Pharmacist Objectives. Pathophysiology. Pathophysiology 9/4/2014. At the conclusion of this program, the pharmacist will be able to:

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1 Speaker Disclosure Amanda Stahnke, PharmD, BCACP declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. Amanda Stahnke, PharmD, BCACP University of Missouri-Kansas City School of Pharmacy Kansas City Veterans Affairs Honor Annex Milena McLaughlin, PharmD, MSc, BCPS, AAHIVP Midwestern University, Chicago College of Pharmacy Northwestern Memorial Hospital Milena McLaughlin, PharmD, MSc, BCPS, AAHIVP declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. Pharmacist Objectives At the conclusion of this program, the pharmacist will be able to: o Describe the pathophysiology of Multiple Sclerosis and Hepatitis Amanda Stahnke, PharmD, BCACP o Discuss the different treatment options for Multiple Sclerosis and Hepatitis C o Recommend appropriate pharmacologic and nonpharmacologic treatment for Multiple Sclerosis and Hepatitis C Pathophysiology o MS is a autoimmune, neurodegenerative disorder characterized by inflammation, demeylination, and axonal damage Pathophysiology o Basics: o Autoreactive T and B-cells cross the BBB and lead to production of proinflammatory cytokines, reactive oxygen species, and myelin-specific antibodies within the CNS Cudrici C, et al. J Rehabil Res Dev 2006, 43(1):

2 Diagnosis o Diagnosis of exclusion o Physical and history o Neuro and cognitive exam o MRI o Enhancing and nonenhancing lesions o Lumbar puncture o Oligoclonal bands o McDonald Criteria o Presentation o Variable o Based on where lesions occurs o Paresthesias o Visual changes, optic neuritis o Gait issues/falls o Fatigue o Weakness o Impaired coordination o Cognitive changes Disease Courses (old) o Relapsing remitting MS (RRMS) o Secondary progressive MS (SPMS) o Primary progressive MS (PPMS) o Progressive relapsing MS (PRMS) Disease Phenotypes (new) o Define course o Clinically isolated syndrome (CIS) o RRMS o SPMS o PRMS o *PRMS removed o Define modifiers o Assessment of activity o Not active o Active (CIS-active = RRMS; PPMS-active = PRMS) o Assessment of progression o Not progressing o Progressing o Ex: RRMS-active and progressing Lublin FD, et al. Neurology. 2014;83:1-9. Expanded Disability Status Scale(EDSS) 10.0 = Death due to MS = Completely dependent = Confined to bed/chair; self-care with help = Confined to wheelchair = Walking assistance is needed = Increasing limitation in ability to walk = Impairment is relatively severe = Impairment is mild to moderate = Impairment is minimal = No impairment 0 = Normal neurologic exam Kurtzke JF, et al. Neurology. 1983;33: MS Case o DF is a 25 yo WF referred to your neurology clinic after experiencing two episodes of painful blurry vision and fatigue (three months ago and last week). An MRI completed last week reveals enhancing and non-enhancing lesions suggestive of MS. Question #1 Which is(are) a key pathophysiological feature(s) of MS? A. Production of proinflammatory cytokines B. Activation of T and B-cells C. Production of myelin-specific antibodies D. All of the above 2

3 Question #2 Which is most likely DF s disease course (phenotype)? A. RRMS, active and progressing B. SPMS, active and progressing C. PPMS, active and progressing D. PRMS, active and progressing Treatment o Non-pharmacologic interventions- Vital!! o National/local MS societies, support groups o Healthy lifestyle: physical activity, healthy diet, smoking cessation o Education regarding: o Disease state o Triggers o Cost of therapy/assistance programs o Rationale for treatment o Acute exacerbation treatment o Disease modifying therapies (DMTs) o Symptom management Disease Modifying Therapies o Interferons (INF) o β-1a (Avonex, 1996; Rebif, 2002) o Peginterferon approved 2014 o β-1b (Betaseron, Extavia ; 1993) o Glatiramer acetate (Copaxone, 1996) o 40mg three times weekly approved 2014 o Mitoxantrone (Novantrone, 2002) o Limited role, last line agent o Natalizumab (Tysabri, 2004) o Fingolimod (Gilenya, 2010) o Teriflunomide (Abagio, 2012) o Dimethyl fumarate (Tecfidera, 2013) Avonex [package insert]. Cambridge, MA: Biogen Idec; Rebif [package insert]. Rockland, MA: EMD Serono; 2009 Betaseron [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals; 2010 Extavia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2009 Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; 2009 Novantrone [package insert]. Rockland, MD: EMD Serono; 2010 Tyasbri [package insert]. Cambridge, MA: Biogen Idec; 2010 Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2012 Aubagio [package insert]. Cambridge, MA: Genzyme Corporation; 2012 Tecfidera [package insert]. Cambridge, MA: Biogen Idec; 2013 Natalizumab o MOA: o Binds α4 integrin subunit on lymphocytes, blocking interaction with VCAM-1, leading to decreased lymphocyte entry into CNS o Dosing: o 300mg IV over 1 hour q4weeks Cudrici C, et al. J Rehabil Res Dev 2006, 43(1): Natalizumab o Efficacy: o ARR Natalizumab o BBW: o Progressive multifocal leukoencephalopathy (PML) 53% o Decreased disability progression o Decreased MRI-related findings ARR = Annualized Relapse Rate, NTZ = Natalizumab, RRR = Relative risk reduction Polman CH, et al. N Engl J Med. 2006;354(9): Rudick RA, et al. N Engl J Med. 2006;354(9): Butzkueven H, et al. J Neurol Neurosurg Psychiatry. 2014;0:1-8. o TOUCH program 3

4 Natalizumab o Side effects: o Hepatotoxicity o Infection o Pain in the extremities/joint pain/abdominal pain o Fatigue o Depression o Diarrhea/Nausea o Pregnancy: o Category C o Monitoring: o PML, Anti-JCV antibodies (baseline, then q3-6mo), LFTs and bilirubin baseline and periodically o Monitor for 1 hr post infusion (hypersensitivity) o Antibodies? Fingolimod o MOA: o Active metabolite: fingolimod-phosphate o Sphingosine-1 phosphate receptor modulator o Blocks lymphocyte egress from lymph nodes o Other locations of receptors: o Heart, Lungs, Eyes, CNS (Possible neuroprotective/reparative properties) o Dosing: o 0.5mg PO daily Fingolimod o Efficacy: o ARR 38% 52% o Decreased disability progression o Decreased MRI-related findings ARR = Annual relapse rate, RRR = Relative risk reduction 54% 60% Cohen JA, N Engl J Med. 2010;362(5): Kappos L, N Engl J Med. 2010;362(5): Fingolimod o Contraindications: o MI, unstable angina, stroke, TIA, decompensated HF w/in the last 6 months, or Class III/IV HF o AV block or sick sinus syndrome, unless pacemaker o Baseline QTc interval 500ms o Treatment with Class Ia or Class III antiarrhythmic drugs o Side effects: o Infection o Edema o Diarrhea o Liver transaminase elevations o Macular edema o Respiratory effects o Bradycardia and AV block Fingolimod o Pregnancy: o May have teratogenic effects, registry o Contraception method during and 2 months post therapy o Drug interactions: o Ketoconazole o QTc prolongation o AV block/bradycardia o Live vaccines- avoid during and 2 months post o No exposure to varicella virus/antibodies administer varicella vaccine prior initiating therapy Fingolimod o Monitoring: o 1 st dose o Observe for ~6 hours o Hourly HR and BP o ECG prior to dosing and at the end of observation period o Continuous ECG- symptomatic bradycardia o Continuous ECG and overnight- symptomatic bradycardia requiring intervention (repeat 1 st dose monitoring), high risk for bradycardia/av block/comorbid conditions; prolonged QTc/concomitant medications that increase risk o CBC, LFTs and bilirubin 6 months prior to starting therapy o Eye exam at baseline and 3-4 months post initiation 4

5 Teriflunomide o MOA: o Not fully understood o Active metabolite of leflunomide (rheumatoid arthritis) o Pyrimidine synthesis inhibitor decreased activation of lymphocytes Teriflunomide o Efficacy: o ARR 31% 32% 22% 36% o Dosing: o 7 or 14mg PO daily o Delays progression of disability (14mg) o Decreased MRI-related findings 22 ARR = Annual relapse rate, RRR = Relative risk reduction O Connor P, et al. N Engl J Med. 2011:362(14); Confavreux C, et al. Lancet Neurol. 2014:13; Teriflunomide o Contraindications: o Severe hepatic impairment o Pregnancy o Elimination protocol: o Pregnancy, suspected liver injury, women of childbearing age upon therapy discontinuation o Side effects: o Paresthesias o Infection o Alopecia o ALT increase/hepatotoxicity o Nausea/Diarrhea o Hypertension Teriflunomide o Drug interactions: o Efflux pump substrate, inhibitor o CYP2C8 inhibitor o CYP1A2 weak inducer o R-warfarin- may decrease INR o Monitoring: o TB test prior to initiation o CBC, LFTs, and bilirubin 6 months prior to starting therapy; ALT monthly for first 6 months o Pregnancy o BP Dimethyl fumarate o MOA: not fully understood o Prodrug monomethyl fumarate o Activates nuclear factor (erythyroid-derived 2)-like 2 (Nrf2) pathway Dimethyl fumarate o Efficacy: o ARR o Dosing: o Initial: 120mg PO BID x 1 week o Maintenance: 240mg PO BID o Protect capsules from light; discard after 90 days 45% 24% 50% 31% o Delays progression of disability o Decreased MRI-related findings ARR = Annual relapse rate, RRR = Relative risk reduction 53% 47% Fox RJ, et al. N Engl J Med. 2012:367(12); Gold R, et al. N Engl J Med. 2012:367(12);

6 Dimethyl fumarate o Side effects: o Flushing o GI upset- abdominal pain, nausea, diarrhea o Lymphopenia o Monitoring: o CBC 6 months prior to starting therapy, then yearly Selecting a DMT o Disease phenotype o Patient factors o Age o Gender o Socioeconomic status/insurance o Preference o Provider approach o Risk vs. benefit MS Case cont o DF is willing to start a DMT at this time. She does not have a route preference, but indicates her and her husband are planning to start a family in a few years. She is overweight and smokes 1ppd. Question #3 Which DMT is contraindicated in pregnancy and should probably be avoided in this patient? A. Dimethyl fumarate B. Glatiramer Acetate C. Teriflunomide D. Interferon beta-1a Question #4 Which is(are) a non-pharmacologic treatment(s) that may benefit DF? A. Smoking cessation B. Healthy diet and physical activity C. Attending support groups D. All of the above Therapies in the pipeline o Alemtuzumab o Laquinimod o Daclizumab o Ocrelizumab 6

7 HCV Epidemiology in the US Milena McLaughlin, PharmD, MSc, BCPS, AAHIVP HCV - Background HCV is a small positive-strand RNA virus with 6 different genotypes Genotype 1 most common in the U.S HCV lacks a latent form and requires constant replication for its survival in the host Seroconversion occurs in 8-9 weeks 97% of exposures are detectable within 6 months Patient can be cured HCV - Life Cycle Chung RT and Baumert TF. N Engl J Med 2014; 370: Lindenbach BD and Rice CM. Nature 436, (18 August 2005). % People Infected HCV Natural History Acute HCV Infection 85% progression Chronic HCV Infection 15% Spontaneous Resolution 20% progression Compensated Cirrhosis 25% progression HCC, Transplantation and Death years for monoinfected; as little as 5 yrs for HCV/HIV coinfected HCV - Diagnosis HCV antibody HCV viral load Hepatic synthetic function and any markers of liver injury (serum ALT/AST, albumin, tbili, dbili, PT) CBC and BMP HCV Genotype Pregnancy test (ribavirin) Staging with biopsy or non-invasive method < 1 year Kohli A et al. JAMA. 2014;312(6); TIME 7

8 HCV Case CH is a 43 y/o male referred to your clinic for HCV treatment. He was diagnosed 5 years ago and is ready to start treatment now because he heard about all oral options from a friend. His PMH includes severe depression and hyperlipidemia. BMI 30 kg/m 2 HCV Genotype 1 HCV Viral load ~2 million Question #1 What characteristic of the Hepatitis C virus allows it to be eradicated from the liver? A. It does not incorporate into the nucleus B. It is a RNA virus C. It is a short virus D. It is contained in the liver Treatment - Important Definitions Responder Relapser: Undetectable viral load at end of treatment, viral load becomes detectable within 24 weeks after stopping treatment Partial Responder: HCV viral load decrease by at least 99% by week 12 of treatment but does not achieve an undetectable viral load at the end of treatment Null Responder: Viral load does not decrease by 99% by week 12 Sustained Viralogic Response (SVR): lack of detection of virus in blood; considered a virologic cure Rapid Virologic Response (RVR): HCV RNA less than 10 IU/mL at 4 weeks Probability of SVR (%) McHutchison J et al. N Eng J Med. 1998; 339 (18): Ponyard T et al. Lancet. 1998; 352: Manns M et al. Lancet. 2001; 358: Carrat F et al. JAMA Dec 15;292(23): Lawitz E et al. N Engl J Med. 2013b;368(20): Poordad F et al. Digestive Disease Week. May 18-21, 2013, 2013; Orlando, FL. Sulkowski M. Lancet Infect Dis Jul;13(7): Martel-Laferriere et al. HIV Med Feb;15(2): Rodriguez-Torres M et al. 53rd ICAAC Sept 10-13, 2013, 2013; Denver, CO. Sulkowski MS et al. AASLD Annual Meeting Nov 1-5, 2013, 2013c; Washington, DC. Sulkowski MS et al. Ann Intern Med. 2013d;159(2):86-96 Non-pharmacologic Management Vaccinate against Hepatitis A and Hepatitis B Abstain from alcohol use Known risk factor for disease progression and severity Weight loss if obese Avoid any potentially hepatotoxic agents Education on avoiding transmission PEG-Interferon/Ribavirin Previous standard of care = 48 weeks Genotypes 1, 4, 5 & 6 ~48% of people with genotype 1 will clear the virus Rapidly phasing out as a treatment option (and adjunctive therapy) Severe side effects Long duration of treatment Development of direct acting antiviral treatments Side effects Flu-like symptoms, nausea, insomnia, depression and low blood cell counts Manns MP et al. Lancet. 2011;358;

9 Direct Acting Antivirals (DAAs) Virus requires the function of non-structural proteins (NS) NS3/4 and NS5 to replicate Blocked by DAAs Adding a protease inhibitor to the pegylated interferon alpha and ribavirin treatment enhanced SVR rates from 45% to 75% in patients with HCV genotype 1 infection SVR rates now > 90% Drug Therapy Targets/Mechanism of Action Nucleoside and nucleotide NS5B polymerase inhibitors NS3/4A Protease Inhibitors NS3 Protease Inhibitors Nucleotide analog is substituted for the correct nucleotide and prevents the virus from replicating Prevent viral cleavage by binding to the protease enzyme so it can t cut long strands of the virus Inhibits the HCV NS3A protease NS5A Protease Inhibitors Inhibits the HCV NS5A protease Chung RT and Baumert TF. N Engl J Med 2014; 370: Kohli A et al. JAMA. 2014;312(6); Boceprevir (Victrelis ) NS3/4A Protease Inhibitor Treatment of genotype 1 infection in combination with peginterferon alfa and ribavirin Adult dosing: 800 mg orally 3 times a day (peginterferon alfa and ribavirin should be initiated 4 weeks before starting boceprevir) ADRs: alopecia, dry skin, diarrhea, loss of appetite, nausea, altered taste, arthralgia, insomnia, irritability, fatigue, shivering DDIs: Strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5 Victrelis (boceprevir). [Package Insert]. Whitehouse Station, NJ. Merck; Boceprevir (Victrelis ) Study Population Treatment Groups SVR Rates SPRINT 2 Genotype 1, Treatment Naïve RESPOND 2 Genotype 1, Treatment experienced Poordad F et al. N Engl J Med Mar 31;364(13): Bacon BR et al. N Engl J Med Mar 31;364(13): Peg IFN + RBV for % weeks+ Boceprevir 68% +Peg IFN + RBV for 40% 24 weeks or Boceprevir + Peg IFN + RBV for 44 weeks or Peg IFN + RBV Peg IFN + RBV for 4 59% weeks+ Boceprevir 21% +Peg IFN + RBV for 66% 32 weeks + Peg IFN or Boceprevir +Peg IFN + RBV for 44 weeks or Boceprevir + Peg IFN + RBV for 44 weeks Telaprevir NS3/4A Protease Inhibitor To be removed from the market 10/14/14 Issues with Telaprevir and Boceprevir Still require the use of PEG-interferonand ribavirin Complex regimens with many treatment limiting side effects Long length of treatment possible (~48 weeks) SVR rates low at 70% Significant drug-drug interactions No longer preferred therapy per current guidelines 9

10 Simeprevir (Olysio ) NS3/4A Protease Inhibitor Treatment of genotype 1 infection in combination with peginterferon alfa and ribavirin Adult dosing: 150 mg orally daily for 12 weeks Continued treatment with peginterferon alfa and ribavirin are based on clinical response ADRs: Pruritus/rash, photosensitivity, nausea, hyperbilirubinemia DDIs: Substrate/inhibitor CYP3A4, multiple DDIs Simeprevir (Olysio ) Presence of virus with NS3 Q80K polymorphism significantly reduces efficacy of simeprevir, therefore alternative treatments should be considered. Counseling points Use sunscreen and avoid tanning beds due to potential for photosensitivity Take with food to enhance absorption and avoid nausea Take a missed dose as soon as possible, but if next dose is in less than 12 hours, skip the missed dose Olysio (simeprevir). [Package Insert]. Titusville, NJ. Janssen Therapeutics; Olysio (simeprevir). [Package Insert]. Titusville, NJ. Janssen Therapeutics; Simeprevir (Olysio ) Study Population Treatment Group QUEST 1 Genotype 1, treatment naïve QUEST 2 Genotype 1, treatment naïve Jacobson IM et al. Lancet Aug 2;384(9941): Manns M et al. Lancet Aug 2;384(9941): Simperevir for 12 weeks+ Peg IFN + RBV for 24 or 36 weeks or Peg IFN + RBV Simperevir for 12 weeks+ Peg IFN + RBV for 24 or 36 weeks or Peg IFN + RBV 80% 50% 81% 50% SVR Rates Sofosbuvir (Sovaldi ) Nucleotide Analog NS5B Polymerase Inhibitor First oral interferon free regimen to be approved! Efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection Adult dosing: 400mg once daily with ribavirin/pegylated interferon for weeks Dependent on patient specific factors Sovaldi (sofosbuvir). [Package Insert]. Foster City, CA. Gilead; Sofosbuvir (Sovaldi ) ADRs: headache, insomnia, fatigue, neutropenia, hyerbillirubinemia, depression, diarrhea, anemia DDIs: Do not use with drugs that are potent intestinal P-gp inducers as it significantly decreases sofosbuvir plasma concentrations and may lead to reduced therapeutic effect Sofosbuvir (Sovaldi ) Study Population Treatment Groups SVR Rates NEUTRINO Genotype 1, 4, 5, 6 treatment naïve FISSION Genotype 2, 3 treatment naïve POSITRON Genotype 2, 3, IFN intolerant, ineligible or unwilling FUSION Genotype 2, 3 treatment experienced Sofosbuvir + RBV + 90% (295/327) Peg IFN for 12 weeks Sofosbuvir + RBV for 12 weeks or Peg IFN + RBV for 12 weeks Sofosbuvir + RBV for 12 weeks or Placebo for 12 weeks Sofosbuvir + RBV for 12 weeks or Sofosbuvir + RBV for 16 weeks 67% (107/253) and 67% (162/243) 78% (161/207) and 0% (0/71) 50% (50/100) 73% (69/95) Sovaldi (sofosbuvir). [Package Insert]. Foster City, CA. Gilead; Lawitz E et al. N Engl J Med 2013; 368: Jacobson IM et al. N Engl J Med May 16;368(20):

11 COSMOS Sim/Sof Monitoring BMP, CBC, LFTs at 2 weeks then monthly HCV Viral Load at 2 weeks then monthly then 12 weeks after completion of therapy HIV Viral Load if co-infected HCC screening every 6 months if indicated Interferon/ribavirin therapy: pregnancy testing, TSH, depression screening Lawitz E et al. Lancet. Published online July 28, Question #2 As a known risk factor for disease progression, which of the following nonpharmacological strategies should be recommended to CH? A. Avoid alcohol use B. Hepatitis A/B vaccination C. Herbal remedies D. Weight loss Question #3 CH meets treatment criteria and is eager to start therapy. Due to his depression, you decided that CH requires an interferon free regimen. Which of the following regimens should be recommended for CH? A. Interferon-free regimen not available B. Simeprevir plus ribavirin C. Simeprevir plus sofosbuvir D. Sofosbuvir plus ribavirin HCV Guidelines Recommended treatment Naïve Non-responder HIV/HCV co-infected When/Whom to treat Continuously updated Prior Authorizations Documentation of interferon ineligibility if applicable Contact health plan for forms Criteria for treatment Required lab work Procedure for follow-up with patient and physician Empiric changes in maintenance medications necessary? 11

12 Drugs in the Pipeline Study Population Treatment Groups SVR Rates HALLMARK Genotype 1b, Asunaprevir + Daclatasvir for 6 Naïve: 90% treatment naïve and intolerant or unresponsive months Intolerant/unresponsive: 82% GS US Genotype 1, treatment naïve and treatment experienced Ledipasvir 90mg + Sofosbuvir 400mg for 12 weeks or Ledipasvir 90mg + Sofosbuvir 400mg + RBV for 12 weeks Naïve: 100% Experienced: 100% Naïve: 96% Experienced: 100% PEARL II (3 direct acting antiviral regimen) Genotype 1b, treatment experienced ABT 450/ritonavir +ABT % ABT 333 for 12 weeks or 97% ABT 450/ritonavir +ABT ABT 333 with RBV for 12 weeks * ABT 267: NS5A inhibitor, ABT 333: non nucleoside polymerase inhibitor Manns MP and von Hahn T. Nature Reviews Drug Discovery Volume: 12, Pages: Year published: (2013). Manns MP et al. Lancet Published online July 28, Gilead Sciences. Press release. June 15, Ferenci P et al. N Engl J Med 2014; 370: Parting thoughts Possibility of re-infection Diagnosed at late stage Challenges for eradication Cost of medications Amanda Stahnke, PharmD, BCACP University of Missouri-Kansas City School of Pharmacy Kansas City Veterans Affairs Honor Annex stahnkea@umkc.edu Milena McLaughlin, PharmD, MSc, BCPS, AAHIVP Midwestern University, Chicago College of Pharmacy Northwestern Memorial Hospital mmclau@midwestern.edu 12