Antiretroviral Drug Interactions

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Antiretroviral Drug Interactions

• Joanne J. Orrick, PharmD, BCPS
• Clinical Assistant Professor
• University of Florida
• Faculty, Florida/Caribbean AIDS Education and
  Training Center
• orricjj_at_ufl.edu
• 352-273-6365

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Disclosure of Financial RelationshipsThis
speaker has the following significant financial
relationships with commercial entities to
disclose

• Boeringher-Ingelheim

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
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Why are HIV/AIDS Patients at Risk?

• Use of 3 and 4 drug antiretroviral regimens
• Multiple agents for treatment/prevention of
  various opportunistic infections
• Patient living longer and being treated for other
  chronic diseases (e.g. diabetes, CAD)
• Many antiretroviral agents have a profound effect
  on the cytochrome P450 enzyme system

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Piscitelli, et al. N Engl J Med, Vol 344 (13)
March 29, 2001
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Types of Drug Interactions

• Pharmacokinetic interaction that alters the
  concentration of active drug in the body
• Absorption
• Distribution
• Metabolism
• Excretion/elimination

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Types of Drug Interactions

• Pharmacodynamic interaction that alters the
  pharmacologic response
• Additive 1 1 2
• Synergistic 11 3
• Antagonistic 1 1 0
• Drugs with overlapping toxicities zidovudine
  with ganciclovir
• Additive/synergistic therapeutic effects
  combination antiretroviral therapy

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Outcomes of Drug InteractionsBeneficial

• Additive desirable pharmacodynamic effects
• Combination antiretroviral therapy
• Use of 2NRTIs PI or NNRTI
• ? potency
• ? resistance
• PK Boosting
• ? bioavailability
• ? pill burden
• Eliminate food restrictions

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Outcomes of Drug Interactions Adverse

• Toxicity
• Torsade de pointes terfenadine, astemizole,
  cisapride
• Rhabdomyolyis HMG-CoA reductase inhibitors
• Hypotension calcium channel blockers, sildenafil
  (Viagra)
• Excessive sedation/respiratory depression
  benzodiazepines
• Drug resistance
• Therapeutic failure

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NRTI Drug Interactions

• Zidovudine
• Agents that cause additive bone marrow
  suppression (i.e. ganciclovir, flucytosine,
  pentamidine)
• Antagonism with stavudine (competition for
  intracellular activation)
• Didanosine (ddI)
• Inhibition of absorption of other agents due to
  ddI buffer in Videx (FQs, tetracyclines,
  dapsone, ketoconazole, indinavir, delavirdine)
• Ribavirin significantly ? ddI levels-do not use
  together

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NRTI Drug Interactions

• Didanosine, Stavudine, Zalcitabine
• Agents causing additive neurotoxicity
  (vincristine, cisplatin, isoniazid)
• Agents causing additive pancreatoxicity (alcohol,
  pentamidine, valproic acid)
• Abacavir
• Metabolized by alcohol dehydrogenase (alcohol can
  increase abacavir levels and toxicity)

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Tenofovir (TDF, Viread) Drug Interactions

• ? ddI levels (Videx and Videx EC)
• ? 60 kg Videx EC? 250 mg with TDF 300 mg qd
  co-administered with/without food
• co-administered with/without food
• ? atazanavir levels
• Boost ATV (300 mg qd RTV 100 mg qd) when given
  with TDF

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Cytochrome P450 (CYP) Enzyme System

• Substrate metabolized by enzyme
• Inhibitor inhibits metabolism of substrate
• Inducer induces metabolism of substrate through
  increased production of enzyme
• Interactions involving induction may be delayed
  since new enzyme must be synthesized
• Some drugs may have properties of all 3
  efavirenz

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Proportion Of Drugs Metabolized by the Major CYP
Enzymes
CYP2C metabolism reflects CYP2C9, CYP2C10,
CYP2C18, and CYP2C19
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NNRTI Drug Interactions

• All NNRTIs are metabolized by the CYP3A4 enzyme
• Delavirdine can inhibit CYP3A4 enzyme
• Nevirapine can induce CYP3A4
• Efavirenz can inhibit or induce CYP3A4 enzyme

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PI Drug Interactions

• All PIs are metabolized all or in part by the
  CYP3A4 enzyme system
• All PIs can inhibit CYP3A4 enzymes
• Ritonavir most potent inhibitor
• Saquinavir least potent inhibitor
• Ritonavir can also induce CYP1A2, CYP 2C9

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Drugs That Should Not Be Given With PIs

• Simvastatin
• Lovastatin
• Astemizole
• Terfenadine
• Cisapride
• Pimozide
• Bepridil

• St. Johns Wort
• Rifampin (except ritonavir)
• Rifapentine
• Midazolam
• Triazolam
• Ergot alkaloids

• Additionally the following should not be given
  with ritonavir amiodarone, flecainide,
  propafenone, quinidine, alfuzosin, voriconazole
• Proton pump inhibitors and Irinotecan should not
  be used with atazanavir

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Inhibitors of Drug Metabolism

• Protease inhibitors
• Delavirdine
• Efavirenz
• Fluconazole
• Itraconazole
• Ketoconazole
• Voriconazole
• Isoniazid
• Ciprofloxacin
• Grapefruit juice

• Clarithromycin
• Erythromycin
• Diltiazem
• Verapamil
• Amiodarone
• Cimetidine
• Omeprazole
• Fluoxetine

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Inducers of Drug Metabolism

• Nevirapine
• Efavirenz
• Ritonavir
• Rifampin
• Rifabutin

• Phenobarbital
• Carbamazepine
• Phenytoin

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Interactions with Lipid Lowering Agents

• Simvastatin and lovastatin are contraindicated
  with PIs or the NNRTI delavirdine
• Pravastatin and fluvastatin least likely to
  interact with ARVs
• Use atorvastatin at low-doses with caution (AUC ?
  71 with NFV, 5-fold with lopinavir/ritonavir)
• Rosuvastatin does not rely on CYP3A4 for
  metabolism-no data with ARVs

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PI Interactions with Statins
Hsyu PH, et al. Abstract 425. 40th ICAAC,
Toronto, Canada. September 2000.
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Interactions with Erectile Dysfunction Agents

• Levels can be significantly increased by PIs and
  delavirdine
• Sildenafil (Viagra) max dose 25 mg in 48 hours
• Vardenafil (Levitra) max dose 2.5 mg in 24
  hours
• Tadalafil (Cialis) max dose 10 mg in 72 hours

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ARV Interactions with Methadone and Recreational
Drugs

• Faragon JJ, Piliero PJ.
• AIDS Reader 200313(9)433-450.

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Methadone Interactions with NRTIs
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Methadone Interactions with NNRTIs

• Opiate withdrawal lacrimation, rhinorrhea,
  diaphoresis, restlessness, insomnia, dilated
  pupils, piloerection
• Opiate toxicity miosis, drowsiness, ? rate and
  depth of respiration, nausea, vomiting,
  constipation, bradycardia, hypotension

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Methadone Interactions with PIs
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Methadone Interactions with PIs
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ARV Interactions with Recreational Drugs
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ARV Interactions with Recreational Drugs
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Rifamycins with PIs and NNRTIs

• Updated Guidelines for the Use of Rifamycins for
  the Treatment of Tuberculosis Among HIV-Infected
  Patients Taking Protease Inhibitors or
  Nonnucleoside Reverse Transcriptase
  Inhibitors-January 20, 2004
• www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm

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Rifamycins with PIs and NNRTIs

• Rifamycins can induce CYP3A4 enzyme and
  significantly ? PI and NNRTI levels
• Rifampin rifapentine rifabutin
• Data has supported the use of rifampin with
  certain ARV combinations
• All single PIs should not be used with rifampin
  (except ritonavir-rarely used as single PI today)
• Rifabutin is also a substrate for CYP3A4 and its
  levels can be affected by PIs and NNRTIs

Rifapentine is a long-acting rifamycin that is
not recommended for use in HIV-infected patients
due to acquired rifamycin resistance
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Co-administration of Rifampin with PIs
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Co-administration of Rifampin with NNRTIs
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Rifabutin Use with PIs
Increase dose of IDV and NFV to 1000 mg q8h
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Rifabutin Use with PIs
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Rifabutin Use with NNRTIs
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Oral Contraceptive Interactionswith NNRTIs and
PIs
Source Table 20 a and 20 b in Guidelines for the
Use of Antiretroviral Agents in HIV-Infected
Adults and Adolescents. MMWR 1998 47(RR-5).
Updated as the Living Document, October 6, 2005
http//www.aidsinfo.nih.gov).
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COC/NNRTI Interactions
EEethinyl estradiaol
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COC/PI Interactions
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COC/PI Interactions
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COC/PI Interactions
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Drug Interaction Resources

• www.hiv-druginteractions.org
• hivinsite.ucsf.edu
• http//hivinsite.ucsf.edu/insite?pagear-00-02
• www.aidsinfo.nih.gov
  (DHHS HIV Treatment Guidelines, TB Guidelines)