Protease Inhibitors in Chronic Hepatitis C: An Update

Chapter 2 – Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and HIV Coinfection

Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto November 2012

Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and HIV Coinfection

Alice Tseng, Pharm.D., FCSHP, AAHIVP Toronto General Hospital University 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

Substrate Definition Interaction Impact Common Examples 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 Inducer 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 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

Dosing Substrate Inhibitor Inducer Boceprevir 800 mg q8h with food Telaprevir 750 mg q8h with food (20 g fat) CYP3A4, P-gp, AKR CYP3A4, Pgp 3A4, P-gp 3A4, P-gp, renal transporters (?) No inducing effects in vitro (in vivo?)

= +++ potential for interactions with other drugs

  can be clinically significant sometimes unpredictable

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%  boceprevir with  risk of toxicity, including myopathy and rhabdomyolysis Boceprevir Telaprevir

Lovastatin, Simvastatin

CONTRAINDICATED

Atorvastatin Pravastatin

May need to  atorvastatin dose; do not exceed >20 mg/d Start with recommended dose and monitor for toxicity.

CONTRA INDICATED Possible  statin; use with caution.

in

Rosuvastatin, Fluvastatin

Possible  in statin; use with caution.

[Victrelis & Incivek Product Monographs, 2011. FDA HIV/AIDS Drug Safety Communication, March 1, 2012]

Atorvastatin Interactions with Boceprevir and Telaprevir

 Atorvastatin 40 mg + boceprevir:  Atorvastatin AUC  Cmax  170%

vs.

130% and atorvastatin alone 30,000  Atorvastatin 20 mg + telaprevir:  Atorvastatin AUC  7.88-fold 100 25,000 20,000 15,000 10,000 Atorvastatin alone Atorvastatin + Boceprevir 10.0

1.00

With telaprevir Without telaprevir 0.10

5,000  0 0 8 16 24 32 40 Time (hrs) Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin 48 0.01

 0 10 20 30 Nominal time (hrs) 40 Combination is contraindicated 50 Hulskotte EGJ et al. HEP DART 2011, Koloa, Hawaii, poster 122 Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74

Effect of Steady-State Telaprevir on the Pharmacokinetics of Amlodipine 5 mg

5.00

0.50

0.05

0.01

With telaprevir Without telaprevir

Calcium channel blockers (CCBs)

  Amlodipine, diltiazem, felodipine, nifedipine, nicardapine, verapamil are CYP3A4 substrates Concentrations may be  boceprevir or telaprevir by  Use with caution, clinical monitoring  Consider dose reduction 0 50 100 150 200 250 Nominal time (hrs)   Amlodipine AUC  179% Monitor for dose-related toxicity Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74

Antihypertensive Medications

Class ACEI ARBs Beta blockers Calcium channel blockers Examples Enalapril, lisinopril, ramipril (renal) Losartan (2C9>>3A4 to active metabolite) Candesartan, irbesartan (2C9) Eprosartan, olmesartan, telmisartan, valsartan (biliary) Propranolol (2D6, 3A4, 2C19), carvedilol (2D6, 2C9> 1A2, 2E1, 3A4) Acebutolol, labetalol, metoprolol, pindolol (2D6) Atenolol, nadolol (renal) Potential DAA Interactions Not expected Possible  effect Low Not expected Possible  Low Not expected Amlodipine, diltiazem, felodipine, nifedipine, verapamil (3A4) Risk of  CCB exposures; use with caution Diuretics Hydrochlorothiazide, furosemide, spironolactone (renal) Indapamide (2C9, 2D6, 3A4) Not expected Possible 

Treatment of Depression in HCV

Place in Therapy First Line Second Line Third Line No Evidence Avoid Examples (route of metabolism) Escitalopram, citalopram (2C19, 3A4>>2D6) Potential DAA Interactions 35%  with TVR, no interaction with BOC Paroxetine, fluoxetine (2D6), bupropion (2B6) Sertraline (2B6>2C9/19, 3A4, 2D6), venlafaxine (2D6>3A4), desvenlafaxine (UGT>>3A4), mirtazapine (2D6, 1A3, 3A4) Nortriptyline (2D6) Imipramine (2D6, 1A2, 2C19, 3A>UGT) Low Possible  Low Possible  Modafinil (3A4; induces 3A4) Amantadine (not metabolized) Duloxetine (1A2, 2D6) - CONTRAINDICATED Possible  ;  DAA Not expected 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  Cmax  10%; no clinical effects noted including opioid withdrawal 16%,  Boceprevir exposures not affected by methadone 

Telaprevir interaction:

 In the presence of steady-state telaprevir, R-methadone Cmin  Cmax  21% and AUC  21%, but median unbound Cmin of 31%, R-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%  Use 2 alternate effective methods of contraception during treatment with BOC and Peg IFN  /RBV Drospirenone (Yaz ® , Yasmin ® , Angelique ® ) is contraindicated AUC EE 

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 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Integrase Inhibitor Maraviroc Avoid efavirenz Etravirine (?) No data Atazanavir/ritonavir OK Dose  with efavirenz Etravirine OK Rilpivirine OK Raltegravir OK Nucleoside Reverse Transcriptase Inhibitors

potential



/

 No data

maraviroc; potential benefit on fibrosis?

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 Antiarrhythmics Antimycobacterials Ergot derivatives Herbal product Statins Neuroleptic Alfuzosin Hypotension, cardiac arrhythmia Quinidine, propafenone, amiodarone.

Flecainide (TVR) Rifampin serious/life-threatening cardiac arrhythmia Loss of virologic response St. John ’s wort Lovastatin, simvastatin.

Atorvastatin (TVR) Pimozide Acute ergot toxicity Loss of virologic response Myopathy including rhabdomyolysis Serious/life-threatening cardiac arrhythmia Victrelis & Incivek. Product Monographs, 2011

Drugs Contraindicated with Boceprevir and Telaprevir (2)

PDE-5 inhibitor Sedatives/ hypnotics Other Anticonvulsants (BOC) OC (BOC) Aldosterone antagonist (TVR) Triptans (TVR) Sildenafil.

tadalafil (BOC); vardenafil (TVR) Oral midazolam, triazolam Visual abnormalities, hypotension, prolonged erection, syncope Cisapride, astemizole, terfenadine Increased sedation or respiratory depression Serious/life-threatening cardiac arrhythmia Carbamazepine, phenytoin, phenobarbital Loss of virologic response Drospirenone Eplerenone Hyperkalemia Hyperkalemia 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

Additional Resources

 General  Hansten PD. Science Med 1998;16-25.

 Kashuba ADM, Bertino JS Jr. Drug Interactions in Infectious Diseases, 2 nd 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.hcvdruginfo.ca

www.hep-druginteractions.org

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.

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.