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