Catia Marzolini Division of Infectious Diseases & Hospital Epidemiology

1. CNS pharmacologyof antiretroviral drugsand relevant interactionsbetween antiretroviral and CNS drugs Catia Marzolini Division of Infectious Diseases & Hospital Epidemiology www.hiv-druginteractions.org

2. Presentationoutline • penetrationof antiretroviral drugs (ARV) in CNS • CSF ARV concentrationsand IC50/IC95 • ARV penetrationeffectivenessand PD effects • open questions • drug-druginteractionsbetween ARV and CNS drugs • combinationof ARV and CNS drugsandriskof QT intervalprolongation

3. Factorsdeterminingdrugentry in thebrain Drugs abletocross BBB Drugs unabletocross BBB physicochemicalproperties (MW, ionization, lipophilicity) bindingaffinitytodrug transporters proteinbinding Drug characteristics Activeefflux Passive influx Activeefflux Passive influx blood Endothelialcells tight junctions brain permeabilityoftheblood-brainbarrier age Patient characteristics CSF flowalteration

4. Predictionofblood-brainpermeationof HIV drugs clinicaldata: CSF/plasma (%) Abacavir (ABC) 36% Didanosine(ddI) 23% Dolutegravir(DTG) 0.5% Emtricitabine (FTC) 43% Lamivudine (3TC) 15% Stavudine(d4T) 32% Tenofovir (TDF) 4% Zidovudine (AZT) 75% Efavirenz (EFV) 0.5% Etravirine (ETV) 4% Nevirapine (NVP) 46% Rilpivirine(RPV) 1.4% Amprenavir (APV) 1% Atazanavir (ATZ) 1.5% Darunavir (DRV) 0.9% Indinavir(IDV) 17% Lopinavir(LPV) 0.3% Ritonavir(RTV) 0.2% Saquinavir(SQV) 0.1% Tipranavir(TPV) na Raltegravir(RLT) 6% Maraviroc(MVC) 4% 7 6 TPV RPV ETV EFV 5 LPV RTV SQV 4 ATZ 3 DRV IDV NVP ABC 2 APV MVC DTG LogD AZT 1 RLT FTC 0 ddI d4T -1 3TC -2 -3 -4 TDF -5 30 40 50 60 70 80 90 100 110 120 130 140 Cross sectional area charged at physiological pH BBB+ : passive influx> efflux BBB-:passive influx < efflux Marzolini C et al. Mol Pharm 2013

5. Protein free EFV CSF:plasma ratio Total EFV CSF: plasma: 0.87% Free EFV CSF: plasma: 85% median 2170 median 18.8 median 4.8 median 4.1 Avery LB et al. AntimicrobAgentsChemother 2013

6. Passive influx and active efflux of antiretroviral drugs Efavirenz passive influx > activeefflux Protease inhibitors passive influx < activeefflux Passive influx and active efflux [molecules s-1 cell-1] Cross sectional area Marzolini C et al. Mol Pharm 2013

7. Blood-brain barrier http://en.wikipedia.org/wiki/File:Blood_Brain_Barriere.jpg

8. Transporters expressed at the blood-brain barrier Effluxtransporters usehydrolysisof ATP as an energysource toexportdrug out of thecell Eyal S et al. PharmacolTher2009, Marzolini C et al. Mol Pharm 2013

9. Interaction of ARV with efflux transporters P-gpATPaseactivityprofileofritonavir ritonavir rangeofritonavir plasmaconcentrations P-gpactivation P-gpinhibition Marzolini C et al. Mol Pharm 2013

10. Binding affinities of antiretroviral drugs to P-gp Protease inhibitorshave strong bindingaffinitiestoeffluxtransportersandthushave a highertendencytomodulatetheactivityofeffluxtransporters Marzolini C et al. Mol Pharm 2013 0 -10 -20 Gtw -30 abacavir  lamivudine emtricitabine tenofovir zidovudine nevirapine raltegravir -40 maraviroc efavirenz darunavir amprenavir indinavir saquinavir atazanavir -50 tipranavir lopinavir ritonavir weak moderatestrong -60

11. Impact of ARV combination on P-gp efflux P-gpATPaseactivityprofileofdarunavirwithout/withritonavir The proteaseinhibitorwiththehighestbindingaffinity will occupythetransporterbindingsitesandslow down theefflux rate ofthecoadministereddrug. Marzolini C et al. Mol Pharm 2013

12. Darunavir CSF: plasma ratio with ritonavir boosting Darunavir + ritonavir 100 mg/day Darunavir + ritonavir 200 mg/day Calcagno A et al. AIDS 2012

13. Older age and drug concentrations in CSF Olderage was associatedwithgreater antiretroviral drugsexposure in the CNS. This couldbeexplainedby a reduceddrugefflux, permissive BBB oraltered CSF flow. Croteau D et al. CROI 2012

14. CSF concentrations in patients with altered BBB raltegravir Clinical significanceunclear: total druglevelsboundtoproteinsmightbehigher but not thefreedruglevels emtricitabine tenofovir Calcagno A et al. JAC 2014; Calcagno A et al. AIDS 2011

15. CSF drug concentrations relative to IC50

16. CSF drug concentrations relative to IC50

17. CSF inhibitory quotients of various antiretroviral drugs Inhibitoryquotient (IQ95) = CSF drugconcentration IC95 18.5 8.2 6.4 Optimal CSF drugexposure : IQ95 >1 anddetectable CSF concentrationsof all drugs in regimen was associatedwithdecreasedprobabilityof CSF escape 5.1 1.5 0.4 2.8 0.7 Calcagno A et al. CID 2015

18. Correlation CPE score and CNS HIV RNA or NC testing * Letendre S et al. ArchNeurol 2008

19. Comparative analysis of ARV neurotoxicity Toxicityriskof 15 ARV on culturesof rat neurons (consideringdrugconcentrationsachieved in CSF) Drugs withsignificantriskofneurotoxicity Drugs withlowriskofneurotoxicity Drugs withnegligibleriskofneurotoxicity Neurotoxiceffectfor 8-OH-EFV (10 timesmoretoxicthan EFV) using rat neuronal cultures Tovar-Y-Romo LB et al. JPET 2012 Robertson K et al. J Neurovirol 2012

20. Summary of available evidence for ARV neurotoxicity Likelytocausetoxicity at clinicaldoses/ reasonableevidenceof toxicity Someevidenceoftoxicity at clinicaldoses Possibleevidenceoftoxicity not significant at clinical dosesorconflictingreports or significanttoxicityunlikely at clinicaldoses Evidencefor ARV neurotoxicityispredominantlyfrompreclinicalwork. Studies areneededtoassessclinicalsignificanceofthesefindingsandtheirimpact on manifestationsof HAND. adaptedfrom Underwood J et al. AIDS 2015

21. PI monotherapy LPV/r, DRV/r MT: no negative effects on NC performance(Perez Valero et al. CID 2014; Santos et al. PLoSOne 2013)

22. ARV dose reduction PlasmaandCSFlevels: DRV/r 600/100 QD vs DRV/r 800/100 QD + NRTIs CSF:plasma = 0.01 DRV dose reductiongives comparableplasmaand CSF levelsandcomparable efficacy. CSF:plasma = 0.008 DRV/r 600/100 mg QD DRV/r 800/100 mg QD Yacovo M. JAC 2015 CSFlevelsof EFV, 8-OH EFV whendosed at 400 mg vs 600 mg QD+ NRTIs 11/14 > 3.3 ng/ml 7/14 > 3.3 ng/ml (toxicitythreshold) all >IC50 0.51 ng/ml nostatistical difference CSF EFV concentrationswereadequatewithboth dose howeverexposureof 8-OH EFV was still withintherangeassociatedwithtoxicities. Winston A et al. CID 2015

23. Are some ARV more effective in the CNS than others? CSF concentrationsofsome ARV do not exceed IC of wild type HIV virus CSF viral escapeisuncommonwithany ARV combinationwhenusingroutine HIV RNA assays Drugs withlow CNS effectivenessareassociatedwith high HIV CSF VL Somestudieshave not shown an associationbetween NC functionanddrugsmore CNS effective For Against Drugs with high CNS effectivenessareassociatedwithbetter NC tests. Some ARV areneurotoxic Estimationof CNS effectivenessisbased on ARV concentrations in CSF andmay not reflectconcentrations in glialcellsorbrainmacrophages Decline in CSF HIV VL andbetter NC functionwereoberved after changesto ARV regimensmore CNS effective Adaptedfrom Nightingale S et al. Lancet Neurol 2014

24. ARV monocyte efficacy score linked to NC impairment Monocytesand HIV neuropathology Correlationbetweenmonocyte efficacy (ME) scoresandcognitive status ARV withhigher ME score inhibitmoreeffectively in vitro infectionofmonocytes ARV effectiveconcentrationinhibiting HIV infectionofmonocytes Williams D et al. Curr HIV Res 2014; Shituma C et al. AntivirTher 2012

25. Is HIV RNA in CSF a useful clinical tool ? BeforetheeraofcART, high HIV CSF VL correlatedwith HAD in individualswithadvancedimmunosuppression Most studieshavefailedtoshow an associationbetween HIV CSF VL and NC status in thecARTera Cases seriesshowed a link betweendecreased NC impairmentanddecrease in HIV CSF VL HIV CSF VL may not accuratelyreflect HIV replication in brainparenchyma For Against Study showedthatpeoplewithhigher HIV CSF VL than in bloodweremorelikelytohave NC impairment Longitudinal studieshave not shownthatpeoplewith CSF viral escapearemorelikelytodevelopresistance Persistent HIV CSF VL duringcARTmightincreaseriskof ARV resistance In peoplesuccessfullytreatedwith ART, NC impairmentmaybecausedbyotherfactors Adaptedfrom Nightingale S et al. Lancet Neurol 2014

26. Factors implicated in pathogenesis of HAND in cART era ongoing neuroinflammation antiretroviral drugs factors patientfactors CNS infectionsacquiredduringprimary HIV infection, education level, useofpsychoactivedrugs (methamphetamine) Adaptedfrom Winston A & Vera JH. CurrOpin HIV AIDS 2014

27. Neurocognitive change in cART era: data from CHARTER Longitudinal studyevaluatingincidenceandpredictorsof NC changeover 16-72 months in 436 HIV infectedpatients. 72 (16.5%) improved 265 (60.8%) stable 99 (22.7%) declined Predictorsof NC declinesorimprovementsincludedfactorsspecificto HIV anditstreatment, factorsrelatedtohealthstatus, baselinedemographics, intelligencequotient, non-HIV relatedcomorbidities, current depressive symptomsandlifetimepsychiatricdiagnoses. Heaton RK et al. ClinInfect Dis 2015

28. Some other open questions • Whatarethetargetdrugconcentrations in CNS? • Whatrolemay ARV neurotoxicityhave on neurocognitivefunction? • Towhichextent do comorbiditiescontributeto HAND? • Wouldearlierinitiationof ART protect CNS?(CD4 cellcountseems • tobe an importantpredictorofneurocognitiveperformance) • Evidenceoflowlevelof CNS inflammatoryreactions: arethese • immune reactionsdrivenby persistent local HIV infectionorby • othermechanisms?

29. Drug-druginteractionsbetween ARV and CNS drugs

30. 60 50 40 DDI contra-indicated DDI requiring dose adjustment no interaction 30 percentage of patients 20 10 0 herbals hormones analgesics methadone CNS agents anti-infectives antihistamines vitamins/minerals bronchodilatators immunosupressants cardiovascular drugs gastrointestinal drugs Prevalenceofdrug-druginteractions in the SHCS • 1497 prescriptionsanalyzed • 31% patientsreceived CNS drug • (anxiolytics (13%); antidepressants (12%); • antipsychotics (3%); anticonvulsants (3%) • 599 (40%) had at least one potential • drug-druginteraction. • Overall, DDI with: • - antidepressants 23% • - anxiolytics 17% • - antipsychotics 6% • HIV populationisagingandhas a • higherriskfordrug-druginteractions Marzolini C et al. Antiviral Therapy 2010 Marzolini C et al. J AntimicrobChemother 2011

31. Mechanismsof PK drug-druginteractions Inhibition/induction intestinal cytochromes ordrugtransporters Metabolism Gastric pH Inhibition/induction ofhepatic cytochromes, glucuronidation, ordrugtransporters Absorption Food, mineral supplements Excretion Inhibition of renal drugtransporters Adaptedfrom Roden DM et al. NatRev 2002

32. Metabolismof antiretroviral drugs http://pharmacoclin.hug-ge.ch/actualites.html

33. Metabolismofantidepressants http://pharmacoclin.hug-ge.ch/actualites.html Spina E et al. Clinical Therapeutics 2008

34. Clinical significanceofdrug-druginteractions • potencyandconcentrationoftheinhibitororinducer • therapeuticindexofthe „victim“ drug • presenceofactiveortoxicmetabolites • extentofmetabolismthroughtheaffectedenzyme 100% eliminatedby CYP2D6 50% eliminatedby CYP2D6 Ito K et al. Drug MetabDispos 2005

35. CYP2D6 inhibitionbyritonavir desipraminealone desipramine + ritonavir 100 mg BID Ritonavir 100 mg BID modestinhibitory effect on CYP2D6 in extensive metabolizers AUC 26% Aarnoutse RE et al. CPT 2005

36. Predictionof DDI withantidepressantsusing PBPK AUC antidepressant + EFV AUC antidepressantalone AUC antidepressant + RTV AUC antidepressantalone observed RTV: 0.56 RTV: 0.93 RTV: 0.51 EFV: 0.59 EFV: 0.92 EFV: 0.61 Hepaticintrinsicclearance [L/h] sertraline venlafaxine RTV: 1.20 RTV: 1.52 EFV: 0.76 EFV: 0.62 mirtazapine citalopram adapted from Siccardi M, Marzolini C et al. ClinPharmacokinet 2013

37. Potential DDI between ARV andantidepressants EACS guidelines 2014; www.hiv-druginteractions.org

38. Potential DDI between ARV andantipsychotics www.hiv-druginteractions.org

39. Potential DDI between ARV andanxiolytics/hypnotics www.hiv-druginteractions.org

40. Whereto check for DDI with antiretroviral agents

41. Drugs selection selectthe antiretroviral drug (s) selecttheco-medication (s)

42. Commentary on drug-druginteraction

43. Pharmacogeneticsofantidepressants Impact of CYP2D6 phenotype on antidepressantdose adjustment significantimpact modestimpact ultrarapid metabolizer extensive metabolizer intermediate metabolizer poormetabolizer Kirchheiner J et al. Mol Psychiatry 2004

44. Geneticimpactsthemagnitudeofdrug-druginteraction drug-druginteractionsmaybeofgreatermagnitude in individualslacking functionalCYP2D6 genes Lindh JD et al. Eur J ClinPharmacol 2003

45. P-gpinhibitionby PI: improvedantidepressanteffect? protease inhibitors O’Brien et al. BJCP 2012

46. QT intervalprolongation • some psychotropes havethe potential todelaycardiacrepolarization, an effectthatcanbemeasuredasprolongationof QT interval. • QT intervalisheart rate dependent (shortenedwithincreasingheart rate), therefore a correctionfactorisgenerallyused (QTc). • excessiveQTcintervalprolongationcanbeproarrhythmicand prompt a potentially fatal ventriculartachyarrhythmiaknownastorsade de pointes (TdP). Trinkley KE et al. CurrMed Res & Opinion 2013

47. RiskfactorsfordruginducedTdP • drugprolongingQTc in presenceofhost riskfactors • (e.g. femalegender, electrolyteabnormalities, pre-existingprolongationof QT interval, • bradycardia, myocardialischemia, congestiveheartfailure, historyofarrhythmias, • geneticvariantsaffectingcardiacionchannels) • drug-druginteractions: • 1) drugprolongingQTc+drugprolongingQTc(PD interaction) • 2)drugprolongingQTc+metabolicinhibitor(PK interaction) • 3) drugprolongingQTc & metabolicinhibitor+ • drugprolongingQTc(PK + PD interaction) Trinkley KE et al. CurrMed Res & Opinion 2013

48. ARV andco-administration ofdrugprolonging QT Saquinavir: dose dependentprolongationof QT and PR intervals in healthyvolunteersreceivingboostedsaquinavir. Concomitantusewithotherdrugsthatprolongthe QT and PR intervalsis contra-indicatedor in patientswithriskfactors. Atazanavir: dose dependentasymptomaticprolongationof PR intervalobserved in clinicalstudies. Cautionwhenprescribingwithotherdrugsthatprolongthe QT and PR intervalsor in patientswithriskfactors. Lopinavir: modestasymptomaticprolongationof PR intervaland moderate elevationofQTcintervalobserved in clinicalstudies. Reports ofcardiacevents. Cautionwhenprescribingwithother drugsthatprolongthe QT andin patientswithriskfactors. Individual drugs SPCs

49. RilpivirineandriskofQTcintervalprolongation 23 ms Rilpivirinecanprolong QTcinterval at supra- therapeuticdoses. 9 ms 4 ms 25 mg 75 mg 300 mg Rilpivirineconcentration (ng/ml) FDA accessdata 2011

50. Thorough QT/QTcstudy • Study conductedearly in clinicaldevelopmenttodeterminewhethertheeffect on QTcintervalshouldbeintensivelyinvestigatedduringlaterstages. • Interpretation of the QT/QTc interval prolongation in study: • Around mean increases of 5 ms* or less  drug does not • appear to cause TdP • (*orwiththeupperboundof 95% CI forthelargest time-matchedmeaneffectofthedrug < 10ms) • Above 5 ms*  threshold of regulatory concern • (*orwiththeupperboundof 95% CI forthelargest time-matchedmeaneffectofthedrug ≥ 10ms) • >20 ms  drug has a substantially increased risk of being proarrhythmic FDA (2005). E14: the clinical evaluation of QT/QTc interval prolongation and pro-arrhythmic potential fornon-arrhythmic drugs