Drug Interactions with HIV and Psychiatric Medications

2/5/2014

Drug Interactions with HIV and Psychiatric Medications

John J Faragon, PharmD, BCPS, AAHIV-P Regional Pharmacy Director, NY/NJ AETC Pharmacist, Albany Medical Center

Guidelines

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2/5/2014

DHHS: Changing Criteria for Initiating ART

CD4+ Count, cells/mm3

> 500

350-500

200-350 < 200 or symptomatic disease

1998

2001

2006

2008

2009

2012/ 2013

Offer if VL > 20,000 Offer if VL > 20,000 Offer if VL > 20,000

Offer if VL

> 55,000 Consider if

VL > 55,000 Offer, but controversy

exists

Consider if VL

100,000 Consider if

VL 100,000 Offer after discussion with patient

Consider in certain groups

Consider in certain groups

Treat

Consider Treat Treat

Treat Treat Treat

Treat

Treat

Treat

Treat

Treat Treat

Initial Regimens: Preferred

NNRTI based

Atripla (Efavirenz + tenofovir + emtricitabine)

PI based

Reyataz + Norvir + Truvada (Atazanavir + ritonavir + tenofovir/emtricitabine)

Prezista + Norvir + Truvada (Darunavir + ritonavir + tenofovir/emtricitabine)

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Atripla Reyataz/Norvir/Truvada

Prezista/Norvir/Truvada

1/day 3/day 3/day

Initial Regimens: Preferred

II based

Isentress + Truvada (Raltegravir + tenofovir/emtricitabine

Tivicay + Truvada or Epzicom (Dolutegravir + tenofovir/emtricitabine OR abacavir/lamivudine

Stribild (Elvitegravir/cobicistat/tenofovir/ emtricitabine)

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Isentress (BID)/Truvada

Tivicay/Truvada OR Epzicom OR

Stribild

3/day 2/day 1/day

Basics of Drug Elimination Pharmacokinetic Interactions

Most common type of interactions in HIV

Absorption ? reduced atazanavir absorption when combined with proton pump inhibitors

Distribution ? protein binding displacement 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

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CYP450 Metabolism for FDA Approved Medications

CYP1A2 CYP2C

CYP2D6

CYP2E1 CYP3A4

Key points ?Majority of drugs metabolized by CYP3A4 & CYP2D6 ?CYP3A4 involved with HIV PI/NNRTI/cobicistat, also HCV PI metabolism ?Enzymes can be induced or inhibited

Adapted from Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed.

2/5/2014

CYP450 Induction

Drug Levels

Steady State Levels

Inducing drug added

Key Points

Time

?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

?Example - Adding efavirenz to a methadone or to a PI

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Select CYP3A4 Inducers

Carbamazepine Efavirenz Fosphenytion Nevirapine St. John's Wort

Oxcarbazepine Phenobarbital Phenytoin Rifabutin Rifampin

2/5/2014

CYP450 Inhibition

Drug Levels

Steady State Levels

Inhibiting drug added

Key Points

Time

?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 or Stribild to simvastatin

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Common CYP3A4 Inhibitors

Clarithromycin Cobicistat Delavirdine Erythromycin Fluconazole

Grapefruit Juice HCV Protease

Inhibitors HIV Protease

Inhibitors Itraconzaole Ritonavir

2/5/2014

Results of CYP450 inhibition Select Toxicities

Drug Alfluzosin Budesonide Colchicine Ergotamine derivatives Fluticasone Midazolam (oral), triazolam Quinidine Sildenafil (and related drugs) Statins (simvastatin, lovastatin)

Potential Toxicity Severe hypotension Cushing's syndrome Fever, diarrhea, paresthesias Ischemia, cyanosis, hypertension Cushing's Syndrome CNS Depression Cardiac arrhythmias Syncope, hypotension Rhabdomyolysis

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Contraindicated Medications

with Protease Inhibitors, Cobicistat

Class

Specific Medications

Cardiac Medications

Flecainide, propafenone, amiodarone, quinidine

Lipid Lowering Medications

Lovastatin, simvastatin

Antimycobacterial Medications

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

Boosters ? RTV, COBI

Ritonavir

We know it, most major interactions worked out

Anything in a new drug label that mentions strong CYP3A4 inhibitors, think or ritonavir

Examples include ketoconazole, erythromycin, etc

Also inhibits PGP, CYP2D6, OAT transporters

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