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Cystic Fibrosis Erin McDade, Pharm.D., BCPS Clinical Pharmacy Specialist Pediatric Pulmonary Service Texas Children’s Hospital Objectives Describe the pathophysiology and clinical symptoms of cystic fibrosis (CF) Describe differences in pharmacokinetics between CF and non-CF children List the medications involved in the treatment of CF Understand the antimicrobials and unique dosing strategies used for the treatment of acute pulmonary exacerbations Page 1 Page 1 xxx00.#####.ppt 5/23/2017 5:51:19 AM Cystic Fibrosis •A chronic, progressive congenital metabolic disorder •Inherited as a recessive trait, in which secretions of exocrine (sweat and mucus) glands are abnormal Page 2 Page 2 xxx00.#####.ppt 5/23/2017 5:51:20 AM History of CF 1936 Middle Ages (5th to 15th Century) Medieval folklore – infants with salty skin considered “bewitched ” because they routinely die an early death Anderson develops description of CF symptoms 1938 Dr. Guido Fanconi first describes previously nameless condition as “cystic fibrosis with bronchiectasis” and “cystic fibrosis of the pancreas” di Sant’Agnese reports that CF patients excrete excessive amounts of salt in their sweat – lead to the development of the sweat test Page 3 Page 3 1953 xxx00.#####.ppt 5/23/2017 5:51:20 AM Tsui and Riordan of the Hospital for Sick Children in Toronto discover the gene responsible for CF 2012 1989 FDA approval of the first CFTR Potentiator Epidemiology •Primary cause of chronic lung disease in children and adolescents •Most common life-shortening hereditary disorder of Caucasians in the U.S. •Incidence ‐1 in 2,500 live births (U.S.) ‐1 in 20 Americans are carriers Page 4 Page 4 xxx00.#####.ppt 5/23/2017 5:51:21 AM Epidemiology •2012 median survival: 41.1 years Page 5 Page 5 Data from CF Foundation Annual Report, 2011 xxx00.#####.ppt 5/23/2017 5:51:21 AM Pathophysiology •Autosomal recessive disorder •~25 known CF causing mutations ‐∆F508 mutation is most common Page 6 Page 6 Data from CF Foundation Annual Report, 2011 xxx00.#####.ppt 5/23/2017 5:51:21 AM Cystic fibrosis transmembrane regulator (CFTR) •CFTR protein regulates the transport of electrolytes and water Page 7 Page 7 xxx00.#####.ppt 5/23/2017 5:51:21 AM CFTR Page 8 Page 8 xxx00.#####.ppt 5/23/2017 5:51:21 AM Abnormal CFTR • Mutations in the CFTR gene result in little to no functional CFTR protein at the cell surface •End result: ‐Thick, viscous, sticky secretions obstruct glands and ducts in multiple organs ‐Increased salt content in sweat and other serous secretions Page 9 Page 9 xxx00.#####.ppt 5/23/2017 5:51:22 AM Gene Mutations Page 10 Page 10 xxx00.#####.ppt 5/23/2017 5:51:22 AM www.cftrscience.com Vetrex Pharmaceuticals 2011 Signs and Symptoms http://www.cftrscience.com/cf_pathophysiology.php Page 11 Page 11 xxx00.#####.ppt 5/23/2017 5:51:22 AM Lung Disease Progression Page 12 Page 12 xxx00.#####.ppt 5/23/2017 5:51:22 AM Pathophysiology – Lungs •Accounts for the majority of morbidity and mortality ‐ >95% of CF patients will die as a result of pulmonary disease •Accumulation of viscous mucous in the airway •Bacterial colonization •Acute exacerbations •Inflammation Page 13 Page 13 xxx00.#####.ppt 5/23/2017 5:51:22 AM Pathophysiology – Lungs Page 14 Page 14 xxx00.#####.ppt 5/23/2017 5:51:23 AM Notorious Bacteria •Pseudomonas aeruginosa ‐Decline in lung function ‐Increased risk of morbidity and mortality •Methicillin Resistant Staphylococcus aureus ‐Decline in lung function ‐Increased risk of morbidity and mortality •Burkholderia cepacia ‐Decline in lung function, can be rapid Page 15 Page 15 xxx00.#####.ppt 5/23/2017 5:51:23 AM Acute Exacerbations •Increased sputum production •Increased WBC •Febrile •Increased cough •Weight loss •Dyspnea on exertion •Decreased pulmonary function tests •Changes in sputum color Page 16 Page 16 xxx00.#####.ppt 5/23/2017 5:51:23 AM Pathophysiology – Pancreas Normal pancreas and GI tract CF pancreas and GI tract Page 17 Page 17 xxx00.#####.ppt 5/23/2017 5:51:24 AM Pathophysiology – GI tract Normal GI tract CF GI tract Page 18 Page 18 xxx00.#####.ppt 5/23/2017 5:51:24 AM Pathophysiology – Liver Page 19 Page 19 xxx00.#####.ppt 5/23/2017 5:51:24 AM Pathophysiology – Reproductive Tract Normal male reproductive tract CF male reproductive tract Page 20 Page 20 xxx00.#####.ppt 5/23/2017 5:51:24 AM Pathophysiology – Skin •Normally Na and Cl are reabsorbed from the secreted sweat •Patients with CF lose large quantities of chloride (and sodium) in their sweat Page 21 Page 21 xxx00.#####.ppt 5/23/2017 5:51:24 AM Diagnosis •Timing of diagnosis ‐ 2/3 by the age of 1 ‐ 85% by the age of 6 ‐ 90% by adulthood •Sweat chloride test ‐ + if >60 mmol/L of chloride •Newborn screening •Genetic testing Page 22 Page 22 xxx00.#####.ppt 5/23/2017 5:51:25 AM Pharmacokinetics and CF •Absorption •Distribution •Metabolism •Elimination Page 23 Page 23 xxx00.#####.ppt 5/23/2017 5:51:25 AM Pharmacokinetics and CF •Absorption •Distribution •Metabolism •Elimination Page 24 Page 24 xxx00.#####.ppt 5/23/2017 5:51:25 AM Absorption •Altered pathophysiology of the GI tract ‐Gastric acid hypersectretion ‐Bile acid malabsorption •Controversial if absorption is altered •Bioavailability is largely unaffected •Delayed time to Cmax for some drugs Page 25 Page 25 xxx00.#####.ppt 5/23/2017 5:51:25 AM Pharmacokinetics and CF •Absorption •Distribution •Metabolism •Elimination Page 26 Page 26 xxx00.#####.ppt 5/23/2017 5:51:26 AM Distribution •Hypoalbuminemia and hypergammoglobulinemia ‐No difference in protein binding •Higher blood volume/kg •Higher volume of distribution for some drugs ‐mg/kg NOT mg/m2 Page 27 Page 27 xxx00.#####.ppt 5/23/2017 5:51:26 AM Pharmacokinetics and CF •Absorption •Distribution •Metabolism •Elimination Page 28 Page 28 xxx00.#####.ppt 5/23/2017 5:51:26 AM Metabolism - Hepatic •Higher hepatic blood flow •Phase I reactions ‐CYP 1A2 and CYP 2C8 •Increased activity •Phase II reactions ‐Glucuronyl transferase, acetyl transferase, sulotransferase •Increased activity Page 29 Page 29 xxx00.#####.ppt 5/23/2017 5:51:26 AM Pharmacokinetics and CF •Absorption •Distribution •Metabolism •Elimination Page 30 Page 30 xxx00.#####.ppt 5/23/2017 5:51:27 AM Elimination - Renal •Glomerular filtration rate and tubular secretion ‐Normal •Renal clearance of many drugs is enhanced •Mechanism unknown Page 31 Page 31 xxx00.#####.ppt 5/23/2017 5:51:27 AM Goals of Treatment •Delay / prevent the development of lung disease •Promote good nutrition and normal growth •Recognize and treat complications •Improve quality of life •Prolong survival Page 32 Page 32 xxx00.#####.ppt 5/23/2017 5:51:27 AM Pulmonary Drug Therapy Page 33 Page 33 xxx00.#####.ppt 5/23/2017 5:51:27 AM Inhaled Bronchodilators •Beta2-agonist given with airway clearance BID ‐ Albuterol •2.5 mg nebulized BID ‐ Levalbuterol •0.63 mg nebulized BID •Airway clearance techniques ‐ P&PD ‐ Vest ‐ IPV ‐ Acapella Page 34 Page 34 xxx00.#####.ppt 5/23/2017 5:51:28 AM Airway Clearance Techniques Page 35 Page 35 xxx00.#####.ppt 5/23/2017 5:51:28 AM Inhaled Mucolytics •Decreases viscosity of secretions ‐Dornase alfa (Pulmozyme) ‐7% Hypertonic saline (HyperSal) Page 36 Page 36 xxx00.#####.ppt 5/23/2017 5:51:28 AM Dornase Alfa (Pulmozyme) •Mechanism of Action ‐ Hydrolyzes the DNA in sputum •Dose ‐ 2.5 mL nebulized once daily •Side effects ‐ Voice alteration, dyspnea, sore throat •$$$ Expensive Page 37 Page 37 xxx00.#####.ppt 5/23/2017 5:51:29 AM 7% Hypertonic Saline (HyperSal) •Mechanism of Action ‐Increases hydration of mucus due to osmotic flow ‐Breaks ionic bonds in mucus ‐Improves ciliary beat – expectoration of mucus •Dose ‐4 mL nebulized BID •Side effects ‐ Bronchospasm • Premedicate with a bronchodilator (albuterol/levalbuterol) 15 min. before treatment Page 38 Page 38 xxx00.#####.ppt 5/23/2017 5:51:29 AM Prophylactic Inhaled Antibiotics •Benefits of inhaled antibiotics ‐Limit the number or slow the development of acute exacerbations (fewer hospital days) ‐Concentrate at the site of infection ‐Limited side effects ‐Improve lung function ‐Minimize Pseudomonas colonization Page 39 Page 39 xxx00.#####.ppt 5/23/2017 5:51:29 AM Prophylactic Inhaled Antibiotics •Tobramycin (TOBI Nebs) ‐ 300 mg nebulized BID (28 days on, 28 days off) ‐ SE: hoarseness, oral thrush, bronchospasm •Tobramycin (TOBI Podhaler) ‐ 112 mg (four 28 mg caps) BID (28 days on, 28 days off) ‐ SE: cough, foul taste, bronchospasm •Aztreonam (Cayston) ‐ 75 mg nebulized TID (28 days on, 28 days off) ‐ SE: pyrexia, bronchospasm, nasal congestion Page 40 Page 40 xxx00.#####.ppt 5/23/2017 5:51:30 AM Anti-inflammatory Therapy •Azithromycin ‐ Not antibiotic prophylaxis ‐ Immunomodulatory properties ‐ Biofilm alteration ‐ Studied in patients with PA •Dose ‐ Monday, Wednesday, Friday dosing •<25 kg: 10 mg/kg •25-40 kg: 250 mg •≥40 kg: 500 mg Page 41 Page 41 xxx00.#####.ppt 5/23/2017 5:51:30 AM Anti-inflammatory Therapy •High dose ibuprofen •Mechanism of action ‐ Inhibits the migration, adherence, swelling, and aggregation of neutrophils, as well as the release of lysosomal enzymes •>5 years old with mild lung disease •Dose ‐ 20-30 mg/kg/dose BID •PK monitoring necessary Page 42 Page 42 xxx00.#####.ppt 5/23/2017 5:51:30 AM Gastrointestinal Drug Treatment Page 43 Page 43 xxx00.#####.ppt 5/23/2017 5:51:31 AM Vitamin and Mineral Supplementation • Fat soluble vitamins ‐ADEK • AquaDEKs • Source CF (non-formulary) • Vitamax (only through CF Services Pharmacy) ‐Monitor concentrations every two years • Vitamin K ‐<1 year: 2.5 mg twice a week ‐>1 year: 5 mg twice a week • Vitamin D Page 44 Page 44 xxx00.#####.ppt 5/23/2017 5:51:31 AM Pancreatic Enzymes •Porcine source •Protease, Lipase, and Amylase ‐ Prevent malnutrition ‐ Promote weight gain ‐ Decrease GI symptoms •Adverse effects ‐ Fibrosing colonopathy •Dosing: 500-2500 lipase units/kg meal Page 45 Page 45 xxx00.#####.ppt 5/23/2017 5:51:31 AM Additional Considerations •Vaccinations ‐Pneumococcal ‐Influenza •Lung Transplant ‐Prolong survival •Comparable to non-CF lung transplant patients ‐Rejection, opportunistic infections, reinfection, bleeding Page 46 Page 46 xxx00.#####.ppt 5/23/2017 5:51:32 AM Treatment of Pulmonary Exacerbations •Antibiotics ‐Mild exacerbations •Oral therapy ‐Moderate – Severe exacerbations or failed oral therapy •IV therapy, usually inpatient •Aggressive Airway Clearance •Maximizing nutrition and ensuring weight gain Page 47 Page 47 xxx00.#####.ppt 5/23/2017 5:51:32 AM IV Antibiotics •Treatment depends on culture and sensitivity results •Current and historical cultures should be considered •Duration of treatment 10-14 days ‐ Sometimes shorter or longer based on PFT results •Home IV therapy can be considered ‐ Completion of hospital course ‐ Known compliance Page 48 Page 48 xxx00.#####.ppt 5/23/2017 5:51:32 AM IV Antibiotics Organism Treatment Options H. influenzae Cephalosporins, TMP/SMX MSSA Nafcillin Pseudomonas aeruginosa (PA) Aminoglycoside (Tobra or Amikacin) plus Ceftazidime, pip/tazo, ticar/clav, cipro For MRPA: Colistin, meropenem, aztreonam MRSA Clindamycin, Vancomycin, Linezolid, doxycycline, TMP/SMX, ceftaroline Stenotrophamonas maltophilia TMP/SMX, Levofloxacin, Ticar/Clav Burkholderia cepacia TMP/SMX, ceftazidime, meropenem, minocycline Page 49 Page 49 xxx00.#####.ppt 5/23/2017 5:51:32 AM Antibiotic Dosing in CF •Often require higher doses and/or more frequent dosing ‐ Higher Volume of Distribution ‐ Faster metabolism/elimination Drug CF dosing Non-CF dosing Tobramycin 3-4 mg/kg q8h OR 10 mg/kg every 24 hours 2-2.5 mg/kg q8h Ceftazidime 200 mg/kg/DAY divided q8h 150 mg/kg/DAY divided q8h Piperacillin/Tazobactam 400-600 mg/kg/DAY divided q6h [max 6g/dose] 100 mg/kg every 8 h (<40 kg) or 3-4 g IV every 6h (≥ 40 kg) [Max 4 gm/dose] Ciprofloxacin 40 mg/kg/DAY (Oral) or 30 mg/kg/DAY (IV) [Max 1.2g/DAY] 20-30 mg/kg/DAY (Oral or IV) [Max 800 mg/DAY] Page 50 Page 50 xxx00.#####.ppt 5/23/2017 5:51:33 AM Future of Cystic Fibrosis Treatment Page 51 Page 51 xxx00.#####.ppt 5/23/2017 5:51:33 AM CFTR Potentiators/Correctors •Ivacaftor (Kalydeco ®) ‐ potentiator •Ataluren (PTC 124) ‐ allows ribosomal stop codon read through •VX-809 ‐ corrector •VX-661 ‐ corrector Page 52 Page 52 xxx00.#####.ppt 5/23/2017 5:51:33 AM Ivacaftor (Kalydeco ®) •CFTR potentiator •FDA approved in Feb 2012 •Indicated for CF patients ≥6 years old with a G551D mutation •MOA: ‐ Increases CFTR protein channel opening •Facilitates increased chloride transport Page 53 Page 53 xxx00.#####.ppt 5/23/2017 5:51:33 AM Ivacaftor (Kalydeco ®) •Dosing ‐150 mg PO BID •Adverse effects ‐Elevated LFTs, headache, dizziness, rash, nasal congestion •Drug interactions! ‐CYP 3A4 substrate ‐Decrease dose to 150 mg twice weekly when combined with strong 3A4 inducers Page 54 Page 54 xxx00.#####.ppt 5/23/2017 5:51:33 AM Ivacaftor (Kalydeco ®) Page 55 Page 55 xxx00.#####.ppt 5/23/2017 5:51:33 AM Ramsey B NEJM 2011 Ataluren (PTC 124) •Facilitates premature stop codon read through •Currently undergoing phase 3 trials •Patients with nonsense mutations (Class I) Page 56 Page 56 xxx00.#####.ppt 5/23/2017 5:51:33 AM Summary •CF is a genetic disorder that results in absent or non-functional CFTR protein affecting many organ systems ‐ Results in thick, viscous mucus •Pharmacokinetics differ in the CF population ‐ Higher volume of distribution ‐ Faster metabolism and elimination •Previous drug treatments targeted symptoms and infectious organisms •New and investigational treatments are focused on making the CFTR protein function properly Page 57 Page 57 xxx00.#####.ppt 5/23/2017 5:51:33 AM References • Cystic Fibrosis Foundation. Patient registry 2012 annual report. Bethesda, MD: Cystic Fibrosis Foundation; 2013 • http://www.cftrscience.com • Davis P. Cystic Fibrosis. Pediatrics in Review 2001;22:257-264. • Rowe SM, Miller S, Sorscher EJ. Mechanisms of Disease: Cystic Fibrosis. NEJM 2005;19:19922001. • Rey E, Treluyer JM, Pons G. Drug Disposition in Cystic Fibrosis 1998;35:313-329. • Lexi-Comp OnlineTM , Pediatric & Neonatal Lexi-Drugs OnlineTM , Hudson, Ohio: Lexi-Comp, Inc.; January 14, 2014. • Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiatior in patients with cystic fibrosis and the G551D mutation. NEJM 2011;365:1663-72. • Pettit R. Cystic fibrosis transmembrane condunctance regulator- modifying medications: the future of cystic fibrosis treatment. Annals of Pharmacotherapy 2012;46:1065-75. Page 58 Page 58 xxx00.#####.ppt 5/23/2017 5:51:34 AM Cystic Fibrosis Erin McDade, Pharm.D. Clinical Pharmacy Specialist Pediatric Pulmonary Service Texas Children’s Hospital