Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University 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
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Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine
Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University 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. - PowerPoint PPT Presentation
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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)
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
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
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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.