Clinical Case Discussion of Drug-Drug Interactions: Minefield or Molehill? David Back

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1 Clinical Case Discussion of Drug-Drug Interactions: Minefield or Molehill? David Back University of Liverpool UK David Back University of Liverpool Rome December 2012

2 Clinical case: patient characteristics at time of treatment Description 54-year-old male Smoker and no alcohol abuse Treatment naïve HCV disease characteristics Genotype: HCV G1a Fibrosis stage: F3 Other medical information BMI: 28 Type 2 diabetes (taking metformin) High cholesterol and cardiovascular risk >20% (taking atorvastatin) Total: 1.70 g/l HDL: 0.42 g/l Suffering from mild depression (receiving behavioural therapy) Hb level: 14 g/dl BMI: body mass index; Hb: haemoglobin; HCV: hepatitis C virus; HDL: high-density lipoprotein

3 Treatment options Telaprevir + PR PR Stop at Week 24 if undetectable at Week 4 and 12 PR if detectable at Week 4 or 12* Patient initiated treatment with a telaprevir regimen PR lead-in BOC + PR Stop treatment at Week 28 if undetectable at Week 8 and 24 If detectable at Week 8 but undetectable at Week 24 BOC + PR* PR* Weeks BOC: boceprevir; PR: peginterferon + ribavirin *PR must be continued up to Week 48 in patients with cirrhosis, prior partial and null responders and in treatment-naïve patients or prior relapsers without cirrhosis not achieving undetectable HCV RNA at Week 4 and 12 (but with HCV RNA <1000 IU/mL at these timepoints) **In patients receiving 32 weeks of BOC, PR alone must be continued up to Week 48 Telaprevir EU SmPC; Boceprevir EU SmPC

4 Question Why are telaprevir and boceprevir predisposed to drug interactions? A: High concentrations accumulate in the liver B: They inhibit the enzyme CYP3A4 C: They induce the enzyme CYP3A4 D: They are chemically similar to many other drugs taken by patients treated for Hep C. CYP: cytochrome

5 Question Why are telaprevir and boceprevir predisposed to drug interactions? A: High concentrations accumulate in the liver B: They inhibit the enzyme CYP3A4 C: They induce the enzyme CYP3A4 D: They are chemically similar to many other drugs taken by patients treated for Hep C. CYP: cytochrome

6 Telaprevir and Boceprevir are metabolised by and strongly inhibit CYP3A4 Slide 6 CYP 3A4 is the most abundant CYP isozyme in the liver CYP 3A4 involved in the metabolism of many drugs CYP 1A2 CYP 2A6 CYP 2B6 CYP 2C8 CYP 2C9 CYP 2C8 CYP 2B6 CYP 2C9 CYP 2A6 CYP 1A2 CYP 2C19 CYP 2D6 CYP 3A4 CYP 2C19 CYP 2D6 CYP 3A4 CYP 2E1 CYP 2E1 Proportion of total CYP enzymes present in human liver Proportion of drugs that are substrates for major CYP enzymes Boceprevir also metabolised by Aldo-Keto Reductase (AKR) CYP: cytochrome P450 Hacker MP, et al. Pharmacology: Principles and All percentages are approximate. For illustrative purposes, Practice. Academic Press 2009 hepatic CYP enzymes present at <5% are all represented as 3.3%

7 Telaprevir and Boceprevir interfere with the way the body handles other drugs Small Intestines Liver Influx DRUG CYPs, UGTs DRUG Efflux CYPs Efflux Influx Efflux Adapted from Bailey DG, et al. Br J Clin Pharmacol. 1998:46:101 10

8 Toxicity HCV med Comed Reduced Efficacy

9 Drug Conc. Key Mechanisms of Drug Interactions: Alteration of steady state of a drug Reasons for increase? Interacting Drug Days Back D Unpublished

10 Key Mechanisms of Drug Interactions: Alteration of steady state of a drug Reasons for decrease? Drug Conc. Interacting Drug Days Back D Unpublished

11 DDI management: a stepwise approach Be vigilant for DDIs when starting PI-based therapy Check all patient s concomitant drugs (prescribed/otc) and herbal/legal/illegal products Consult the SmPCs or Prescribing Information Consult on-line resources and a pharmacist or a pharmacologist to seek guidance DDI: drug-drug interaction; OTC: over-the-counter; PI: protease inhibitor; SmPC: summary of product characteristics

12 DDIs: patient s medications Telaprevir PR Atorvastatin Metformin

13 Question Which of the patient s medications are you concerned could interact with telaprevir? A: PR B: Atorvastatin C: Metformin D: Atorvastatin and metformin

14 Question Which of the patient s medications are you concerned could interact with telaprevir? A: PR B: Atorvastatin C: Metformin D: Atorvastatin and metformin

15 Telaprevir and Lipid Lowering Agents Drug Atorvastatin Lovastatin Simvastatin Pravastatin Rosuvastatin Fluvastatin Pitavastatin (US) Major Clearance Pathway CYP3A4, OATP1B1 CYP3A4 CYP3A4 OATP1B1/3 CYP2C9 (minor); OATP1B1 CYPs(Multiple); OATP1B1/ 2B1 CYP2C9 (minor) UGT1A3; OATP1A2/1B3 Effect of TVR D Gemfibrozil Enzymes unknown D = Data from study Contraindication or Caution when co-administering statins with CYP3A4 mediated metabolism but can you avoid using a statin during DAA treatment? From or individual SPCs

16 Telaprevir and lipid lowering agents Atorvastatin was temporarily stopped for 12 weeks after consultation with the cardiologist

17 Week 2 8 visits: results HCV RNA (log 10 IU/mL) HCV RNA levels Telaprevir + PR Patient health Patient develops an upper respiratory tract infection (deemed unrelated to treatment) He develops mild rash His depression worsens (becomes moderate) Weeks

18 Management of the patient s upper respiratory tract infection Clarithromycin CYP 3A inhibitor & substrate Concern about increase in telaprevir exposure Also concern of increase in CLA this may warrant ECG monitoring due to the possible risk of QT prolongation Azithromycin Not a CYP 3A inhibitor or substrate Drug interactions unlikely A 5-day course of azithromycin was chosen due its reduced likelihood of interactions ECG: electrocardiogram

19 Question How would you manage the patient s mild rash? A: Systemic prednisone or methylprednisolone B: Topical corticosteroids or systemic antihistamines C: Discontinuation of telaprevir D: Do not treat the rash

20 Question How would you manage the patient s mild rash? A: Systemic prednisone or methylprednisolone B: Topical corticosteroids or systemic antihistamines C: Discontinuation of telaprevir D: Do not treat the rash

21 Management of mild rash: which corticosteroid? Systemic corticosteroids Not recommended with telaprevir and boceprevir Prednisone and methylprednisolone are CYP3A substrates; levels may significantly increase and lead to side effects Topically applied steroids OK to use concomitantly with HCV PIs Although not expected to cause significant systemic absorption be watchful In this patient, a topically applied corticosteroid was initiated Cacoub P, et al. J Hepatol 2012;56:

22 Corticosteroid metabolism and formulations Drug Oral Inhaled Topical Eye/ear drops Budesonide CYP3A4 Dexamethasone CYP3A4 Fludrocortisone CYP3A4 Fluticasone CYP3A4 Hydrocortisone CYP3A4 Prednisolone CYP3A4 Beclomethasone Esterase to active met Triamcinolone CYP3A4 Mometasone CYP3A4 Injection Rectal Created from SmPCs for all included drugs. Available at:

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24 Management of mild rash: which antihistamine? Chlorpheniramine Extensive metabolism but poorly characterized Metabolism largely unknown Promethazine OK to use with HCV PIs Desloratidine Metabolism not identified: no effect of enzyme inhibitors Levocetirizine Minimal metabolism In this patient, desloratadine was initiated

25 Management of the patient s worsening depression: which antidepressant? A: Because of DDI would not be confident to give any antidepressant B: Escitalopram C: Paroxetine D: Trazodone

26 Management of the patient s worsening depression: which antidepressant? A: Because of DDI would not be confident to give any antidepressant B: Escitalopram C: Paroxetine D: Trazodone

27 Management of the patient s worsening depression: which antidepressant Only data available - escitalopram (CYP 2C19 substrate) Effect on telaprevir Effect on comedication Comedication Escitalopram (SSRI antidepressant) AUC C min AUC C min 7% 9% 35% 42% Escitalopram AUC reduction of 21% also observed with BOC Mechanism: not clearly determined; clinical relevance? However, escitalopram has a wide therapeutic index In this case, a higher escitalopram dose (15 mg) was initiated Escitalopram: 10 mg qd C min : minimum plasma concentration; SSRI: serotonin-specific reuptake inhibitor Telaprevir EU SmPC; Hulskotte EGJ, et al. Global Antivir J 2011;7(Suppl. 1):108 van Heeswijk R, et al. IWCPHT Abstract 12

28 Other antidepressants that have not been studied with telaprevir Antidepressants metabolized by CYP 3A4 Antidepressants metabolized primarily by non CYP 3A4 Trazodone Mirtazapine Paroxetine Fluoxetine Sertraline Venlafaxine Interaction is likely, caution is advised Interaction is unlikely

29 Treatment outcome Telaprevir + PR PR HCV RNA (log 10 IU/mL) Azithryomycin stopped (infection cleared) Atorvastatin restarted Rash disappeared; antihistamine and topical steroid stopped Depression symptoms improved. Escitalopram stopped SVR Weeks SVR: sustained virologic response

30 Summary: DDI management with HCV PI a stepwise approach Telaprevir/ Boceprevir Telaprevir and Boceprevir show marked inhibition of CYP 3A Telaprevir and Boceprevir are metabolised by CYP 3A Concomitant drug Check if it is a CYP 3A substrate Risk: toxicity Check if it is a CYP 3A inducer/inhibitor Risk: telaprevir/boceprevir efficacy or toxicity Actions Note ALL co-medications Consult specialist pharmacist and on-line resources Consider temporary interruption of co-med if interaction is anticipated OR seek alternative drug Many interactions can be managed by dose adjustment. However, monitoring is required Telaprevir EU SmPC; Boceprevir EU SmPC

31 Summary: DDI management with HCV PI some caveats Relatively few DDI studies are actually performed and therefore the potential for a DDI is based on metabolic profile and expert opinion. Drug interaction studies performed with the DAAs have been predominantly performed in healthy volunteers and the magnitude of an interaction may be different in some patients. Telaprevir EU SmPC; Boceprevir EU SmPC

32 Physiological changes (versus healthy volunteers) Parameter HIV-infected HCV-infected Albumin 1,2 * 3 4 α1-acid glycoprotein 5 6 Gastric ph 7 8 Cytochrome P450 Cytokines HIV/HCV co-infected * Decreased albumin associated more with cirrhosis and significant liver damage Significantly lower than HIV or HCV mono-infected patients 1 Mehta SH, et al. AIDS Res Human Retrovir 2006;22:14 21; 2 Graham SM, et al. AIDS Res Human Retrovir 2007;23: Nagao Y & Sata M. Virology Journal 2010;7:375; 4 Monga HK, et al. Clin Infect Dis 2001;33:240 7 ; 5 Boffito M, et al. Drug Metab Dispos 2002;30:859 60; 6 Ozeki T, et al. Br J Exp Path 1988;69: Welage LS, et al. Clin Infect Dis 1995;21: ; 8 Nam YJ, et al. Korean J Hepatol 2004;10:216 22

33 Summary: DDI management with HCV PI some caveats Remember that some patients may be on other drugs ie herbals, drugs of abuse or legal highs! Heroin, dihydrocodeine, oxycodone Cannabis and synthetic cannabinoids Cocaine, crack cocaine Amphetamine, ecstasy, methamphetamine, GHB and GBL LSD, ketamine, phencyclidine, Mephedrone, BZP (piperazines), MDPV, 2 DPMP, benzo fury Butane, nitrites Anabolic steroids

34 Other Drugs of Abuse/Legal Highs Slide 34 Drug Major Clearance Pathway Effect of DAA Dihydrocodeine CYP2D6, CYP3A4, UGT Likely to increase Oxycodone CYP2D6, CYP3A4 Likely to increase Cannabis CYP2C9, CYP2C19, CYP3A4 Likely to increase Cocaine Non-CYP; CYP3A4 minor Unlikely to increase Amphetamine Not well worked out; CYP2C Not sure Ketamine CYP3A4, CYP2B6, CYP2C9 Likely to increase Mephedrone Not well worked out. Not sure

35 Web resources List of CYP substrates, inhibitors, inducers Drug interactions HIV co-infection Hepatitis co-infection

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37 Drug-Drug Interactions: Minefield but with the correct tools and resources it is possible to see a way through safely. David Back University of Liverpool UK