schloesser Caratteristiche.

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Presentation on theme: "Workshop 2: Il paziente con problematiche neuropsichiatriche e neurocognitive Moderatori: E. Sagnelli, F. Suter Discussant: F.v. Schloesser Caratteristiche."— Presentation transcript:

1 Workshop 2: Il paziente con problematiche neuropsichiatriche e neurocognitive Moderatori: E. Sagnelli, F. Suter Discussant: F.v. Schloesser Caratteristiche farmacologiche S. Bonora

2 CNS Penetration-Effectiveness Ranks: Standard of evidence 4321 NRTIs Zidovudine AbacavirLamivudineDidanosine EmtricitabineStavudineTenofovir Zalcitabine NNRTIsNevirapineDelavirdineEtravirine Efavirenz PIsIndinavir-rDarunavir-rAtazanavirNelfinavir Fosamprenavir-rAtazanavir-rRitonavir IndinavirFosamprenavirSaquinavir Lopinavir-rSaquinavir-r Tipranavir-r Entry Inhs Vicriviroc Maraviroc Enfuvirtide Integrase Inhs Raltegravir Red = Drug Characteristics Only, Yellow = PK Data, Green = PD Data Letendre et al, CROI 2010

3 Estimation of Penetration-Effectiveness in CNS Better Penetration = Lower CSF Viral Loads Letendre S et al, 17 th CROI 2010, Abstract 172

4 FAQs Il CPE score ha limiti interpretativi?

5 Raltegravir concentrations in CSF are in the therapeutic range for inhibition of wild-type hiv Raltegravir concentrations in blood (red) and CSF (blue). IC 50 Croteau et al., AAC December 2010 IC 50 : 3.2 ng/ml

6 Plasma and CSF raltegravir concentrations CSF raltegravir concentrations - median 18.4 ng/ml - range 2.0 – 126 - CSF/plasma ratio: 0.03 Yilmaz et al, PloS One 2009 Sep 1;4(9):e6877 IC 95 : 9 – 15 ng/ml 1 1 Iwamoto et al, Clin Pharmacol Ther 2008; 83:293-299

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8 CAVEATS of measuring CSF drug concentration In the majority of cases the ISF concentration is lower than CSF concentration. A downward CSF-to-ISF concentration gradient is particularly a concern when efflux transport at the BBB is likely (e.g., for candidate molecules that are substrates for P-glycoprotein mediated efflux). The presence of drug in CSF only reflects extracellular drug availability and does not reveal access of drugs to the intracellular sites within the brain parenchyma Macrophages, as the main cells infected by HIV in the brain, need to be considered in the evaluation of the potential efficacy of antivirals in CNS: the efficacy of antivirals in such cells is not superimposable to that in lymphocytes Shen, Adv Drug Deliver rev 2004 Perno C.F. et al., Antiviral Research 2006

9 FAQs Il CPE score ha limiti interpretativi? Il CPE score è valido per tutti i pazienti?

10 Population Pharmacokinetics in CSF Protease Inhibitors Capparelli et al, AIDS 2005; 19:949–952 Extent of CSF penetration was 0.23% of plasma concentrations IC 50 = 2 ng/mL Best et al, AIDS 2009; 23: 83-87 Extent of CSF penetration was 1% of plasma concentrations Lopinavir Atazanavir

11 Etravirina NVP 400 QD Darunavir/r 800/100 QD Maraviroc 150 QD? ATV unboosted?? Farmaci concomitanti? EFV 600, RGV 800 bid con RIF Dati PK mancanti o incompleti

12 Virologic Failure in the CNS Presenting with Neurologic Symptoms 11 patients with new neurological symptoms on ART –Median CSF viral load: 880 copies/mL –Median duration of ART: 13 months CSF-Plasma discordance –CSF HIV RNA > 200 copies/mL while plasma levels were < 50 copies/mL (n = 8) or –CSF HIV RNA level that was 1 log > plasma vira load (n = 3) Resistance mutations detected in 7 of 8 CSF specimens –ART modified based on resistance and CPE All patients clinically improved with reduction of HIV in CSF Canestri et al, Clinical Infectious Diseases 2010, 50:773–778

13 FAQs Il CPE score ha limiti interpretativi? Il CPE score è valido per tutti i pazienti? Cosa posso fare per ottimizzare lattività della HAART nel SNC?

14 How could effectiveness of ART in CNS be optimised? - Adequate use of the CPE score (which role > 8?) - TDM on CSF? - Increase of ARV dosing? - Pharmacogenetics/modulation of transporter? Dose-response assessment of tariquidar and elacridar and regional quantification of P- glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET. Kuntner C et al, Eur J Nucl Med Mol Imaging. 2010 Kuntner C

15 Antiretroviral Pharmacology in the Nervous System Measure drug concentrations in CSF for all antiretrovirals –Adequate sample size to accurately model pharmacokinetics –Prospect of new pharmacokinetic enhancers Determine the relationship between CSF and intracellular and extracellular brain concentrations –Human: Brain biopsies, Autopsy studies, Specialized imaging –Animal: Ante-mortem CSF vs. post-mortem brain tissue Determine the correlates of inter-individual variability –BBB permeability, DMD gene variability, Chronic Co- infections, Aging, Body weight, Adherence –Adequate sample size to accurately estimate inter- individual variability

16 Clinica Universitaria di Malattie Infettive Università di Torino Laboratorio di Farmacologica clinica Laboratorio di Biologia molecolare Ringraziamenti Prof. Giovanni Di Perri MariaCristina Tettoni Laura Trentini Letizia Marinaro Margherita Bracchi Marino Bonasso Bernardino Salassa Caterina Bramato Ilaria Motta Divisione Ospedaliera di Mal Inf TO Giancarlo Orofino Francesca Gaiottino Antonio DAvolio Marco Siccardi Mauro Sciandra Lorena Baietto Marco Simiele Valeria Ghisetti Tiziano Allice Maria Grazia Milia Neurologia Ospedale Maria Vittoria Daniele Imperiale Giulia Guastamacchia Lucia Appendino Neuropsicologia Ospedale Maria Vittoria TO Daniela Vai Neuroradiologia Ospedale S.Giovanni Bosco TO Paolo Vaudano Paolo Busolli Adolfo Prochet


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