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Basics of Drug Elimination Pharmacodynamic Interactions
Overview of Drug Interactions in HIV Medicine
• Pharmacodynamic defined simply as what the drug does to the body • Select examples in HIV – Antagonistic Antagonistic interaction with zidovudine interaction with zidovudine and and stavudine – binding site competition – Zidovudine and ganciclovir – increased bone marrow toxicity – Stavudine and zalcitabine – increased peripheral neuropathy
John J. Faragon, PharmD, BCPS, AAHIV‐P Regional Pharmacy Director, NY/NJ AETC Pharmacist, Albany Medical Center
CYP450 Metabolism for FDA Approved Medications
Basics of Drug Elimination Pharmacokinetic Interactions • Most common type of interactions in HIV – Absorption – reduced atazanavir absorption when combined with proton pump inhibitors – Distribution – p protein binding displacement g p when warfarin and SMZ/TMP are combined – Metabolism – elevated simvastatin levels when ritonavir inhibits CYP450 enzyme – Elimination – competition for renal elimination with probenicid and penicillin
• Also other transporters such as PGP, OAT, etc
CYP1A2
CYP2D6
CYP3A4
Key points •Majority of drugs metabolized by CYP3A4 & CYP2D6 •CYP3A4 extensivelyy involved with HIV PI/NNRTI and also HCV PI metabolism •Enzymes can be induced or inhibited
Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed.
Top CYP3A4 Inducers Important to HIV Care
CYP450 Induction
Drug Levels
CYP2E1
CYP2C
Steady State Levels
Inducing drug added Time Key Points •Adding a CYP3A4 INDUCER leads to DECREASED levels of the other medication that is also metabolized by CYP3A4 •Peak effect of inducer occurs SLOWLY based upon half-life of drug & time to synthesize new CYP3A4 enzyme •Classic example - Adding efavirenz to protease inhibitors
• • • • • •
Carbamazepine Dexamethasone Efavirenz Etravirine Fosphenytion Nevirapine
• • • • • •
Oxcarbazepine Phenobarbital Phenytoin Rifabutin Rifampin St John’s Wort
HIV PIs and NNRTIs likely to be DECREASED when these medications above are added
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Top CYP3A4 Inhibitors Important to HIV Care
CYP450 Inhibition Steady State Levels Drug Levels
Inhibiting drug added Time Key Points •Adding a CYP3A4 INHIBITOR leads to INCREASED levels of the other medication that is also metabolized by CYP3A4 •Peak effect occurs RAPIDLY, as soon as adequate concentrations of the CYP3A4 inhibitor being added are reached •Classic example - Adding Lopinavir/rtv to simvastatin
• • • • • • •
Amiodarone Clarithromycin Cyclosporin Delavirdine Diltiazem Erythromycin Fluconazole
Potential Toxicity
Alfluzosin
Severe hypotension
Budesonide
Cushing’s syndrome
Colchicine
Fever, diarrhea, paresthesias
Ergotamine derivatives
Ischemia, cyanosis, hypertension
Fluticasone
Cushing’s Syndrome
Midazolam (oral), triazolam
CNS Depression
Quinidine
Cardiac arrhythmias
Sildenafil (and related drugs)
Syncope, hypotension
Statins (simvastatin, lovastatin)
Rhabdomyolysis
Contraindicated Medications with Most Protease Inhibitors Class
Specific Medications
Cardiac Medications
Flecainide, propafenone, amiodarone, quinidine
Lipid Lowering Medications
Lovastatin, simvastatin
Antimycobacterial Medications
Rifampin, rifapentine Rifampin, rifapentine
Gastrointestinal Medications
Cisapride
Neuroleptics
Pimozide
Psychotropics
Oral midazolam, triazolam
Ergotamine derivatives
DHE, ergotamine, ergonovine, etc
Herbal Therapy
St John’s Wort
Other
Alfluzosin, salmeterol, sildenafil in PAH
Classes of Interest
Why does it matter in HIV? • Non‐nucleoside reverse transcriptase inhibitors – Efavirenz, nevirapine, & etravirine are 3A4 inducers • Efavirenz also inhibits 3A4, 2C9 & 2C19 • Etravirine is also 2C9 & 2C19 inhibitor • Rilpivirine also 3A4, not as potent as an inducer • Protease inhibitors Protease inhibitors – CYP3A4 substrates & inhibitors – Ritonavir one of most potent 3A4 inhibitors • Inhibits: 2D6, 2C9, 2C19, 1A2, 2E1, P‐glycoprotein • Induces: 3A4, glucuronyl transferase • Cobicistat, booster in Elvitegravir/cobicistat/tenofovir/emtricitabine – CYP3A4 inhibitor • Inhibits: P‐glycoprotein
Grapefruit Juice HCV Protease Inhibitors HIV Protease Inhibitors Itraconzaole Phenytoin Verapamil Voriconazole
The above medications are likely to be INCREASED when HIV Protease Inhibitors are added
Why should we care about CYP450? Select Toxicities Drug
• • • • • • •
• • • • • • •
Statins, other lipid lowering medications Select cardiovascular medications Inhaled corticosteroids Select psychotropics, narcotics, anti‐gout meds BPH meds, ED medications Proton pump inhibitors and H2 blockers Rifampin/rifabutin
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Cardiovascular Medications
Statins and Protease Inhibitors • Simvastatin and lovastatin considered contraindicated with ALL protease inhibitors • Safest statins are pravastatin, pitavastatin • Atorvastatin – Atorvastatin – Initiate at low doses, titrate, Initiate at low doses titrate caution if >20mg
Medication
Fitchenbaum CJ, et al. AIDS. 2002;16:569‐577, Hsyu PH, et al. Antimicrob Agents Chemother. 2001;45:3445‐3450, Carr RA, et al. 40th ICAAC. Toronto, 2000. Abstract 1644, Calza L, et al. AIDS. 2003;17:851‐859, Doser N, AIDS. 2002;1:1982‐1983, Prezista PI. DHHS Guidelines, March 2012, Morgan, et al. 6th IAS Conference. Rome, 2011. Abstract MOPE170.
• Potential toxicity of antiarrhythmics • Use with caution • Monitor concentrations of antiarrhythmics closely
Warfarin
• Lack of PK data • CYP‐450 involvement • Potential for or exposure of warfarin
• Potential warfarin toxicity or reduced efficacy • Monitor INR closely
CCBs
• exposure of diltiazem with ATV • potential for exposure of CCBs with other PIs and cobicistat
• potential CCB‐associated toxicity • diltiazem dose by ½ with ATV • monitor ECG and for CCB‐associated toxicity with all PIs and cobicistat
DHHS Guidelines March 2012
Steroids and Protease Inhibitors
Cardiovascular Medications Medication
PK Interaction
Management
Beta blockers
• Potential for exposure of metoprolol and timolol with PIs (no PK data) • negligible effect on atenolol when when administered with ATV
• potential for toxicity of beta‐ blockers which are metabolized by CYP‐450 • monitor for beta‐blocker‐ associated toxicity associated toxicity • may use atenolol safely with ATV (& likely with other PIs, no data)
Digoxin
• exposure of digoxin when administered with RTV, SQV/r, DRV/r • p‐glycoprotein inhibition by RTV •Likely with other boosted PIs as well
• potential for digoxin toxicity • monitor digoxin concentrations closely • monitor for digoxin‐associated toxicity
DHHS Guidelines March 2012
• Ritonavir inhibits the CYP‐450 metabolism of fluticasone • Cushing’s syndrome reported with ritonavir‐ containing PI regimens and inhaled fluticasone: – Mean duration of fluticasone use was 75.5 weeks M d ti f fl ti 75 5 k (range 20 days – 18 months) • Case reports with oral and inhaled budesonide • Recent reports with OCULAR topical steroids!
St. Germain St. Germain RM et al. AIDS Patient Care & STDs 2007;21:373‐ RM et al. AIDS Patient Care & STDs 2007;21:373‐7, 7, Pessanha Pessanha TM et al. AIDS 2007;21:529‐ TM et al. AIDS 2007;21:529‐32. Molloy A, Matheson NJ, Meyer PAR, et al. AIDS, 2011, 25(10): 1337‐1338 Frankel JK. Ann Pharmacother, 2011, 45(6): 823‐824. DHHS Guidelines March 2012.
Inhaled Steroids and RTV Boosted Protease Inhibitors • Nasal fluticasone – Switch to beclomethasone, possibly mometasone • Inhaled fluticasone or budesonide – Switch to beclomethasone • Salmeterol, contained in Advair® – Concurrent use of salmeterol and ritonavir to be avoided due to CV risk – tachycardia, QT prolongation, palpitations – Not clear if same risk exists for formoterol? – Consider safer steroid listed above alone, plus montelukast, plus rescue albuterol as needed
DHHS Guidelines, March 2012
Management
• Lack of PK data • CYP‐450 involvement • Potential for exposure
– Do not co‐administer with tipranavir/rtv
• Rosuvastatin – Initiate at low doses, titrate • All statins – monitor CPK, myalgias, LFTs
PK Interaction
Antiarrhythmics
Antidepressants • CONTRAINDICATED – Fluvoxamine (Luvox®) – Nefazodone (Serzone®) • Selective Serotonin Reuptake Inhibitors – Fluoxetine (Prozac®) & paroxetine (Paxil®, Pexeva®): • Interactions not clinically significant Interactions not clinically significant • Paroxetine (Paxil®) levels decreased by darunavir/rtv and fosamprenavir/rtv (about 50%) – Citalopram (Celexa®), escitalopram (Lexapro®), & sertraline (Zoloft®) have fewest interactions • Sertraline levels decreased by efavirenz and darunavir/ritonavir (about 50%) • Tricyclic antidepressants – All boosted PIs and cobicistat expected to increase levels of TCAs DHHS Guidelines, March 2012
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Benzodiazepines
Antidepressants • Dual‐action agents: – Venlafaxine (Effexor®) & duloxetine (Cymbalta®) – Well tolerated without adjusting dose – Vilazodone (Viibryd®) likely to be increased by PIs • Bupropion (Wellbutrin Bupropion (Wellbutrin®, Zyban Zyban®) ) – AUC decreased 57% with lopinavir/rtv – AUC decreased 46% with tipranavir/rtv • Mirtazapine (Remeron®) – Well tolerated, although some 3A4 metabolism • Trazodone (Deseryl®) – With ritonavir‐boosted PIs and cobicistat, start low, titrate DHHS Guidelines, March 2012, Prescribing Information, Viibryd, Prescribing Information, Stribild
• CONTRAINDICATED – Triazolam (Halcion®) and oral midazolam with PIs or cobicistat – Midazolam (Versed®) – Single dose for sedation acceptable if in a controlled environment • Safest to use glucuronidated benzodiazepines (LOT) – Lorazepam (Ativan®) – Oxazepam (Serax®) – Temazepam (Restoril®) • Use at lower doses & titrate – Alprazolam, clonazepam, diazepam DHHS Guidelines, March 2012
Antipsychotics • CONTRAINDICATED – Pimozide (Orap®) • Avoid chlorpromazine (Thorazine®), thioridazine (Mellaril®) • When used with ritonavir, start with lowest dose – Haloperidol (Haldol Haloperidol (Haldol®) – ) risk of EPS & TD risk of EPS & TD – Olanzapine (Zyprexa®), clozapine (Clozaril®), risperidone (Risperdal®) • Metabolized by CYP3A4 – Aripiprazole (Abilify®), ziprasidone (Geodon®), quetiapine (Seroquel®) clozapine (Clozaril®) iloperidone, lurasidone – Likely to be increased by protease inhibitors
Narcotics • Methadone, buprenorphine – See AETC Pocket Guide, DHHS Guideline Tables • Fentanyl – HIGH dose ritonavir increased fentanyl – Low dose patches to start, titrate slow, monitor closely
• H Hydrocodone, tramadol – d d t d l All have the potential to be All h th t ti l t b increased with ritonavir via CYP2D6 inhibition • Oxycodone and Lopinavir/rtv 400/100 twice daily – 2.6 fold increase in oxycodone levels (range 1.9‐3.3 fold) – Use lowest doses, titrate slow, especially if on boosted PIs – Additional caution with longer acting narcotics
Eur J Clin Pharmacol. August 2010, www.nynjaetc.org , DHHS Guidelines March 2012.
DHHS Guidelines, March 2012
Colchicine (Colcrys®) • Fatalities reported with concurrent use of colchicine and clarithromycin, a strong CYP3A4 inhibitor • Increases in colchicine also expected with ritonavir‐ boosted protease inhibitors, ketoconazole, itraconzole • Dosing if on a protease inhibitor + ritonavir Dosing if on a protease inhibitor + ritonavir – Acute attack – Max of 0.6mg, followed by 0.3mg (1/2 tab) one hour later. Do not repeat for 3 DAYS! – Prevention – cut dose in half – IE: if on 0.6mg daily, max per day is 0.3mg
• See insert for additional info – chart available in label, and in DHHS Drug Interaction Tables Colcrys PI, DHHS Guidelines March 2012.
BPH & HIV Meds • Avodart (dutaseride) – Metabolized by CYP3A4, CONTRAINDICATED in Norvir Label • Uroxatral (alfuzosin) – Metabolized by CYP3A4, CONTRAINDICATED with potent CYP3A4 inhibitors CYP3A4 inhibitors • Cardura (doxazosin) – Metabolized by 3A4, drug levels can be increased PIs (esp. ritonavir) • Flomax (tamsulosin) – Metabolized by CYP3A4 and CYP2D6, drug levels can be increased by PIs (esp ritonavir and in poor metabolizers) • Detrol LA (tolteridine) – Not metabolized by 3A4 DHHS Guidelines March 2012.
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Erectile Dysfunction Meds • All are CYP3A4 substrates • Potential for hypotension, cardiac complications and abnormal vision if protease inhibitors used concomitantly • Start with lowest possible doses ® (sildenafil): 25 mg q 48 hours ® – Viagra Vi ( ild fil) 25 48 h • AUC 11‐fold by ritonavir – Cialis® (tadalafil): 10 mg q 72 hours • AUC 125% by ritonavir – Levitra®(vardenafil): 2.5 mg q 72 hours • AUC 49‐fold & 16‐fold by Indinavir/rtv • See DHHS Guidelines for PAH dosing DHHS Guidelines March 2012.
Proton Pump Inhibitors • Proton pump inhibitors such as omeprazole, lansoprazole, esomperazole, etc. • Atazanavir – Do not use if atazanavir unboosted – If ARV experienced, proton pump inhibitors not recommended – If ARV naïve and using atazanavir with ritonavir, can use up to the equivalent of omeprazole 20mg daily
• Rilpivirine, nelfinavir, delavirdine – Proton pump inhibitors not recommended at all – Contraindicated with rilpivirine, also Complera® DHHS Guidelines March 2012.
H2 Blockers • Boosted Atazanavir – H2 blockers simultaneously with and/or 10 hours after the H2 receptor antagonist (H2RA) – Maximum H2RA dose equivalent to famotidine 20mg BID for treatment‐experienced, and 40mg BID for naives • Unboosted atazanavir – Atazanavir given at least 2 hours before and at least 10 hours after the H2RA – Maximum H2RA dose equivalent to famotidine 20mg BID – Only acceptable in treatment naïve patients • Fosamprenavir – Fosamprenavir given at least 2 hours before H2RA
Rifampin and Rifabutin • Rifampin – potent CYP450 inducer, contraindicated with PIs – Efavirenz – can use together, consider 800mg EFV (>60kg) – Raltegravir – increase RAL to 800mg BID – Etravirine, rilpivirine – not recommended • Rifabutin Rifabutin – less potent inducer, but still problematic less potent inducer, but still problematic – All boosted PIs – 150mg every day or TIW • Most studies in healthy volunteers, TDM recommended
– Efavirenz – Rifabutin 450‐600mg daily or 600mg three times weekly if NOT on a boosted PI – Etravirine – if with a boosted PI, not recommended, otherwise, rifabutin 300mg once daily – Rilpivirine – not recommended DHHS Guidelines , March 2012
DHHS Guidelines March 2012.
Cobicistat
HCV Protease Inhibitors
• New booster in QUAD pill, Stribild®, co‐formulated with elvitegravir, cobicistat, tenfovir and emtricitabine • Contraindicated medications almost identical to boosted PI regimens ie Alfluzosin, lovastatin, boosted PI regimens – ie Alfluzosin lovastatin simvastatin, pimozide, ergotamine derivatives, rifampin, St Johns Wort, etc • Review product label prior to using other medications with cobicistat • Anything you would use with caution in the PI class should be used with caution with cobicistat Product Information, Stribild 2012
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Web Resources of Interest
www.hiv‐druginteractions.org
– DHHS Guideline Tables – BEST RESOURCE • http://www.aidsinfo.nih.gov/ • Go Go to Tables 11, 14, 15a‐e, 16a,b to ab es , , 5a e, 6a,b – University of Liverpool • www.hiv‐druginteractions.org – NY/NJ AIDS Education and Training Center • http://www.nynjaetc.org/
www.hiv‐druginteractions.org
NY/NJ AETC – www.nynjaetc.org
Upper Left Corner New data, reports
Top middle – Charts and Recommendations
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