Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine
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Transcript of Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine
Edited byMorris Sherman MD BCh PhD FRCP(C)
Associate Professor of MedicineUniversity of Toronto
Protease Inhibitors in Chronic Hepatitis C:An Update
Chapter 2 – Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and HIV Coinfection
November 2012
Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and
HIV Coinfection
Alice Tseng, Pharm.D., FCSHP, AAHIVP
Toronto General HospitalUniversity of Toronto
Outline
Review principles of drug interactions
Understand how the pharmacology of DAAs contribute to drug interactions
Highlight important HCV drug interactions
Outline a strategy for identifying and managing drug interactions
Identify pertinent HCV drug interaction resources
Drug Interactions
Pharmacodynamic Change in pharmacological effect of a drug Additive, synergistic, or antagonistic activity or toxicity
e.g., ribavirin + AZT = anemia Pharmacokinetic
Change in the amount of drug(s) in body Absorption, distribution, metabolism, elimination may
be affected Often involves CYP450 system or transporters
Interactions Affecting Drug Metabolism
Majority of drugs transformed to inactive forms prior to elimination through Phase I (oxidation) or Phase II (conjugation) reactions
Phase I primarily involves cytochrome P450 system
Superfamily of microsomal heme-containing enzymes
Primarily located in liver, small bowel; also kidney, lung, brain CYP3A is the most abundantly expressed isoenzyme, is involved in
the metabolism of ~50% of clinically used drugs others: CYP2D6, 2C9, 2B6, 1A2, etc.
P-glycoprotein Efflux membrane transporter which prevents drug accumulation in
cells; has broad substrate specificity, and inhibiting or inducing the activity of this protein can lead to significant alterations in drug exposure
Terms
Definition Interaction Impact Common Examples
Substrate Agent which is primarily cleared via a certain enzymatic pathway
Rate of drug breakdown is affected by presence of enzyme inhibitors or enzyme inducers
antidepressants, azoles, benzodiazepines, statins, corticosteroids, calcium channel blockers, macrolides, rifamycins, HIV PIs & NNRTIs
Inhibitor Agent which competes with another drug for binding at enzymatic site
Decreased clearance of substrate drug; quick onset & resolution of interaction effect
macrolides, azoles, HIV protease inhibitors
Inducer Drug that stimulates the production of additional metabolic enzymes
Increased clearance of substrate drug; slower onset and resolution of interaction effect
anticonvulsants, rifamycins, HIV NNRTIs, St. John’s wort
Boceprevir and Telaprevir Pharmacology
= +++ potential for interactions with other drugs can be clinically significant sometimes unpredictable
Boceprevir Telaprevir
Dosing 800 mg q8h with food 750 mg q8h with food (20 g fat)
Substrate CYP3A4, P-gp, AKR CYP3A4, Pgp
Inhibitor 3A4, P-gp 3A4, P-gp, renal transporters (?)
Inducer No inducing effects in vitro (in vivo?)
Potential Consequences of DAA Drug Interactions
Interactions may occur in a two-way manner: Concentrations of DAA may be altered by other
drug(s) Concentrations of concomitant drug(s) may be
altered by DAA
Potential consequences include: Increased risk of toxicity Decreased efficacy
Statin Interactions
Most statins are P450 substrates
DAAs can significantly increase statin levels: Atorvastatin: 130% with
boceprevir,7.88-fold with telaprevir
Pravastatin: 60% with boceprevir
risk of toxicity, including myopathy and rhabdomyolysis
Boceprevir Telaprevir
Lovastatin, Simvastatin CONTRAINDICATED
AtorvastatinMay need to
atorvastatin dose; do not exceed
>20 mg/d
CONTRA-INDICATED
PravastatinStart with
recommended dose and monitor
for toxicity.
Possible in statin; use with
caution.
Rosuvastatin, Fluvastatin Possible in statin; use with caution.
[Victrelis & Incivek Product Monographs, 2011. FDA HIV/AIDS Drug Safety Communication, March 1, 2012]
Atorvastatin 40 mg + boceprevir: Atorvastatin AUC 130% and
Cmax 170% vs. atorvastatin alone
Suggest atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin
Atorvastatin 20 mg + telaprevir: Atorvastatin AUC 7.88-fold
Combination is contraindicated
Atorvastatin Interactions with Boceprevir and Telaprevir
Hulskotte EGJ et al. HEP DART 2011,Koloa, Hawaii, poster 122
Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74
0.010 10 20 30 40 50
0.10
1.00
10.0
100
Nominal time (hrs)
Con
cent
ratio
n (n
g/m
L)
With telaprevir
25,000
30,000
20,000
15,000
10,000
5,000
00 8 16 24 32 40 48
Time (hrs)
Ato
rvas
tatin
con
cent
ratio
n (p
g/m
L)
Atorvastatin aloneAtorvastatin + Boceprevir
Without telaprevir
Effect of Steady-State Telaprevir on the Pharmacokinetics of Amlodipine 5 mg
Calcium channel blockers (CCBs)
Amlodipine, diltiazem, felodipine, nifedipine, nicardapine, verapamil are CYP3A4 substrates
Concentrations may be by boceprevir or telaprevir
Use with caution, clinical monitoring
Consider dose reduction
Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74
Amlodipine AUC 179% Monitor for dose-related toxicity
0.010 250
Nominal time (hrs)
Con
cent
ratio
n (n
g/m
L)
With telaprevir
Without telaprevir
20015010050
0.05
0.50
5.00
Antihypertensive MedicationsClass Examples Potential DAA
Interactions
ACEI Enalapril, lisinopril, ramipril (renal) Not expected
ARBs Losartan (2C9>>3A4 to active metabolite) Candesartan, irbesartan (2C9)Eprosartan, olmesartan, telmisartan, valsartan (biliary)
Possible effectLowNot expected
Beta-blockers
Propranolol (2D6, 3A4, 2C19), carvedilol (2D6, 2C9> 1A2, 2E1, 3A4)Acebutolol, labetalol, metoprolol, pindolol (2D6)Atenolol, nadolol (renal)
Possible
LowNot expected
Calcium channel blockers
Amlodipine, diltiazem, felodipine, nifedipine, verapamil (3A4) Risk of CCB exposures; use with caution
Diuretics Hydrochlorothiazide, furosemide, spironolactone (renal)Indapamide (2C9, 2D6, 3A4)
Not expectedPossible
Treatment of Depression in HCVPlace in Therapy
Examples (route of metabolism) Potential DAA Interactions
First Line Escitalopram, citalopram (2C19, 3A4>>2D6) 35% with TVR, no interaction with BOC
Second Line Paroxetine, fluoxetine (2D6), bupropion (2B6)Sertraline (2B6>2C9/19, 3A4, 2D6), venlafaxine (2D6>3A4), desvenlafaxine (UGT>>3A4), mirtazapine (2D6, 1A3, 3A4)
LowPossible
Third Line Nortriptyline (2D6)Imipramine (2D6, 1A2, 2C19, 3A>UGT)
LowPossible
No Evidence Modafinil (3A4; induces 3A4)Amantadine (not metabolized)
Possible ; DAANot expected
Avoid Duloxetine (1A2, 2D6) - CONTRAINDICATED Additive risk of hepatotoxicity
Methadone Interactions
Methadone is metabolized by CYP2B6, CYP2C19 & CYP3A,85% protein bound; R-isomer is biologically active enantiomer
Boceprevir interaction: In the presence of steady-state boceprevir, R-methadone AUC 16%,
Cmax 10%; no clinical effects noted including opioid withdrawal Boceprevir exposures not affected by methadone
Telaprevir interaction: In the presence of steady-state telaprevir, R-methadone Cmin 31%,
Cmax 21% and AUC 21%, but median unbound Cmin ofR-methadone was similar before and during telaprevir coadministration and no withdrawal symptoms were noted
A priori methadone dose adjustments are not required when initiating DAA therapy, but close monitoring is recommended, with methadone dose adjustments if necessary
Hulskotte et al. 2012, Van Heeswijk et al. 2011.
Hormonal Contraceptives with DAAs
Hormonal contraceptives may not be as effective in women taking boceprevir or telaprevir
Boceprevir (Victrelis): 99% AUC drospirenone, 24% AUC EE Use 2 alternate effective methods of contraception
during treatment with BOC and Peg IFN/RBV Drospirenone (Yaz®, Yasmin®, Angelique®) is
contraindicated Telaprevir (Incivek):
28% AUC, 33% Cmin of EE Use 2 additional non-hormonal methods of effective
birth control during TVR dosing and for 2 months after the last intake of TVR.
Benzodiazepine Interactions
Majority are substrates of CYP3A4 Risk for prolonged/excessive sedation
Oral midazolam & triazolam are contraindicated with boceprevir and telaprevir
IV midazolam: consider dose, close monitoring for respiratory depression or prolonged sedation
Other benzodiazepines: dose and monitor Consider using benzodiazepines that are
glucuronidated: Lorazepam, oxazepam, temazepam
Inhaled Corticosteroids
Corticosteroids are CYP3A4 substrates Potential for corticosteroid concentrations resulting in
significantly reduced serum cortisol concentrations Inhaled/nasal fluticasone, budesonide:
Avoid co-administration with HCV PIs if possible, particularly for extended durations.
May wish to use corticosteroid associated with less adrenal suppression (e.g., beclomethasone, ciclesonide)
Use lowest possible dose, consider non-steroidal options
Victrelis & Incivek. Product Monographs, 2011
PDE5 Inhibitors (sildenafil, tadalafil, vardenafil)
PDE5 inhibitors are substrates of CYP3A4 Potential for DAAs to concentrations Dose-related side effects (headache, vasodilation,
dyspepsia, visual disturbances) Contraindicated with DAAs if using for PAH For erectile dysfunction, use a lower dose with DAAs:
Sildenafil: 25 mg q48h, tadalafil: 10 mg q72h Do not use vardenafil
Interactions Between HCV & HIV Medications
Challenges in treating HIV/HCV co-infected patients Additive toxicities:
Anemia: ribavirin, zidovudine, DAAs CNS: interferon, efavirenz
Potential for negative 2-way interactions concentrations of HIV agents concentrations of HCV DAAs
Antiretroviral Treatment Options for Patients on Boceprevir or Telaprevir
Boceprevir Telaprevir
Protease Inhibitors (PIs) Avoid with ritonavir-boosted protease inhibitors
Avoid ritonavir-boosted darunavir, fosamprenavir and
lopinavir
Atazanavir/ritonavir OK
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Avoid efavirenz Dose with efavirenz
Etravirine (?) Etravirine OK
No data Rilpivirine OK
Integrase Inhibitor Raltegravir OK
Maraviroc No data potential / maraviroc; potential benefit on fibrosis?
Nucleoside Reverse Transcriptase Inhibitors
Tenofovir OK
Avoid AZT (anemia)
Managing Drug Interactions:1) Medication Reconciliation
Ensure medication records are up to date at each visit Prescription, OTC, vitamins/herbals, recreational
drugs, inhalers, topical, prn agents Confirm doses, prn drugs Include all agents that have been started or stopped
Patient education: Encourage patients to ask before taking any new
prescription/non-prescription drug or supplement Communication with other HCP!
Managing Drug Interactions: 2) Identify Potential Interactions
Use a systematic approach to identify combinations of potential concern
Apply knowledge of known PK characteristics Overlapping CYP pathways, substrate, inducer,
inhibitor High index of suspicion with key classes of drugs
Utilize current drug information resources: Product monographs, CPS, literature Conference abstracts, specialized HCV drug
interaction websites
Drugs Contraindicated with Boceprevir and Telaprevir (1)
1-adrenoreceptor antagonist
Alfuzosin Hypotension, cardiac arrhythmia
Antiarrhythmics Quinidine, propafenone, amiodarone.Flecainide (TVR)
serious/life-threatening cardiac arrhythmia
Antimycobacterials Rifampin Loss of virologic response
Ergot derivatives Acute ergot toxicity
Herbal product St. John’s wort Loss of virologic response
Statins Lovastatin, simvastatin.Atorvastatin (TVR)
Myopathy including rhabdomyolysis
Neuroleptic Pimozide Serious/life-threatening cardiac arrhythmia
Victrelis & Incivek. Product Monographs, 2011
Drugs Contraindicated with Boceprevir and Telaprevir (2)
PDE-5 inhibitor Sildenafil.tadalafil (BOC); vardenafil (TVR)
Visual abnormalities, hypotension, prolonged erection, syncope
Sedatives/ hypnotics Oral midazolam, triazolam Increased sedation or respiratory depression
Other Cisapride, astemizole, terfenadine
Serious/life-threatening cardiac arrhythmia
Anticonvulsants(BOC)
Carbamazepine, phenytoin, phenobarbital
Loss of virologic response
OC (BOC) Drospirenone Hyperkalemia
Aldosterone antagonist (TVR)
Eplerenone Hyperkalemia
Triptans (TVR) Eletriptan Coronary artery vasospasm, MI, vent. tachycardia, VF
Victrelis & Incivek. Product Monographs, 2011
Managing Drug Interactions:Therapeutic Options
Determine clinical significance
Evaluate therapeutic options: Alter drug dose/dosing frequency Substitute with alternate agent Can any drugs be permanently or temporarily
discontinued while on DAA treatment? Consider patient convenience and cost factors
Patient counselling & close monitoring is critical
Summary
High potential for pharmacokinetic interactions between directly acting antivirals and other drug classes
Consequences may include therapeutic failure and increased toxicity
Often, interactions can be managed, but heightened level of awareness is needed
Use a systematic approach to identify and manage individual drug regimens
Importance of a specialized, inter-disciplinary team including pharmacy
General Hansten PD. Science Med 1998;16-25. Kashuba ADM, Bertino JS Jr. Drug Interactions in Infectious Diseases,
2nd edition, c. 2005, pp:13-39. Metheny CJ et al. Pharmacotherapy 2001;21:778-96.
Interactions in HCV and HIV: Kiser J et al. Hepatology 2012;55:1620-8. Tseng & Foisy. Curr Infect Dis Rep 2012;14:67-82.
Internet Toronto General Hospital Immunodeficiency Clinic; www.hivclinic.ca Liverpool Pharmacology Group; www.hep-druginteractions.org www.hcvdruginfo.ca
Additional Resources
The Canadian Liver Foundation (CLF) was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease,
raise funds for research and provide support to individuals affected by liver disease.
For more information visit www.liver.ca or call 1-800-563-5483.
This project made possible through the financial support of Merck Canada Inc. The views, information and opinions contained herein are those of the authors and do not necessarily reflect the views and opinions of Merck Canada Inc.
The Canadian Liver Foundation gratefully acknowledges the participating health care professionals for their contributions to this project and for their commitment to the liver health of Canadians.