New Discoveries, New Challenges: Cystic Fibrosis and Inpatient Care

In 1938, Dorothy Anderson published the first written report detailing the characteristic finding of pancreatic insufficiency seen in patients with cystic fibrosis (CF), although at the time she described the symptomology as being related to celiac disease.¹ Over the next decade, researchers confirmed that the disease was also characterized by excessive salt loss as a result of faulty sweat glands on the skin’s surface.² Fast-forwarding almost 75 years, cystic fibrosis is now known to be a deadly genetic disease that extends from early childhood into adulthood and is characterized by excessive mucus buildup in the lungs leading to lung damage, decreasing lung function, and eventually lung failure.

As of 2011, approximately 30,000 people in the United States were living with the disease with a life expectancy that has steadily increased over the last 25 years to roughly 37 years of age.³ This article will discuss current and emerging pharmacotherapy options for cystic fibrosis patients by reviewing current treatment strategies and highlighting a recently approved medication, ivacaftor (Kalydeco), that targets the source of cystic fibrosis symptomology.⁴

Current Treatment Strategies

Exacerbations

CF exacerbations are usually caused by a bacterial infection in the respiratory tract caused by gram-positive and gram-negative organisms such as staphylococcus aureus and pseudomonas aeruginosa, respectively. However, many other organisms can be part of the infectious process, including stenotrophomonas, burkholderia, achromobacter, and aspergillosis, all of which may be pathogenic. Intravenous infusion administration techniques such as extended infusions, infusions of larger than FDA-approved doses, and targeting much higher peak concentrations for aminoglycosides still cause much debate, although recent literature is providing more supporting evidence. The definitive answer to the age-old question—to double cover or not to double cover for pseudomonas—also lingers, but now discussion is spilling over to staphylococcus, not just pseudomonas.^5-16 Table 1 lists commonly used antibiotics for the various organisms that can lead to a CF exacerbation.

CF Maintenance

Current goals for improving lung health and lung function should aim to maximize the time between pulmonary exacerbations, decrease the overall number of exacerbations, and preserve current lung function (FEV1). Recent guidelines recommend the continued use of chest physiotherapy, airway clearance strategies, mucus-altering agents, inhaled antibiotics targeting P aeruginosa, and anti-inflammatory agents (age specific, presence of pseudomonas).^16-22

Nutrition and Cystic Fibrosis—Related Diabetes

Poor nutritional status creates complications for the CF patient, most notably decreased body mass index, declining lung function, and osteopenia. Current guidelines offer providers, patients, and their families opportunities to use a framework for enhancing the patient’s overall health status. Within these guidelines, the regular use of vitamin replacement, including vitamin D and other fat-soluble vitamins, appropriate caloric intake, and adequate pancreatic enzyme replacement are just a few steps that lead to improved nutritional status, thus improving pulmonary function. Many patients may require nutritional supplements by mouth or by tube feeds (overnight).^23-25 Distal intestinal obstructive syndrome (DIOS) is a partial or complete obstruction of the ileum/cecum with thick mucus fecal material. Uncontrolled steatorrhea secondary to pancreatic insufficiency is a risk factor. This complication is more likely to occur in adolescent and older CF patients. Those that have undergone lung transplantation are also at an increased risk for developing DIOS.^26,27

Cystic fibrosis—related diabetes (CFRD) is a comorbidity affecting approximately half of the CF population as they reach adulthood. The pathophysiology and clinical impact have not been understood until recently. Its presence is associated with declining lung function and microvascular complications but little macrovascular disease. Patients with CFRD create unique challenges in glucose control, exhibiting traits of both type 1 and type 2 diabetes, insufficient insulin production and impaired utilization (insulin resistance), especially during exacerbations. In order to meet the high caloric demands for CF patients, traditional diabetic dietary restrictions are limited in practice. This does not replace monitoring carbohydrate intake and adjusting insulin doses accordingly.^28-30

Emerging Therapies: Ivacaftor

Ivacaftor received FDA approval in January 2012 for the treatment of cystic fibrosis in patients aged 6 years and older who have a G551D mutation in the cystic fibrosis transmembrane regulator (CFTR) protein.⁴ Discovered more than 20 years ago, the CFTR protein is a cyclic adenosine monophosphate (cAMP) regulated chloride (Cl-) ion channel that is responsible for Cl- and water transport in the apical membrane of lung epithelial cells. When a mutation occurs and leads to a defective CFTR protein, the characteristic signs and symptoms of CF emerge in the lungs, including mucus accumulation, impaired ion transport, mucus stasis, airway obstruction, and pathogen-induced inflammation.^31,32

The G551D mutation is a Class III mutation resulting from the substitution of glycine for aspartic acid at amino acid 551 and occurs in approximately 4% to 5% of patients with CF. This leads to the deregulation of absorption and secretion of both salt and water in many organs, including the sweat glands, pancreas, gastrointestinal (GI) tract, and especially the lungs.³¹ Whereas current therapies target the secondary effects of CFTR dysfunction, treatment with ivacaftor aims to improve the defective CFTR function by targeting the G551D gating mutation, leading to an improved probability that the ion channel will open properly, allowing for the appropriate ion transport across the apical membrane.^31,33 The recommended dosing for ivacaftor for patients 6 years or older is 150 mg by mouth twice daily. Safety and efficacy have not been established in patients less than 6 years old. No dosage adjustments are required for patients with renal disease. For patients with moderate and severe hepatic impairment it is recommended that ivacaftor is taken once daily or less frequently.^34,35

Clinical Efficacy

The STRIVE study, a phase 3, randomized, double-blind, placebo-controlled, international study, was conducted to evaluate the efficacy of ivacaftor. A total of 161 subjects were enrolled in the study and patients had to be 12 years or older, diagnosed with CF, have at least 1 CFTR allele with the G551D mutation, and have an FEV1 of 40% to 90% of the predicted value for persons of similar age, sex, and height.³¹ ENVISION, a phase 3, randomized, double-blind, placebo-controlled study, was conducted to evaluate the efficacy of ivacaftor in patients with CF, aged 6 to 11 years. Like the STRIVE study, patients had to have at least 1 allele with the G551D mutation, and similar baseline characteristics.³⁵

At 48 weeks, both trials demonstrated that patients had significant improvements in the primary end point: the absolute change from baseline in the percent of predicted FEV1.^31,35 Secondary end points, including the time until first pulmonary exacerbation, change in weight from baseline, and change in baseline concentration of sweat chloride, also displayed improvement at week 48. Based on these results, ivacaftor was approved for use and a 96-week follow-up study (PERSIST) is currently being conducted.^31,35

Medications in the Pipeline

Several other genetic therapies are currently being investigated for their potential use in cystic fibrosis. VX-809, a CFTR “corrector,” in combination with ivacaftor, is currently being studied in 2 phase III trials for subjects with CF and the F508del CFTR mutation, the most common mutation in CF. Similarly, VX-609, also a “corrector,” is being studied in combination with ivacaftor. Both medications showed promising results in phase II studies.³

Summary

The approval of ivacaftor brings new hope for future therapies in the treatment of cystic fibrosis, not just treatments for prevention or immediate complications. Newer understandings of current therapies and their optimization are the backbone of care today.

As patients with CF live longer and their medication regimens become more complex, pharmacists will have the opportunity to improve the care of the CF patients in many areas. Ensuring that current guidelines are followed, counseling to improve patient adherence, and managing drug shortages for key agents are just a few of the ways that pharmacists can have a positive impact for patients with cystic fibrosis.

Dr. Lamm is lead pharmacist at University of North Carolina Hospitals—Hillsborough Campus.Dr. Barrow is a clinical specialist in adult medicine at the University of North Carolina Hospitals.

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