HIV Drug-Drug Interactions Cristina Gruta, Pharm.D., Assistant Clinical Professor of Clinical Pharmacy and Family and Community Medicine National HIV/AIDS Clinicians’ Consultation Center

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. Pharmacodynamic Interactions 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 interactions

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: Decreased absorption Drugs with high potential for drug interactions in HIV patients Quinolone Antibiotics Didanosine Antacids Antifungal agents (ketoconazole/itraconazole) Delavirdine

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) 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 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 2D6 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 HIV-Infected Pts May Take PI’s (RTV>>>IDV=NFV=APV>SQV) ketoconazole>itraconazole delavirdine efavirenz (partially) Macrolide antibiotics erythromycin > clarithromycin (NOT azithromycin) PPIs

Inhibition: So what’s the big 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 HIV-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 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): Contraindicated 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 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 Combinations 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 Induction 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 Inhibition 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 induction 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 H2 blockers/antacids can play a big role XTC/MJ/garlic, SJW

Case- 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 interactions: 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 interactions: Internet 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 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 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 Ex: NRTIs usually renally eliminated, low potential for pp450 interactions

Case- 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? CCB not correlated with drug levels

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– 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- Sildenafil Drugs of concern Data Suggested management 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- 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- 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- 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- Methadone Drugs of concern Data Suggested management 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