Distribution of antivirals in the brain: what do we know?

Presenting author Marie Studahl, Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Sweden

ECCMID 10 April 2016

© ESCMID by eLibraryauthor To which part of the brain should the antiviral be transported?

© ESCMID by eLibraryauthor Different cells are targets

Neurons in cortex Oligodendrocytes HSV, JEV, WNV, TBEV JCV Perivascular cells HEV, HIV, HEV, JEV, mumps, Nipahvirus

Ependymal cells CMV, mumps, HEV

Microglial cells © ESCMID by eLibraryauthorHIV Studying antivirals in the brain

Microdialysis

Brain sampling

Post-mortem examination of brain tissue

Animal studies

Plasma and cerebrospinal fluid antiviral levels in humans © ESCMID by eLibraryauthor Intracranial fluid compartment

© ESCMID eLibrary by authorDerived from Nau et al, Clin Microbiol Rev Blood brain barrier – damage is important

Differs in healthy controls, patients with acute or chronic CNS infections

CNS inflammation often leads to an increase of

- the permeability of the blood-CSF/blood-brain barrier and/or a decrease of the CSF flow

- the drug concentrations in the CNS compartments © ESCMID by eLibraryauthor Ideal antiviral drug characteristics for CNS viral diseases

Drug characteristics • Molecular weight • Protein binding • Lipophilicity • Ionization • Molecular pumps © ESCMID by eLibraryauthor http://home.szbk.u-szeged.hu/~krizbai/capillary-s.png © ESCMID by eLibraryauthor Calgagno et al, Clin Pharmacokinet 2014 CNS penetration – effectiveness (CPE) index

Antiretroviral Drug Class 4 3 2 1

Nucleoside analogue reverse Zidovudine Abacavir Didanosine Tenofovir transcriptase inhibitors Emtricitabine Lamivudine Zalcitabine Stavudine

Nonnucleoside analogue reverse Nevirapine Delavirdine Etravirine transcriptase inhibitors Efavirenz

Protease inhibitors Indinavir/ritonavir Darunavir/ritonavir Atazanavir Nelfinavir Fosamprenavir/ Atazanavir/ritonavir Ritonavir ritonavir Fosamprenavir Saquinavir Indinavir Saquinavir/ Lopinavir/ ritonavir ritonavir Tipranavir/ ritonavir

Entry/fusion inhibitors Maraviroc Enfuvirtide Integrase©strand ESCMIDtransfer inhibitors byRaltegravir eLibraryauthor Letendre et al, Arch Neurol 2008; Top HIV Med 2010 IC50- role for estimating in vivo effectiveness?

In vitro – the concentration of the antiviral drug needed to inhibit 50% of viral replication

Limitations • large variability in IC-values • the drug concentration required for effect is largely unknown • not suitable for individual subjects • not to be used as MIC for bacterial infections in an individual © ESCMID by eLibraryauthor Studies on CSF valacyclovir (VACV) and acyclovir

Valacyclovir Acyclovir © ESCMID by eLibraryauthor Clinical efficacy studies of acyclovir i.v.

Efficacy of acyclovir i.v. has been shown in neonatal herpes and herpes simplex encephalitis (HSE) through randomized, controlled trials

© ESCMID eLibrary Sköldenberg et al, 1984; Whitley et al, 1986; Whitley et al, New Engl byJ Med 1991; author Kimberlin et al, Pediatrics, 2001 CSF studies on ACV concentrations after valaciclovir (VACV) orally

Six patients without CNS infection and normal renal function VACV 2g X 4, and 3 with chronic renal impairment VACV 1.5g X 2-serial sampling

Fifteen patients with MS sampled 6 days and 6 months during treatment with VACV 1 g X 3

Four patients with HSE (in Vietnam) VACV 1g X 3

Seven patients with different diagnoses with different doses of©VACV ESCMID orally eLibrary Smith et al, Antimicrob Agents and Chemother, 2010; Lycke et al , Antimicrob Agents Chemother , 2003;by Pouplin authoret al, Antimicrob Agents Chemother, 2011; Hellden et al, J Antimicrob Chemother, 2006 CSF ACV concentration patients with MS after ACV and VACV orally

30 Serum ACV 800mg tid uM 25 CSF ACV 800mg tid

20 Serum VCV 1g tid

15 CSF VCV 1g tid

10

5

0 HSV-1 HSV-2 VZV IC in clinical isolates © 0hESCMID 2h 4h 6h by 8h 10h eLibraryauthor 12h 50 Conclusions CSF ACV concentrations during VACV treatment

Higher concentrations were found in patients with HSE than in patients with MS, potentially reflecting the impaired and more permeable BBB in the early stage of HSE

CSF exhibit a slowly equilibrating compartment compared to plasma and the concentrations are stable © ESCMID by eLibraryauthor The role of measuring concentrations of ACV

CSF and serum concentrations of ACV and CMMG are valuable during acyclovir or valaciclovir treatment in cases where intoxication is suspected

© ESCMID by eLibraryauthor Ganciclovir (GCV) and valganciclovir (V-GCV) – in CMV CNS disease

Few studies on CSF concentrations

In congenital cytomegalovirus infection moderately favorable effect on hearing and neurodevelopmental outcomes shown through randomized, controlled trials

© ESCMID eLibrary Kimberlin et al, J Pediatr , 2003;by N Engl authorJ Med 2015; Oliver et al, J Clin Virol 2009 CSF studies on GCV concentrations after i.v. GCV and after oral V-GCV

Two patients after SCT with CMV pneumonia or retinitis (GCV i.v. 2.5 or 5 mg/kg X 2-3) for 20 days

One infant with congenital cytomegalovirus infection treated with oral V-GCV 16 mg/kg/dose twice a day

One 13-year old boy with ALL and CMV retinitis treated with V-GCV 450 mg every two days – acute neurotoxicity

Four transplanted patients with CMV infection and GCV- induced© ESCMIDencephalopathy eLibrary Fletcher et al, Clin Pharmacol Ther 1986; Natale et al, Italian J Ped, 2015; Peyriere byet al, Annals author pharmacother 2006; Sakamoto et al, Case Report Neurol, 2013; Conclusions CSF GCV concentrations during GCV or V-GCV treatment

CSF GCV concentration studies are generally lacking

CSF concentrations of GCV indicated a penetration of 24-67% to the CSF

CSF concentrations exhibited little variability

Brain extracellular fluid concentrations in one patient with glioblastoma through microdialysis © ESCMID eLibrary Fletcher et al, Clin Pharmacol byTher 1986; Nataleauthoret al, Italian J Ped, 2015; Hellden et al, 2015 Foscarnet – in herpes virus CNS diseases

Some studies on CSF concentrations

No published randomized, controlled treatment trials with foscarnet in viral CNS infections

© ESCMID by eLibraryauthor Foscarnet – CSF concentrations studies

Five patients with HIV (mean CD4 0.45x 109/L) were given continous foscarnet (0.14-0.19 mg/kg per min)

Twenty-one patients with HIV concentrations after single infusion foscarnet 90 mg/kg and during steady state (n=5)

Twenty-seven patients with AIDS were given various doses of foscarnet twice daily © ESCMID eLibrary Sjövall J et al, Antimicrob Agents Chemother, 1989; Hengge UR et al, Antimicrob Agents Chemother,1993; byRaffi et al, AntimicrobauthorAgents Chemother, 1993 Conclusions – foscarnet CSF concentrations

Penetration to the CSF varied between 13 and 68% in one study, 23 % after a single dose and 54-80 % in steady state in patients with minor BBB-damage

CSF concentrations correlated highly to the presence of cells in the CSF and length of therapy © ESCMID eLibrary Sjövall J et al, Antimicrob byAgents Chemother author, 1989; Hengge UR et al, Antimicrob Agents Chemother, 1993; Raffi et al, Antimicrob Agents Chemother, 1993 Antivirals against Influenza CNS manifestations

Four Japanese and 4 Caucasian healthy men were given a single dose of oseltamivir 150 mg orally

One 15 year-old Japanese female with influenza infection

Conclusion Low CSF concentrations of oseltamivir in healthy adults. CSF levels of oseltamivir and its active metabolite were both under the detection limit (0.5 ng/mL)

No published randomized, controlled treatment trials of influenza© ESCMIDCNS manifestations eLibrary byJhee SS et al,author al, Antimicrob Agents Chemother, 2008; Morimoto et al, BMC Neurol 2015; Ribavirin – CSF concentrations and clinical studies

. Seven patients with subacute sclerosing panencephalitis (SSPE) were given ribavirin intraventricularly . Fifteen children with La Crosse encephalitis were given ribavirin i.v. . Low therapeutic window . One randomised, controlled trial with oral ribavirin in Japanese encephalitis (n=153) showed no evidence of efficacy . No published randomized, controlled treatment trials with ©ribavirin ESCMIDi.v. against CNS infections eLibrary Hosoya et al, Antimicrob Agents Chemother by2001 author and 2004; McJunkin JE et al, Pediatrics 1997 and Ped Infect Dis J 2011; Crumpacker et al, Lancet 1986; Kumar et al, Infect Dis, 2009 Antivirals against enterovirus CNS infections-pleconaril

. No data on pleconaril cerebrospinal fluid och brain concentrations in humans . Small randomized, controlled treatment trial of pleconaril in enteroviral meningitis in adults – a slightly shortened duration of symptoms . Small randomized, placebo-controlled trial of pleconaril in neonatal enterovirus sepsis – shorter times to negative viral cultures and PCR © ESCMID eLibrary Desmond RA et al,by Antimicrob authorAgents Chemother, 2006: Abzug MJ et al, Pediatr Infect Dis J, 2003; 2016 Summary – from a clinical point of view

Knowledge of brain /CSF pharmacokinetic data of antivirals is in its early stage and more data is needed to improve the treatment of viral CNS infections

The role of monitoring antivirals in blood and cerebrospinal fluid for evaluation of efficacy in patients with acute viral CNS infections remains to be established

Multicenter, randomized, controlled trials of antivirals in different viral CNS diseases are warranted © ESCMID by eLibraryauthor Acknowledgements

Sahlgrenska University Hospital Karolinska University Hospital Gothenburg, Sweden Stockholm, Sweden Department of Infect Dis Departments of Clinical Aylin Yilmaz Pharmacology and Infect Dis Kristina Weilöv Anders Hellden Lars Hagberg Elisabeth Aurelius Johan Lindström Anna Grahn

Department of Virology Tomas Bergström © ESCMID by eLibraryauthor