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HIV Drug-Drug InteractionsHIV Drug-Drug Interactions
Cristina Gruta, Pharm.D.,Cristina Gruta, Pharm.D.,Assistant Clinical Professor of Clinical Pharmacy Assistant Clinical Professor of Clinical Pharmacy
and Family and Community Medicineand Family and Community Medicine
National HIV/AIDS Clinicians’ Consultation National HIV/AIDS Clinicians’ Consultation CenterCenter
HIV Drug-Drug Interactions HIV Drug-Drug Interactions
Complexities of treating HIV and related illnesses increase potential for drug-drug interactions
In the age of HAART, pts living longer to develop other medical problems requiring pharmacologic treatment
Complications/adverse effects stemming from ARV use being treated with additional medically
Assessment of drug interactions must be a routine part of HIV management
Presentation Goals
Review interaction concepts – Types of interactions, review of mechanisms– Common drugs most likely to interact with ARVs– Sample cases
Review process of evaluating interactions– Where to find information– Evaluating the data
Propose steps in managing interactions Case discussions
Pharmacokinetic vs. Pharmacokinetic vs. Pharmacodynamic InteractionsPharmacodynamic Interactions
Pharmacokinetic:
related to physical disposition of the drug (“what the body does to the drug”)
absorption distribution metabolism elimination
Pharmacodynamic: refers to an extension of the pharmacologic
effect of the drug resulting in enhanced
toxicity or in antagonism of two
agents
(“what the drug does to the body”)
Examples of pharmacodynamic Examples of pharmacodynamic interactionsinteractions
Interacting Drugs Pharmacodynamic EffectZidovudine (AZT) and
stavudine (d4T)Competes for binding site
antagonismZidovudine (AZT) and
ganciclovir bone marrow toxicity
Stavudine (d4T) andzalcitibine (ddC)
peripheral neuropathy
Pharmacokinetic Drug Interactions Changes in GI absorption Displacement from plasma
protein binding– e.g. warfarin and T/S
P450 Mediated– Enzyme inhibition– Enzyme induction
Decreased renal elimination– 2 drugs compete for renal
secretion, e.g. probenecid/PCN P-glycoprotein mediated
– New concept: intracellular efflux pump
Bioavailability Interactions: Bioavailability Interactions: Decreased absorptionDecreased absorption
DDrugs with high potential for drug interactions in HIV patients
– Quinolone Antibiotics– Didanosine– Antacids– Antifungal agents
(ketoconazole/itraconazole)– Delavirdine
Cytochrome p450 Enzymes (I)Cytochrome p450 Enzymes (I)
Cytochrome families 1,2,3,4 called xenobiotic enzymes and evolved from more primitive enzymes present in unicellular organisms
Function was to degrade dietary toxins produced by plants preventing potential poisoning
Cytochrome p450 Enzymes (II)Cytochrome p450 Enzymes (II)
Found primarily in hepatocytes and cells of the gut wall
They are responsible for phase I or oxidative metabolism, i.e. enzymes convert the substance (via insertion of oxygen) into a more polar species
Substance then eliminated in urine or feces or undergoes further processing (phase II) to produce an even more polar compound
Cytochrome P450 System Multiple isoenzymes involved in drug
metabolism– 1A2, 2C19, 2C9, 2D6, 3A4– 3A4 and 2D6 responsible for majority of
significant drug interactions in HIV
P450 enzyme substrate table– http://medicine.iupui.edu/flockhart/
Substrates vs. Inhibitors/Inducers Recall relationship b/w substrate (drugs) and
enzyme (p450 enzyme) Some drugs alter the enzyme function by inhibiting
or inducing them Not all substrates of an enzyme pathway induce or
inhibit that enzyme– e.g. sildenafil is a substrate of CYP 3A4 but it’s not
known to induce/inhibit it Inhibitors or inducers of an enzyme pathway are
usually substrates of that enzyme– hence caution with bi-directional interactions, e.g. APV +
rifabutin
Other Principles to RememberOther Principles to Remember Imperative to consider potential bi-directional
interaction, e.g. APV + rifabutin Drugs often metabolized by several enzyme
pathways– e.g. fluoxetine goes through 2D6 then 3A4
Certain drugs may inhibit one pathway but induce others (e.g. RTV can ethinyl estradiol levels)
Concomitant induction and inhibition not necessarily additive/subtractive (RTV+SQV+ EFV)
Not all clinically significant interactions are documented, not all documented interactions are clinically significant
Common Substrates of 3A4 and Common Substrates of 3A4 and 2D6 Isoenzymes2D6 Isoenzymes
3A4 substrates benzodiazepines macrolides quinidine cisapride (Propulsid) sildenafil (Viagra) methadone verapamil Protease inhibitors NNRTI’s
2D6 substrates beta blockers tricyclic
antidepressants SSRI’s haloperidol Risperidone Ritonavir
Common p450 Enzyme Inhibitors Common p450 Enzyme Inhibitors HIV-Infected Pts May TakeHIV-Infected Pts May Take
PI’s (RTV>>>IDV=NFV=APV>SQV) ketoconazole>itraconazole delavirdine efavirenz (partially) Macrolide antibiotics
– erythromycin > clarithromycin (NOT azithromycin)
Inhibition: So what’s the big Inhibition: So what’s the big deal?deal?
Inhibition decreases P450 activity, which can decrease metabolism/clearance of substrates and lead to increased levels and effects of substrates
Clinical concern-- Increased effects can mean increased risk of toxicities!
Common p450 Enzyme Inducers Common p450 Enzyme Inducers HIV-Infected Pts May TakeHIV-Infected Pts May Take
Nevirapine Efavirenz (partially) Rifampin Rifabutin Antiepileptics
– (phenytoin, carbamazepine, phenobarbital) Herbal supplements
– St. John’s Wort (Piscitelli, Lancet 2000)– Garlic (Piscitelli, Retrovirus 2001)
Possibly ritonavir/nelfinavir-maybe not p450?
Induction: So what’s the big Induction: So what’s the big deal?deal?
Increased P450 activity can increase metabolism of substrates and lead to decreased levels and effects of substrates
Clinical concern– Subtherapeutic levels can lead to decreased/lack of efficacy, e.g. with ARV’s decreased levels can lead to viral resistance!
Ritonavir (and Kaletra): Ritonavir (and Kaletra): Contraindicated medicationsContraindicated medications
– Antiarrhythmics: Amiodarone, Bepridil, Flecainide, Propafenone, Quinidine
– Antihistamines: Astemizole, Terfenadine (off market)
– Antimigraines: Dihydroergotamine, Ergotamine– GI Motility: Cisapride (off market)– Sedative/Hypnotics: Midazolam, Triazolam– Neuroleptic: Pimozide– Antilipemics: Simvastatin, lovastatin– St. John’s Wort
Other Protease InhibitorsOther Protease Inhibitors
Contraindicated medications:– terfenadine, astemizole– cisapride– triazolam, midazolam– ergot derivatives (DHE, ergotamine)– rifampin– Simvastatin, lovastatin– St. John’s Wort
Drug interactions can be exploited for therapeutic benefit
Dual protease inhibitors– RTV/IDV, RTV/SQV, RTV/AMP, RTV/LPV
Elimination of indinavir food requirements Ritonavir to offset induction by efavirenz
– RTV/AMP + EFV (Piscitelli CROI 2000) Potential for once-daily dosing of protease
inhibitors-- investigational
Common Boosted PI Common Boosted PI CombinationsCombinations
RTV 400 mg + SQV 400 mg BID RTV 400 mg + IDV 400 mg BID RTV 200 mg + IDV 800 mg BID RTV 100-200 mg + APV 600 mg BID Kaletra 3 pills BID
Not as common…. RTV 400 mg + NFV 750 mg BID NFV 1250 BID + SQV 1600 mg BID
Nevirapine and PI’s: P450 Nevirapine and PI’s: P450 InductionInduction
SQV (without RTV) should not be co-administered with NVP
RTV requires no dose adjustment NFV levels may be decreased, but no dose
change recommended IDV dose increased to 1000 mg Q 8 hr APV no data available – concern of [APV] LPV/r dose increased to 533/133 (4 pills BID)
Delavirdine and PI’s: P450 Delavirdine and PI’s: P450 InhibitionInhibition
SQV levels increased, no dose adjustment needed
RTV levels increased 70%, concern using 2 potent inducers
NFV levels increased, no dose adjustment needed
IDV dose decreased to 600 mg Q8 hr APV/DLV no data available LPV/r levels expected to increase – dose
adjustments not yet studied
Efavirenz and PI’s : Inhibition and Efavirenz and PI’s : Inhibition and induction of P450induction of P450
SQV (without RTV) levels decreased 60%, should not be co-administered
RTV requires no dose adjustment NFV levels increased, but no dose change IDV dose should be increased to 1000 mg
Q8 hr APV levels decreased by 36%, add 100-200
mg BID RTV or APV alone at 1200 TID LPV/r dose increased to 533/133 (4 pills BID)
Selected drugs with high potential for drug interactions in HIV patients
P450 Substrates / Narrow Therapeutic Window– Statins (esp. simvastatin, lovastatin)– Methadone– Anticonvulsant drugs– Warfarin– Sildenafil (Viagra)– Oral contraceptives– Some benzodiazepines (midazolam, triazolam)– Astemizole/terfenadine/cisapride (off the market)– Ergot derivatives– Antiarrhythmics
Systematic approach to drug interaction evaluation
Complete and accurate medication history
Check for documented drug interactions Consider theoretical interactions Assess clinical significance and
consequence of interaction Management of interaction Monitoring of interaction
1. Complete and accurate medication history
Include OTC, herbal/nontraditional medications, illicit drugs
Medications from other providers All all medications medically necessary? Address adherence - Is patient taking all
medications? Medication schedule
– Food interactions and drug administration may be relevant
Case- Female DentistCase- Female Dentist
A female dentist sustained a percutaneous injury while cleaning the teeth of a an HIV-infected pt with gingival disease. She starts on AZT/3TC/nelfinavir. The dentist only takes oral contraceptives.
How should she be counseled on taking her PEP regimen?
2. Check for documented drug interactions Check at least two references for drug interactions Primary literature
– Medline– AIDSline– International Pharmaceutical Abstracts (IPA)
HIV Specific References– DHHS Guidelines for the use of antiretroviral agents in
adults and adolescents (www.hivatis.org)
2. Check for documented drug 2. Check for documented drug interactions: Textsinteractions: Texts
Drug interaction texts– Hansten and Horn’s Drug Interaction Facts– First Data Bank Evaluation of Drug Interactions– Drug Interaction Facts (published by Facts and
Comparisons) General Drug Info References
– Facts and Comparisons– AHFS Drug Formulary– Clinical Drug Data– Micromedex– CRLonline.com
2. Check for documented drug 2. Check for documented drug interactions:interactions: Internet ResourcesInternet Resources
Liverpool Pharmacology Group– http://www.hiv-druginteractions.org
Medscape Drug Interaction Calculator– http://www.medscape.com (go to HIV/AIDS
specialty page, interaction calculator) Toronto General Hospital Immunodeficiency
Clinic – http://www.tthhivclinic.com/interact_tables.html
Project Inform Drug Interaction Page (good for lay audience)– http://www.projinf.org/fs/drugin.html
2. Check for documented drug interactions Manufacturer Package Inserts (PI)
– Contains “official” information on drug interactions and metabolism, but many interaction studies haven’t been conducted
– Many PIs are available on web» Try www.brandname.com or www.manufacturer.com
www.kaletra.com, www.combivir.com, www.sustiva.com www.gsk.com, www.bms.com
– Pharmaceutical company medical affairs/drug info may be useful
Case- Female DentistCase- Female Dentist
Female dentist starts on AZT/3TC/nelfinavir for PEP. She only takes oral contraceptives. How should she be counseled on taking her PEP regimen?
Drugs of concern– Nelfinavir and ethinyl estradiol (EE)
DHHS Guidelines, Nelfinavir pkg insert– Nelfinavir shown to cause a 47% decline in ethinyl
estradiol– Would counsel her to use “BUM”
Note: RTV, Kaletra, and nevirapine can also cause declines in [EE]– also need “BUM”
Caveats about resources
Textbooks only updated annually at most– websites, DHHS guidelines tend to be more
current Some websites may not explain the
significance of the interactions Resources often do NOT take into account
interactions among 3 or more drugs Management of interaction may not be
provided
Case- Theoretical InteractionsCase- Theoretical Interactions
A psychiatrist wishes to start an atypical anti-depressant for an HIV-infected client whose meds include d4T/3TC/RTV/IDV, co-trimoxazole, and testosterone. The agents being considered are venlafaxine or citolapram.
Will either agent be okay to combine with pt’s current meds?
3. Consider theoretical drug interactions
Consider clearance route, metabolic pathways, P450 isoenzyme systems involved
Drugs may interact by acting as precipitant (inhibitor/inducer) or object (substrates) drugs
P450 3A4 responsible for many drug interactions– Other inhibitors of 3A4 include erythromycin, ketoconazole– Other inducers of 3A4 include phenytoin, carbamazepine,
rifampin, phenobarbital, St. John’s wort– Interactions would be expected if P450 inhibitor used with
P450 substrate Package insert or drug references contain information on
hepatic metabolism, isoenzymes involved
Case- Theoretical InteractionsCase- Theoretical Interactions
Can an HIV-infected client whose meds include d4T/3TC/RTV/IDV, co-trimoxazole, and testosterone safely take either venlafaxine (Effexor) or citalopram (Celexa)?
Drugs of concern– Ritonavir, indinavir, atypical antidepressant
From Facts and Comparisons and CRL online:– Venlafaxine– CYP 2D6 and 3A4 substrate, weak 2D6
inhibitor– Citalopram– CYP 3A4 and 2C19, weak inhibitor of
2D6 and 2C19
4. Assess clinical significance / consequence of drug interaction
Is the interaction consistent and reproducible? Study design? What is the consequence of the interaction? Onset of interaction?
– Inhibition usually occurs quickly, induction may take days-weeks
What is a clinically significant change in drug levels?
At what point does toxicity occur? Can toxicity be monitored?
5. Management of interaction
Are there therapeutically acceptable alternatives?– e.g. rifabutin instead of rifampin
Are there recommended dose adjustments?– Future role of ARV drug levels?
Empiric dose adjustments? Monitoring for toxicities or subtherapeutic
responses.
Conclusions Drug interactions represent a challenge
to clinicians Current knowledge is inadequate and
constantly changing Successful management requires
familiarity with a variety of references and vigilant surveillance
PK data should be critically evaluated A systematic approach ensures accurate
answers based on available information
Case– SildenafilCase– Sildenafil
A 38 y.o. male patient taking d4T/ABC/amprenavir complains of erectile dysfunction and asks his provider for Viagra because he hears it works wonders. After ruling out other causes of of ED, his provider asks you the pharmacist if there would be a problem starting the patient on this agent.
Case- SildenafilCase- Sildenafil
Drugs of concern– Amprenavir and sildenafil
Data– Both agents are CYP 3A4 substrates– sildenafil AUC 2-11 fold with APV
Suggested management– Do not exceed 25 mg q 48h of sildenafil
Same sildenafil dosing recommendation if co-administered with other PI’s
Case- AntidyslipidemicsCase- Antidyslipidemics
A 57 y.o. male patient has a T cell count = 358 and an undetectable viral load on d4T/3TC/Kaletra. Baseline cholesterol panel: Total cholesterol = 268, LDL= 195, HDL=43, triglycerides=277. After 9 months of HAART, Total cholesterol=345 and LDL=247. Patient is a non-smoker but has a positive family history of heart disease. His provider discusses treatment with an anti-cholesterol agent.
Which agent would you recommend?
Case- AntidyslipidemicsCase- Antidyslipidemics Drugs of concern
– Kaletra and “statins”– Both agents go thru CYP 3A4– Inhibition: RTV in Kaletra
Data– Atorvastatin AUC 5.88-fold– Lovastatin, simvastatin contraindicated– Pravastatin AUC 33%
Suggested management:– Caution with atorvastatin– Can use pravastatin, no dosage adjustment needed
Case- MethadoneCase- Methadone
A 33 y.o. female HIV+ client is on methadone maintenance and is being started on Trizivir/nevirapine and dapsone because her CD4+ count is 176 and viral load 120,000.
What potential interactions would you want to discuss with her and her provider?
Case- MethadoneCase- Methadone Drugs of concern
– Nevirapine and methadone Data
– Methadone a CYP 3A4, 2D6, 1A2 substrate– Nevirapine can cause a “significant” decline in methadone
levels Suggested management
– Titrate methadone dose to effect Note: Efavirenz as well as RTV and Kaletra may cause
[methadone]– Recall certain drugs may inhibit one enzyme pathway but
induce others
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