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.