Managing potential drug-drug interactions to achieve success in HCV triple therapy. David Back University of Liverpool

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1 Managing potential drug-drug interactions to achieve success in HCV triple therapy David Back University of Liverpool

2 Understanding the metabolic pathways of DAAs Drug CYP 3A4 P-gp Telaprevir Boceprevir Metabolised by Inhibitor Metabolised by Inhibitor Transported by Inhibitor Transported by Non-CYP metabolism AKR Metabolised by CYP 3A isozymes are The most abundant CYP enzymes in the liver Involved in the metabolism of many drugs P-gp: P-glycoprotein; AKR: aldo-keto reductase Telaprevir EU SmPC; Boceprevir EU SmPC Kassera C, et al. CROI Abstract 118; Garg V, et al. CROI Abstract 629 Hacker MP, et al. Pharmacology: Principles and Practice. Academic Press 2009

3 The effect of introducing another drug when steady state has already been reached Enzyme inhibition Enzyme induction Drug concentration Inhibiting drug Drug concentration Inducing drug Days Days Drug toxicity increases Drug efficacy decreases

4 Clinical case: patient characteristics at initial visit Description 54-year-old male Prior relapser HCV disease characteristics Genotype: HCV G1a Fibrosis stage: F3 Other medical information BMI: 28 kg/m 2 Type 2 diabetes (taking metformin) High cholesterol and cardiovascular risk >20% (taking atorvastatin) Total cholesterol: 1.70 g/l HDL: 0.42 g/l Hypertension (taking propranolol) Suffering from mild depression (receiving behavioural therapy) Using sildenafil for erectile dysfunction Hb level: 12.5 g/dl HDL: high-density lipoprotein

5 Drug-drug interactions: implications for clinical practice Telaprevir: CYP 3A4 substrate and inhibitor, P-gp substrate and inhibitor TVR + PR PR PR weeks weeks PR BOC + PR Boceprevir: CYP 3A4/5 substrate and inhibitor, P-gp substrate, and aldo-keto reductase substrate P-gp: P-glycoprotein; TVR: telaprevir; BOC: boceprevir Telaprevir EU SmPC; Boceprevir EU SmPC

6 Which medications are a concern with telaprevir? Metformin Renal excretion no interaction expected Not anticipated to cause a problem when combined with DAAs Propranolol Metabolised by CYP 2D6 (major) no interaction expected Sildenafil Not recommended Tadalafil for treatment of ED: use with caution at a single dose 10 mg in 72 hours and with increased monitoring for tadalafil AE ED: erectile dysfunction; AE: adverse event

7 Telaprevir increases exposure to statins Telaprevir Recommendation Atorvastatin AUC 788% Contra-indicated Other recommendations: 1,2 Simvastatin Pravastatin Rosuvastatin Contra-indicated (CYP 3A4 substrate) Potential interaction may require close monitoring or change of dosing AUC: area under curve 1. Telaprevir EU SmPC 2.

8 Treatment decision Atorvastatin was temporarily stopped for 12 weeks after consultation with the cardiologist No changes were made to the metformin and propranolol prescriptions For sildenafil: replaced by tadalafil

9 Week 2 visit Patient general status Develops mild rash Hb declines to 9.9 g/dl Depression worsens (becomes moderate)

10 Question How would you manage the patient s mild rash? 1. Systemic prednisone or methylprednisolone 2. Topical corticosteroids and/or systemic antihistamines 3. Discontinuation of telaprevir 4. Do not treat the rash

11 Management of mild rash: which corticosteroid? Systemic corticosteroids Not recommended with telaprevir or boceprevir Prednisone and methylprednisolone are CYP 3A substrates; levels of these steroids may significantly increase leading to further side effects Dexamethasone can act as an enzyme inducer and may lead to reduced DAA levels Topically applied steroids OK to use concomitantly with HCV PIs Not expected to cause significant systemic absorption Cacoub P, et al. J Hepatol 2012;56:455 63

12 Management of mild rash: which antihistamine? Chlorpheniramine Extensive metabolism but poorly characterised Metabolism largely unknown Promethazine OK to use with HCV PIs Desloratadine Metabolism not identified: no effect of enzyme inhibitors Levocetirizine Minimal metabolism

13 Treatment decision In this patient, topical betamethasone was initiated and desloratadine was added

14 Question How would you manage this patient s worsening depression? 1. Fluoxetine 2. Mirtazapine 3. Escitalopram 4. None of the above because of the risk of DDIs DDI: drug-drug interaction

15 Potential DDI with antidepressants Antidepressants metabolised by CYP 3A4 Antidepressants metabolised primarily by non CYP 3A4 Mirtazapine Trazodone Fluoxetine Paroxetine Sertraline Venlafaxine Interaction is likely, caution is advised Interaction is unlikely (but note hepatic impairment)

16 Week 4 8 visits: how is the patient responding? Telaprevir + PR Telaprevir + PR HCV RNA (log 10 IU/mL) RBV 600 mg/day Weeks Patient broke his leg at visit 8 and emergency unit contacts you for advice since the patient informed them about his medication

17 Question The internist intends to administer temporarily midazolam IV and morphine to the patient. What would be your recommendation: A. Interaction with morphine is unlikely B. Morphine exposure may be increased putting the patient at risk for respiratory depression C. Interaction with midazolam IV is unlikely D. Midazolam exposure may be increased and requires appropriate monitoring E. A and D F. B and C

18 Interaction with morphine and midazolam Morphine Based on metabolism and clearance, a clinically significant interaction is unlikely Midazolam IV Midazolam IV exposure is likely to be increased (respiratory depression and/or prolonged sedation risk) Co-administration should be done in a setting ensuring clinical monitoring and appropriate medical management Back home, the patient is prescribed paracetamol Telaprevir EU SmPC

19 Treatment outcome: summary Telaprevir + PR Betamethasone Fluoxetine Desloratadine PR Restart statin Rash disappeared; topical steroid stopped Morphine and midazolam IV Depression symptoms improved SVR12

20 What to consider for transplant patients?

21 Telaprevir increases exposure to immunosuppressants (CYP3A4 & P-gp substrates) Calcineurin Inhbitor Cyclosporine A Tacrolimus C max AUC t 1/2 1.3-fold increase 9.4-fold increase 4.6-fold increase 70-fold increase From hours From hours Significant immunosuppressant dose reductions and prolongation of the dosing intervals will be required Close monitoring of immunosuppressant blood levels, renal function and immunosuppressant related side effects are recommended when co-administered with telaprevir Garg V, et al. Hepatology 2011;54:20 7; Telaprevir EU SmPC

22 Boceprevir increases exposure to immunosuppressants (CYP3A4 & P-gp substrates) Calcineurin Inhbitor Cyclosporine A Tacrolimus C max AUC t 1/2 2-fold increase 10-fold increase 2.6-fold increase 17-fold increase From hours From hours Boceprevir co-administration significantly increased blood concentrations of cyclosporine and tacrolimus Therapeutic drug monitoring is recommended when administering boceprevir with CYP3A4/5 substrates that have a narrow therapeutic window (e.g., tacrolimus, cyclosporine) Individual patients may require additional titration of their immunosuppressant dosage when boceprevir is started or stopped to ensure clinically effective blood levels Hulskotte EGJ, et al. Global Antivir J 2011;7(Suppl. 1):110; Boceprevir EU SmPC

23 Managing a patient on tacrolimus and telaprevir 23 Xavier Forns

24 Changes in immunosuppression during the first 12 weeks of TVR-based therapy Immunosuppression Patients (N) Daily dose at baseline mg ± SD Av daily dose during triple therapy mg ± SD Av daily dose reduction Tacrolimus ± ± (5-33.6) Sirolimus Cyclosporin ± ± (2-3.8) Werner CR Liver Transplantation 2012; 18:

25 A stepwise approach to DDI management Telaprevir/ boceprevir Concomitant drug Actions Telaprevir and boceprevir are strong CYP 3A inhibitors Check if it is a CYP 3A substrate Risk: toxicity Note all co-medications (including prescribed, OTC and herbal products) Consult pharmacist and online resources Telaprevir and boceprevir are CYP 3A substrates Check if it is a CYP 3A inducer/inhibitor Risk: telaprevir/boceprevir efficacy or toxicity Consider temporary interruption of co-medication if significant interaction is anticipated OR seek alternative drug Many interactions can be managed by dose adjustment. However, monitoring is required OTC: over-the-counter Telaprevir EU SmPC; Boceprevir EU SmPC

26 What about drugs of abuse and legal highs?

27 Remember drugs of abuse and 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

28 Other Drugs of Abuse/Legal Highs Slide 28 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

29 Medication use in patients with chronic hepatitis C from a U.S. Commercial Claims Database Time period : N= , of whom were included Mayer CL et al. AASLD 2012; #136

30 Published literature Burger D, et al. Journal of Hepatology 2013 vol. 58 ;

31 Web resources

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