Polypharmacy And Drug-Drug Interactions - HIV Workshop
Polypharmacy and Drug-DrugInteractionsDavid BackUniversity of LiverpoolUKDavid BackNovember 2016
Disclosures Honoraria received for advisory boards andlectures from AbbVie, BMS, Gilead, Merck,ViiV, Janssen, Teva Educational grants for www.hepdruginteractions.org andwww.hiv-druginteractions.org from AbbVie,BMS, Gilead, Janssen, Merck, ViiV
More patientson txPolypharmacyIncreasedOTCAgeingDDIs:Are not going away!DifferentprescribersLess Clinicvisits?Recreational drugsOnline access drugsAdapted from Okoli C - with permission
ARVs, Older Patients and Co-medsARVs1. Which ARVs?Guidelines2. Drug handlingwith Age?4. InteractionimpactAgeingPatientCo-Meds3. Which co-meds;how many?
Overview1234Which ARVs; Guidelines
Recommended Regimens: rWHO2016TDF/FTC (or 3TC) EFVTDF/FTC (or 3TC) DTGNAEACS (v8.1) 2016TAF/FTC/RPV orTDF/FTC RPV*TAF/FTC or TDF/FTCwith EVG/c Or RALor DTGTAF/FTC orTDF/FTC DRV/ror DRV/cobiABC 3TC with DTGIAS-USA2016TAF/FTC RPV* (or EFV) ifINSTI not appropriateTAF/FTC with EVG/cOr RAL or DTGTAF/FTC DRV/r(if INSTI notappropriate)ABC 3TC with DTGDHHS2016* In viral loads 100K copies/mL Guideline update Oct 2016WHO 2016: index.htmlEACS v8: http://www.eacsociety.org/files/guidelines 8.0-english-revised 20160610.pdfIAS-USA 2016: http://jama.jamanetwork.com/article.aspx?articleid 2533073DHHS 2016: /adultandadolescentgl.pdfTDF/FTC with EVG/cOr RAL or DTGTAF/FTC with EVG/cor RAL or DTGTDF/FTC DRV/rTAF/FTC DRV/rABC 3TC with DTGTDF, tenofovir disoproxil fumarate; TAF, tenofovir alafenamide; FTC,Emtricitabine; 3TC, Lamivudine; ABC, Abacavir; DRV/r,Darunavir/ritonavir, RPV, rilpivirine; EFV, efavirenz; EVG/c,elvitegravir/cobicistat; RAL, raltegravir; DTG, dolutegravir; NNRT, nonnucleoside reverse transcriptase inhibitor; PI/r, boosted proteaseinhibitor; INST, integrase inhibitor
EACS Guidelines (v8.1) Oct 2016: Initial CombinationRegimens (Recommended and Alternative) for ARTnaïve Adult HIV-positive personsEACS Recommended RegimenClassINSTI BoostedPI TAF/FTC or TDF/FTC DRV/c orDRV/rTAF/FTC or TDF/FTC RALTAF/FTC/EVG/c or TDF/FTC/EVG/cABC/3TC/DTGTAF/FTC/DTG or TDF/FTC/DTG16 of the 26 regimens haveboostersNNRTI TAF/FTC/RPV or TDF/FTC/RPVAlternative Regimens ABC/3TC RAL ABC/3TC ATV/c or ATV/r TAF/FTC or TDF/FTC ATV/c or ATV/r ABC/3TC DRV/c orDRV/r TAF/FTC or TDF/FTC LPV/r ABC/3TC EFV TDF/FTC/EFVAlso listed are 3TC LPV/r and RAL DRV/c or DRV/rFor specific details and cautions please go to the Guidelineswww.eacsociety.org/guidelines
Interaction Potential of ARVsHigher potentialModeratePotentialLower PotentialBoosted PIsRilpivirineRaltegravirPerpetrators – enzyme andtransporter InhibitionVictim - absorption (ATV);inductionVictim of enzymeinhibition and induction.Also absorption.Victim of few inductionand absorptioninteractionsEVG/cobi(Maraviroc)Most NRTIsPerpetrator – enzyme andtransporter inhibitionVictim - absorption;inductionVictim of enzymeinhibition and induction.Victim of transportermediated interactions.TDF & TAFEfavirenz, (Nevirapine,Etravirine)Perpetrators – enzyme andtransporter inductionDolutegravirVictim of enzymeinduction and absorptioninteractionsPerpetrator of renalinteractionBased on www.hiv-druginteractions.org
Drug- Drug InteractionsAEsComedHIVdrugLoss ofefficacyAEsPerpetratorVictimLoss ofefficacyNeed to understand: The disposition or handling of each drug The therapeutic window of each drugPersonal Communication: Professor D J Back
Therapeutic WindowDrug Plasma concentrationTOXICITYARVCoMedDrug concentrations intherapeutic windowREDUCED EFFICACYNarrow Therapeutic Window Drugs including:Anticoagulants, Antiarrhythmics, Anticonvulsants, Steroids, Statins,Immunosuppressants
Overview1Which ARVs; Guidelines2Drug Handling with Age34
SPC Statements re ElderlyARVStatement in SPCs (accessed 20/11/16)TDFPK studies have not been performed in 65 years of ageFTCPK studies have not been performed in 65 years of ageABCNo PK data available in patients 65 years3TCNo PK data available in subjects 65 yearsEFVPK Studies have not been performed in the elderlyRPVPop PK shows RPV exposure not different over age range18-78 but only 3 patients 65.ATV/rNo clinically important PK differences based on age.DRV/rLimited PK data in patients 65 (n 12). CautionRALNo effect of age on RAL PK over age 19-71 (n 8 in 65)DTG*Pop PK shows no clinically relevant effect of age, but data in 65 is limited.EVGPK of EVG have not been fully evaluated in age 65.SmPCs Accessed through the Electronics Medicines Compendium (EMC): www.medicines.org.uk/emc/ Nov 20th 2016
Should we be concerned about age anddrug pharmacokinetics?AbsorptionDistributionIncreased gastric pH anddecreased small bowelsurface area may lead to ahigher inter individualvariability in drugexposure. [1]MetabolismReduced liver volume andblood flow with reducedenzyme activity can givedecreased drug clearance.Also altered transporters.Hepatic Impairment.Increase in body fat with olderage increases Vd of some drugsand may increase the t1/2.Greater drug accumulationand increased risk of toxicityare possible.Renal eliminationGFR may decrease as much as50% with increasing age, which canaffect renal elimination of somedrugs. Clinical consequence(toxicity) depends on the extent ofrenal elimination.Vd volume of distribution; CL clearance; GFR glomerularfiltration rate1. Boffito M and Back DJ, Personal communication;
Best evidence for age-related changesis from older studies! Paracetamol metabolised to formglucuronide and sulphateconjugates Clearance declines from 4.8 to 3.8to 2.7 ml/min/kg. Means that drug exposureincreases by 30% (fit elderly)and 80% (frail elderly).18-30 60Wynne HA et al Age & Ageing 1990; 19: 419-424; Wynne HA et al 1993; 22: 354-9
19 HIV subjects with mean (SD) age of 66 (3.4) switchedto RAL containing regimen. No difference in RAL apparent oral clearance whencompared to 38 younger HIV subjects with mean age of41 (9.2) based on population PK. RAL metabolised by enzyme UGT1A1HIV Clin Trials 2015; 16: 39-43.
Higher rates of neuropsychiatric adverse events leadingto dolutegravir discontinuation in women and olderpatientsSabranski M et al HIV Glasgow 2016; Abs O214
Relationship between DTG plasma trough concentration,UGT1A1 polymorphisms and side-effects of the CNS inJapanese HIV-1 infected patients N 101 UGT1A1 *6 and *28 studied Median DTG Ctrough wassignificantly higher in patientswith CNS side effects However, no difference inCNS AEs in terms of geneticpolymorphismsYagura H et al HIV Glasgow 2016; Abs P312.
Mean age 43 (range 22 – 65)AIDS 2014; 28: 59-66
Prospective Studies EFV/TDF/FTC in patients 55y (n 6)ATV/r TDF/FTC in patients 55y (n 6)Exposure compared to general population. ATV/r 2NRTIs in pts - median age 46y compared tomedian age 41.9 (n 22).Higher ATV conc in older. LPV/r FTC d4T PK in patients aged 18-30 (n 37)and 45-79 ( n 40)Older age associated with higher LPC Ctrough at wk24but not wk 36 or 90.1. Dumond JB et al HIV Med 2013; 14: 404-9; 2. Avihingranon A et al AIDS Res Hum Retro 2013; 29: 1541-1546; 3.Crawford K et al AIDS Res Hum Retro 2010; 26: 635-643.
Overview1Which ARVs; Guidelines2Drug Handling with Age3Which co-meds; how many?4
Predicted burden of NCDs in HIV-infectedpatients between 2010 and 2030 (modelsimulation)
Predicted prevelance of comedication use in 2030 as cross section of number of patientson different types of co-meds based on representative 400 patients (each squarerepresenting a patient)
Mixpanel Analysis
N 250 search events
Overview1Which ARVs; Guidelines2Drug Handling with Age3Which co-meds; how many?4Specific DDIs
Absorption of Tenofovir (TFV), TenofovirDisoproxil Fumarate (TDF) and TenofovirAlafenamide (TAF)GI oxilfumarate(TDF)DIANIONTFVPLASMATFVHIVTARGET CELLTDF300 mgESTERTAFTenofoviralafenamide(TAF)25 mgor 10 mg*T1/2 5 min†T1/2 90†minTFVHIVTFVAMIDATE 91% lower plasma TFV levels after E/C/F/TAF than E/C/F/TDFadministration – TFV AUC is 290 vs 3308 ng.h/ml for Genvoya vs Stribild†T1/2 based on in vitro plasma data.1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66.4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014;67(1):52-8. 6. Sax P, et al. Lancet 2015;385:2606-15.FDA Center for Drug Evaluation and Research. Clinical Pharmacology & Biopharm Rev 2014 Gupta SK, et al. IAS 2015. Vancouver, CA; #TUAB0103.
AVT 2014; 19: 687-692
Differences in the DDI Profile of TDF & TAFTDFAspirinCelecoxibDiclofenacIbuprofenMefenamic onic acidTAFPotential MechanismNSAIDS and RenalNSAIDS and RenalNSAIDS and RenalNSAIDS and RenalNSAIDS and RenalNSAIDS and RenalNSAIDS and RenalRenal transportRenal transportRenal transportRenal transportRenal transportP-gp/absorptionRenal toxicityRenal toxicityRenal toxicityRenal toxicityRenal dysfunctionRenal dysfunctionNSAIDS (inhibit MRP4) – important to consider dosing frequencywww/hiv-druginteractions.org
721 patients with median use of TDF of 54 months 321 pts had renal transport inhibitors (NSAIDS; PDE5-I; salicylates)which were categorised as cumulative defined daily doses (DDDs).JID 2016; 213: 561-568
Differences in the DDI Profile of TDF & TAFTDFTAFPotential MechanismRifabutinNRInduction of P-gpRifampicinNRInduction of P-gpRifapentineNRInduction of P-gpCarbamazepineNRInduction of P-gpOxcarbazepineNRInduction of P-gpPhenobarbitoneNRInduction of P-gpPhenytoinNRInduction of P-gpSt John’s WortNRInduction of P-gpFluconazoleDose 10 mg TAFInhibition of P-gpItraconazoleDose 10 mg TAFInhibition of P-gpKetoconazoleDose 10 mg TAFInhibition of P-gpCyclosporinDose 10 mg TAFInhibition of P-gpBoceprevirNRStops intracellular activationTelaprevirNRStops intracellular activationConsider dosing of azoles (short course)NR Not RecommendedN Could argue could be red (personal communication, David Back Nov 16)www/hiv-druginteractions.org
www.hiv-druginteractions.org
losinDutasterideFinasterideExpert Opinion on Drug Met & Tox 2016; 12: 1211-1224;www.hiv-druginteractions.org
BHIVA Guidelines 20161. We suggest avoiding ritonavir or cobicistat boostedART in patients who are to receive cytotoxic chemoagents metabolised by CYP450.2. We suggest switching ARV agents in patients whoare to receive cytotoxic chemotherapy to avoidsevere and/or overlapping toxicities.www.bhiva.org/guidelines
ARVs and rhiza glabra(Liquorice)Modest inducer ofCYP3A4; May induceUGTs; Inhibitor of P-gpCould decrease RPV &MVC; possiblydecrease RAL & DTGIncrease of TDF & TAFZingiber officinale(Ginger)Moderate inhibition ofCould increase RPV &CYP2C9, 2C19 and 3A4. MVCInula racemosaModerate inhibition ofCYP3A4 in vitroCould increase RPV &MVCPiper cubebaSeveral constituentsstrongly inhibit CYP3A4and piperine inhibitsP-gpPotentially increaseRPV & MVC (CYP3A4)Could increase TDFand TAF (P-gp)MentholModerate inhibitoryeffect on CYP3A4.Possible effect on RPVand MVCLiverpool website team - unpublished
Overview5Take home points.
ARVs, Older Patients and Co-medsARVs4. Interaction impactnot always clear.Need more goodstudies.1. Use ARVs withleast interactionpotential.Consider tabletsize2. Drug handlingchanges with age:Renal and hepaticimpairment.AgeingPatientCo-Meds3. Older pts willtake more comeds. Review!
Thank You
Drug- Drug Interactions Need to understand: The disposition or handling of each drug The therapeutic window of each drug . ARV Co-Med TOXICITY . TFV HIV FDA Center for Drug Evaluation and Research. Clinical Pharmacology & Biopharm Rev 2014 Gupta SK, et al. IAS 2015. Vancouver, CA; #TUAB0103.
Seven steps to managing polypharmacy: P Medicines Use and Safety Polypharmacy and medication review - Seven Steps Vs2- Jan 2015 (NB) 2 S S Introduction Medicines are the most common intervention to improve health and concerns about the risks of polypharmacy in primary and secondary care are growing. Published evidence associates polypharmacy .
constructs a multimodal graph of protein-protein interactions, drug-protein target interactions, and the polypharmacy side effects, which are represented as drug-drug interactions, where each side effect is an edge of a different type. Decagon is developed specifically to handle
This quick reference guide accompanies the Polypharmacy Guidance, Realistic Prescribing 2018, which aims to provide guidance on preventing inappropriate polypharmacy at every stage of the patient journey. Greater emphasis has been placed on shared-decision making to actively engage the patient with the 7-Step medication review.
LSS/DIS Holdings Updated 2/6/15 Page 3 sjb The Pharmacist’s Guide to Drug Eruptions and Interactions (Litt) 6 Managing Clinically Important Drug Interactions, 2005 (Hansten & Horn) 7 Herbal-Drug Interactions and Adverse Effects (Philp) 8 Handbook of Food-Drug Interactions (McCabe, Frankel, Wolfe) 9 Neoral Drug Interactions, Novartis 2006 Literature Review (Novartis) 10
Keywords: Drug-drug interactions, HIV, Suspected meningitis, Acute care, Cohort studies, DDIs Key findings The result of this analysis shows that potential drug-drug interactions, ranging from minor to contradicted interactions, in this subset of the population are signifi-cant and sometimes unavoidable. Although frequency
potential for a drug to be a substrate, inhibitor, or inducer of that process, we can predict the potential for drug interactions. In Vitro models/Tools Reza Fassihi Ph.D. 20 The integration of in vitro and in vivo (both animal and human) data can identify the role of transporters in drug‐drug interactions.
3 -Drug-Drug Interactions and Contraindications OVERVIEW General Information Both components of nirmatrelvir/ritonavir (Paxlovid) inhibit CYP 3A4 an p-gp and have numerous drug-drug interactions, some which contraindicate its use. Ritonavir also inhibits CYP 2D6 to a lesser extent. Nirmatrelvir and ritonavir are
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