Ivacaftor (KalydecoTM): Targeting the Core of Cystic Fibrosis

By: Eugene Kolomiyets, PharmD Candidate c/o 2013, AMSCOP at LIU

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Cystic fibrosis (CF) is an autosomal recessive disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7.¹  The disease has been linked to thousands of possible mutations, but only as many as 25-30 are tested for in newborns.^1,2  CFTR is responsible for chloride transport in epithelial cells throughout the body.¹  The defective gene causes increased salt production in sweat, as well as increased mucus production in the lungs and gastrointestinal tract.¹  These changes lead to decreased respiratory function and chronic Pseudomonal pneumonia, malnutrition  and malabsorption of crucial vitamins, pancreatic dysfunction and insulin-dependent diabetes, hepatobiliary disease, meconium ileus, and reproductive dysfunction.^1,2

Ivacaftor (Kalydeco^TM) potentiates CFTR receptor opening in patients six years and older who have a G551D mutation in the CFTR gene.^3,4  Only up to five percent of patients with cystic fibrosis have this G511D missense mutation.^3,4  The drug is not efficacious for patients with the F508del mutation, for which as many as 50% of CF patients are homozygous and 40% are heterozygous.^3-5

A phase III, randomized, double-blind, placebo-controlled, international study of orally administered ivacaftor, designed by Vertex Pharmaceuticals, looked at the absolute change from baseline through week 24 in predicted FEV₁% as the primary endpoint.³  It found that there was 10.4% increase from baseline in the predicted FEV₁% in the ivacaftor group, as compared with a decrease of 0.2% in the placebo group; a treatment effect (or absolute difference) of 10.6% (p < 0.001).³  The study also revealed a 55% reduction in the risk of pulmonary exacerbations (p = 0.001) and a decrease in the total number of hospitalization days for pulmonary exacerbations with ivacaftor (p = 0.03).³

Ivacaftor is a 150 mg oral tablet taken every 12 hours with fat-containing food.⁴  Patients with moderate and severe hepatic impairment require dose reductions.⁴  The drug interacts with moderate or strong CYP 3A4 inhibitors (e.g. azole antifungals), CYP 3A4 inducers (e.g. rifampin, phenytoin, St. John’s Wort).⁴  It should also be used with caution with P-glycoprotein substrates (e.g. digoxin, cyclosporine, tacrolimus).⁴  Although ivacaftor is pregnancy category B, it has not been extensively studied in pregnant or nursing women.⁴

Ivacaftor may also elevate hepatic transaminases.⁴  ALT and AST should be assessed prior to initiating the drug, every three months during the first year of treatment, and then annually afterward.⁴  Patients who develop increased transaminases should be closely monitored until the abnormalities resolve.⁴  Common side effects of ivacaftor include headache, upper respiratory tract infections, nasal congestion, nausea, rash, rhinitis, dizziness, and arthralgia.⁴

Overall, ivacaftor is the first of a new class of medications that could revolutionize the treatment of CF for some patients.  It targets the root of the problem by potentiating the CFTR receptor and improving the various qualities of the disease.  Although it is limited to a small subset of the CF population, it is a vital first step in researching and developing similar CFTR potentiating drugs for more common CFTR mutations like F508del.

SOURCES:

1. Wright CC, Vera YY.  Chapter 37.  Cystic Fibrosis.  In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach.  8th Ed.  New York: McGraw-Hill; 2011.
2. Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for the diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation Consensus Report.  J Pediatr 2008;153(2):S4–S14.
3. Ramsey BW, Davies J, McElvaney G, et. al. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation.  N Engl J Med 2011; 365:1663-1672.
4. Product Information: KALYDECO(TM) oral tablets, ivacaftor oral tablets. Vertex Pharmaceuticals Incorporated. Cambridge, MA, 2012.
5. Weck K, Booker J. UNC Molecular Genetics Laboratory. Cystic Fibrosis (CFTR gene) Mutation Testing. 24 April 12. Available at http://labs.unchealthcare.org/forms/cf.pdf. Accessed November 1, 2012.