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Immune%20Potentiating%20Agents_2011_6pp - Mechanism...

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Unformatted text preview: 10/3/2011 Mechanism Mechanism of Action Immune Potentiating Agents Trinh Pham, PharmD, BCOP Associate Clinical Professor PHRX 4041 Immunology Module Objectives Students should be able to: Granulocyte Granulocyte Colony Stimulating Factors (G-CSF) (GIdentify Identify the indications for the use of G-CSF GIndicate Indicate when to administer and discontinue these agents Recommend Recommend options to treat side effects Plerixafor Plerixafor Know Know the indication for the use of this agent Interferon Interferon Recognize Recognize the difference between acute and chronic side effects Recommend Recommend how to manage side effects Interleukine (ILInterleukine -2 (IL-2) Recognize Recognize the side effects associated with IL-2 ILRecommend Recommend appropriate agents to prevent or treat the side effects Interleukin-2; IL-2 Aldesleukin (Proleukin®) Endogenous Endogenous glycoprotein that is formed and released during helper T-cell activation TEnhances Enhances natural killer cell and cytotoxic lymphocyte antitumor killing (TILs) FDA FDA Approved Indications Metastatic renalMetastatic renal-cell carcinoma- FDA approved 1992 carcinomaAdvanced Advanced metastatic melanoma – FDA approved 1998 Patient Case #1 Mrs. Johnson is about to start Interleukin 2 (IL-2) therapy for her metastatic melanoma at a (ILdose of 720,000 IU/kg every 12 hours for 8 doses PMH: PMH: Hypertension Meds: Meds: Captopril 5 mg every day Orders: Orders: Discontinue Discontinue antihypertensive medication Why is there an order to: Discontinue Discontinue the antihypertensive medication? Obtain Obtain daily weights, ins and outs, blood pressure and O2 saturation status and Scr ? 1 10/3/2011 SIDE EFFECT CAPILLARY LEAK SYNDROME Endothelial cells line the capillary. Fluid and small molecules move from the capillary lumen to the outside via intercellular clefts and intracellular channels Hold Dose • New onset atrial fibrillation (Afib) (Afib) • Supraventricular tachycardia (SVT) • Ventricular arrythmia • Bradycardia • EKG changes consistent with Acute Myocardial Infarction (AMI) • > 4L of by nasal canula for saturation > 95% • 40% O2 mask for saturation > 95% • SCr > 3 mg/dl • Urine < 80 ml/shift or < 10 ml/hr Fishel RS, et al. Critical Care Med 2003; 31(8): Suppl:S502-S511 SIDE EFFECT CAPILLARY LEAK SYNDROME MANIFESTATIONS MANAGEMENT Hypotension - Fluid replacement • Dizziness, fainting 0.9% NaCl, D5W • Fast and irregular heart Lactated Ringers rate Shortness of breath - Pressors • Cough Dopamine 1-5 µg/kg/min or Weight gain Phenylephrine • Edema of feet, neck, 1-5 µg/kg/min hands Decrease renal function After discharge ↓ urine output Furosemide 40 mg qd ↑ serum creatinine ↑ BUN What What is the reason for Mrs. Johnson to receive scheduled acetaminophen and naproxen at the same time? SIDE EFFECT Target Systolic Blood Pressure Normal Blood Pressure for Patient < 100 mmHg 100 – 120 mmHg > 120 mmHg Target Blood Pressure During Therapy > 80 mmHg > 85 mmHg > 90 mmHg MANIFESTATIONS Fever, myalgias, chills, Flu-like rigors increasing fatigue Symptoms • Occurs 2-8 hrs after treatment MANAGEMENT APAP 650 mg PO Q4h & Indomethacin 50 mg PO Q8h Meperidine 12.5 mg IV q8h prn shivering or rigors Buzaid AC, et al. Clinical Cancer Research Sep 2001; 7: 2611-2619 2 10/3/2011 SIDE EFFECT Dermatologic Why shouldn’t a steroid be prescribed to control nausea and vomiting? MANIFESTATIONS • Dry desquamation (palms of hands soles of feet) • Pruritus • Rash MANAGEMENT Moisturizing lotion with camphor/menthol lotion PRN (Sarna®) Diphenhydramine 50 mg q4h prn Hydroxyzine 20 mg q6h prn Why is it necessary to prescribe cefazolin when IL-2 is an immune stimulating agent? IL- SIDE EFFECT GI Side Effects MANIFESTATIONS Nausea/vomiting MANAGEMENT Ondansetron 8 mg IV q12 hrs, prior to each of IL-2 Prochlorperazine 10 mg q4h prn Do not administer steroids Diarrhea GI Irritation BACTERIAL INFECTION Codeine 60 mg PO PRN Diphenoxylate/atropine 2 tabs q3h prn Loperamide 2 mg q3h prn Famotidine 20 mg qd Bacteremia and sepsis Staph Aureus and Staph Epi Gm- bacilli in HIV patients Cefazolin (IV) or cephalexin (PO) OR Clindamycin oral or IV SIDE EFFECT What What other PRN medications should be prescribed to manage other side effects? CENTRAL NERVOUS SYSTEM ELECTROLYTE IMBALANCE MANIFESTATIONS • Difficulty concentrating • Disorientation, • Confusion • Hallucinations • Mood changes • Anxiety • Insomnia • Hypocalcemia • Hypomagnesemia • Hyponatremia MANAGEMENT Haldol 1-5 mg IV every 3 hours Lorazepam 0.5 – 1mg q6h prn Electrolyte supplementation PRN 3 10/3/2011 Indications Granulocyte Colony Stimulating Factors Febrile Neutropenia Prophylaxis after Chemotherapy uses Filgrastim – G-CSF – (Neupogen®) Pegfilgrastim – (Neulasta®) Sargramostim – GM-CSF ( Leukine®) GM- Following High Dose Chemotherapy & Stem Cell Transplant Harvesting of Peripheral Blood Stem Cells X X X Filgrastim Pegfilgrastim X Sargramostim X X X X Indicates more common uses Filgrastim (Neupogen®) (G-CSF) Sargramostim (Leukine®) (GM-CSF) • Stimulates the activation, proliferation and differentiation of neutrophil progenitor cells • Covalent conjugate of filgrastim and monomethoxypolyethylene glycol • Stimulates granulocytes, macrophages, and eosinophils • Enhances the function of mature neutrophils MOA Pegfilgrastim (Neulasta®) • Same MOA as GCSF • E.Coli. derived product Half-Life 3.5 hours Agranulocytosis Agranulocytosis AIDS AIDS – Neutropenia 5-10 mcg/kg/day for 2-4 weeks 2- Myelodysplastic Myelodysplastic Syndrome (GM-CSF also indicated) (GMNeutropenic Neutropenic Disorders – chronic severe, symptomatic • Yeast derived product 33 hours Non - Oncology Indications for Granulocyte Colony Stimulating Factors Congenital Congenital - 6 mcg/kg SC twice daily Idiopathic Idiopathic or cyclic – 5 mcg/kg/day SC 2 hours Case # 2 Mrs. Smith is a 56 year old woman diagnosed with stage III breast cancer. She is scheduled to receive chemotherapy with the AC regimen to be given every 21 days for a total of 4 cycles: Doxorubicin 60 mg/m2 day 1 Cyclophosphamide 600 mg/m2 day 1 This regimen is considered to be at high risk (> 20%) for causing febrile neutropenia. neutropenia. 4 10/3/2011 Duration of Therapy Case # 2 Should Should Mrs. Smith be started on filgrastim or sargramostim? sargramostim? If yes, what is the dose and duration of therapy? After After Chemotherapy or Stem Cell Transplant Continue Continue until ANC is at least 2 to 3 x 103/ml OR OR Total WBC is > 5 x 103/ml For For peripheral Stem Cell Mobilization Until Until enough stem cells have been collected Explain your rationale for choosing filgrastim vs. sargramostim. sargramostim. - Example WBC count prior to leukapheresis 44 x 103/ml - Stem cells (CD34+) collected = 3 x 106/kg Febrile Neutropenia Prophylaxis after Chemotherapy Chemotherapy Intent March 12 March 13 March 14 March 15 Normal WBC (x 103/ mm3) 2.9 2.4 1.4 1 4-10 % Segs Segs --- 49 --- --- 38-71 38- % Bands --- 34 --- --- 0-10 % Neutrophils --- --- 72 --- 38-81 38- % Granulocytes --- --- --- 65 % Lymphocytes 12 --- --- --- 14-46 14- Febrile Neutropenia Potential of Chemotherapy Curative > 20% 10-20 % G_CSF Symptom Management/ Quality of Life G_CSF Consider G_CSF Consider G_CSF % Monocytes 4 --- 10 --- 2-15 % Eosinophils --- --- 3 --- 0-5 No G_CSF ANC (x 103/ mm3) < 10% No G_CSF Filgrastim Dose Myelotoxic Chemotherapy, High Dose Chemotherapy with Autologous Stem Cell Rescue: 5 mcg/kg/day Subcutaneous Peripheral Blood Progenitor Cell (PBPC) Mobilization: 10 mcg/kg/day Subcutaneous 300 µg/0.5 ml syringe ($1,975/10) 300 µg/1ml vial ($2050/10) 480 mcg/0.8 ml syringe ($3295/10) 480 µg/1.6 ml vial ($2995/10) Pegfilgrastim 1.9 x 1.99 x 1x 103/mm3 103/mm3 103/mm3 650 neutroneutrophil cells Sargramostim 6 mg 250 mcg/m2/day Do not administer 14 for all clinical days before and 24 settings hours after chemotherapy 6 mg dose should not be used in infants, children or adolescents less than 45 kg 6 mg/0.6 ml syringe 250 µg/ml vial ($2650) ($729/5) 500 µg/ml vial ($1450/5) Case # 3 Mr. Johnson is a 60 year old man with newly diagnosed with extensive stage small cell lung cancer. He is to be started on the first cycle of the following chemotherapy regimen to be given every 28 days for 4 cycles: Carboplatin Carboplatin AUC of 5 day 1 Etoposide Etoposide 100 mg/m2 IV day 1 through 3 This regimen is considered to be at low risk (<10%) for causing febrile neutropenia. neutropenia. 5 10/3/2011 Case # 3 Case # 3 cont. Should Mr. Johnson be started on filgrastim or sargramostim? sargramostim? If yes, what is the dose and duration of therapy? Should Should Mr. Johnson receive filgrastim with the second cycle of chemotherapy? Case # 3 cont. Mr. Johnson’s team decided not to give him filgrastim with the first cycle of chemotherapy. He is scheduled to receive his 2nd cycle of chemotherapy on day 28, however, the dose had to be delayed because of he experienced febrile neutropenia and his white count has not recovered for the chemotherapy to be administered safely. G-CSF (filgrastim, Neupogen®), Pegfilgrastim (Neulasta®) GM-CSF (sargramostim, Leukine®) Primary Primary Prophylaxis Administration When When the risk of febrile neutropenia (FN) is in the range of 20% 20% or higher Secondary Secondary Prophylaxis Administration Neutropenic Neutropenic complication from a previous cycle of chemotherapy, for which primary CSF prophylaxis was not received Reduced Reduced dose of chemotherapy may compromise diseasedisease-free or overall survival or treatment outcome Case # 3 cont. Should Mr. Johnson be given filgrastim now to bring his white count up prior to administering the chemotherapy? G-CSF (filgrastim, Neupogen®), Pegfilgrastim (Neulasta®) GM-CSF (sargramostim, Leukine®) SIDE SIDE EFFECTS (Most Frequent) Bone Bone pain and myalgias Most Most severe at time of rapid neutrophil recovery, often just precedes actual rise in WBC count Fever Fever Responds Responds well to acetaminophen Mild Mild nausea and headache Bruising, Bruising, generalized rash 6 10/3/2011 G-CSF (filgrastim, Neupogen®), Pegfilgrastim (Neulasta®) GM-CSF (sargramostim, Leukine®) SIDE SIDE EFFECTS (Less Frequent) Spleen Spleen pain or splenomegaly Resolves Resolves with cessation of growth-factor therapy growthInjection Injection site erythema, swelling, pain Alternating Alternating sites, application of ice to site usually helps Stem Cells = CD 34+ Cells http://www.mozobil.com/patients/why_mozobil.asp Monitoring and Counseling Monitor Monitor patient’s WBC on a daily basis Instruct Instruct patients about the side effects of CSF - flu-like syndrome, malaise, fever, and bone pain fluIf If necessary, pre-medicate with acetaminophen on a predaily basis for fever or bone pain. Discontinue Discontinue CSF after WBC is > 5,000/mm3 or ANC is above 2 to 3 x103/mm3 Instruct Instruct patient in appropriate self-injection technique selfif SC route is chosen Instruct Instruct patient to notify health care provider if any erythema, erythema, pain, or edema occurs at injection site Stem Cell Mobilization Process Process where stem cells are stimulated to move from the bone marrow into the blood stream for autologous stem cell transplant or allogeneic stem cell transplant Need Need to collect a minimum number of stem cells (CD 34+) for the transplant process to be effective 2 x 106 cells/kg to 10 5 x 106 cells/kg http://www.mozobil.com/patients/why_mozobil.asp Plerixafor (Mozobil®) Approved Approved by the FDA to be used with G-CSF Gto mobilize hematopoietic stem cells into the stem peripheral blood for collection for subsequent autologous autologous stem cell transplantation NonNon-Hodgkin’s Lymphoma Multiple Multiple Myeloma CXCR4: chemokine receptor found on stem cells SDF-1 (Stromal Derived Factor 1): ligand for CXCR4 http://www.mozobil.com/patients/why_mozobil.asp 7 10/3/2011 Stem Cell Transplant Process Mozobil: blocks the SDF-1 ligand from binding to CXCR4 http://www.mozobil.com/patients/why_mozobil.asp http://www.mozobil.com/patients/why_mozobil.asp Interferon Pegylated interferon Fold increase in circulating CD34+ cell count 24 hours after GCSF/Plerixafor http://www.mozobil.com/patients/why_mozobil.asp 8 10/3/2011 MECHANISM MECHANISM OF ACTION Glycoproteins Glycoproteins that help regulate the immune system Has Has antiviral, anticancer, antimicrobial, and immunomodulation effects Two Two Types (I and II) and Three Classes (α, β, γ) TYPE TYPE I IFN IFN α Produced Produced by macrophages and lymphocytes Two Two commercially available IFN-α products (IFN-α 2a and IFN-α 2b) IFN(IFNIFNEach Each is prepared from cultures of genetically modified E.Coli using E.Coli recombinant DNA technology IFN IFN β Produced Produced by fibroblast and epithelial cells Interferon Interferon β -1B (rIFN-B) is produced by recombinant technology (rIFNHas Has antiviral and immune regulatory properties TYPE TYPE II IFN IFN γ Produced Produced by T-Lymphocytes and alveolar macrophages THas Has phagocyte activating effects and can increase antibody-dependent antibodycellular cytotoxicity (ADCC), and natural killer (NK) cell activity, which are important for fighting viruses and cancer. Case #4 Mr. Lewis is a 56 year old male diagnosed with cutaneous T- cell Lymphoma and the decision is made to start him on interferon therapy. therapy. Interferon alfa 2a 3 MIU daily Acute Adverse Effects Flu-like syndrome FluFever, Fever, chills, malaise, myalgias, headache, and slight tachycardia Dose Dose related fatigue (20 MU or higher doses) Most Most patients will experience fatigue after several doses of the drug Prophylaxis Prophylaxis with acetaminophen to prevent symptoms Indomethacin Indomethacin at 25 mg PO three times a day should be tried if acetaminophen is not effective Management of Acute Adverse Effects Flu-like symptoms are dose related, predictable, Fluand occur after initial dosing lasting 4 to 8 hours Tolerance fluTolerance to flu-like symptoms develop but can be lost if therapy is interrupted and reinitiated. Symptoms may be more severe subsequent times Bedtime Bedtime administration allows patient to sleep through symptoms If If symptoms persist despite interventions, a 333350% dose reduction is warranted Case # 4 (Cont.) What side effects will Mr. Lewis not develop tolerance to? What side effects will Mr. Lewis develop tolerance to? What can be done to prevent this side effect from occurring? 9 10/3/2011 Chronic Adverse Effects (AEs) Fatigue, Fatigue, weakness Especially Especially in elderly or patients with poor performance status Lack Lack of motivation, mental lethargy Anorexia, weight loss (40-70% of patients) (40- What is a relative contraindication (medical diagnosis) to starting interferon? Depression Depression (mild to severe, 4-30% of patients) 4Suicide Suicide reports noted Psychiatry Psychiatry consult Management Management of AEs Encourage Encourage patient to plan rest periods Include Include strategies for light exercise program Chronic Adverse Effects Hypothyroidism Hypothyroidism (20% of patients) Monitor Monitor thyroid function if fatigue is persistent Transaminase Transaminase elevations Check Check liver function monthly Mild Mild myelosuppression Leukopenia Leukopenia & thrombocytopenia Monitor Monitor patient’s CBC weekly initially Peripheral Peripheral neuropathies, dizziness, confusion, somnolence (up to 30% of patients) What is the recommendation if Mr. Lewis’ liver enzymes are three times above the upper limit of normal? For all chronic AEs: • Debilitating chronic symptoms warrant discontinuation for 1-2 weeks • Then re-initiate at 33-50% dose reduction Pegylated Interferon Alfa-2b Longer Longer duration of action than alfa-2b (Intron A®) alfa- (I Administered Administered once weekly Same Same side effects as short acting interferon Most Most common: Fatigue, elevations in liver enzymes, fever Common: Common: Headache, anorexia, myalgia, nausea, chills myalgia, Depression Depression (59% vs 25% in placebo) Cardiovascular: arrythmia, Cardiovascular: arrythmia, cardiovascular decompensation Other: Other: retinopathy, severe hepatic injury, thyroid dysfunction, diabetes mellitus Pegylated Interferon Alfa-2b (PegIntron®, Sylatron®) Sylatron®: Approved Approved for adjuvant treatment of malignant melanoma after surgery Initial Initial dose of 6 mcg/kg/week for 8 weeks then 3 mcg/kg/week for up to 5 years Administer Administer APAP 500 – 1000 mg 30 minutes before first dose and as needed for subsequent dose Cost Cost of 6 mcg/kg for 70 kg patient is $1,336.64 PegIntron®: Approved for chronic hepatitis C 10 10/3/2011 Summary G-CSF, pegfilgrastim, GM-CSF GMAppropriate Appropriate indications Appropriate Appropriate dose Appropriate Appropriate time to initiate dose Management Management of side effects When When to discontinue Summary Interferon Interferon Acute Acute vs. Chronic Side Effects Tolerance Tolerance to side effects Management Management of side effects InterleukinInterleukin-2 Side Side effects Monitoring Monitoring parameters Management Management of side effects DrugDrug-drug interactions 11 ...
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