Ivacaftor and CFTR

Ivacaftor is medication that is used to treat cystic fibrosis (CF) in patients with specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor works by increasing the ability of CFTR protein to transport chloride. The usual adult dose of ivacaftor is 150 mg by mouth every 12 hours.

The CFTR gene codes for the CFTR protein, which is located on certain cell membranes (e.g. the lungs) and acts as a channel for chloride ion transport. Chloride ion transport helps to balance the movement of water within tissues. Water movement helps to create thin mucus. With a functional CFTR protein chloride transport is normal and water and salt is more balanced, resulting in mucus with normal thickness. In a cell with a defective CFTR, chloride transport is decreased leading to an imbalance of salt and water absorption, which results in thick mucus.

The specific CFTR allele that ivacaftor treats is the G551D mutation. In this specific mutation, the protein is located in the correct place on the cell membrane, but it cannot transport chloride through the channel. In patients with one or two copies of the G551D allele, ivacaftor is strongly recommended for CF treatment. Ivacaftor can also be used for treatment in patients with at least one copy of any of the following alleles: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H. For the treatment of patients with two copies of the F508del mutation, ivacaftor is available in combination with lumacaftor (Orkambi ®).

Alex, 24-year-old white male, visits the clinic to develop a treatment plan for his cystic fibrosis. Upon admission, the doctor recommends a genetic test be performed to determine Alex’s genotype to ensure ivacaftor would be the best therapy to effectively treat his disease state. The doctor tells Alex that about half of CF patients are homozygous for a mutation of their CFTR gene, which could render the ivacaftor therapy ineffective. Alex refuses the genetic test due to time constraints, but will still begin the medication therapy. Alex returns to the clinic 3 weeks later reporting that the medication is not making him feel better. Upon inspection the doctor finds no change in Alex’s sweat chloride concentration, spirometric measurements, pulmonary exacerbations, or body weight. The doctor orders a genetic test to determine Alex’s CFTR genotype. Test findings exhibit Alex to be homozygous for the F508del mutation allele on the CFTR gene. As a result, Alex is unlikely to respond to treatment from ivacaftor and thus the doctor reevaluates the medication therapy.

A few months later, the same doctor is developing a treatment plan for Heather, a 20-year-old white female with cystic fibrosis. He explained to Heather that a person homozygous for the F508del mutation in the CFTR gene will not respond to ivacaftor, and recommends that a genetic test be performed to verify her genotype. Heather agrees to have the genetic testing done and the results show that she is homozygous for G551D (rs75527207). This means that she has a strong recommendation for ivacaftor therapy and may have significant improvement in lung function, weight, and sweat chloride concentrations. The doctor decides to begin Heather’s treatment with ivacaftor as recommended by the label. Due to the genetic testing, they were confident this therapy would be beneficial for Heather and avoided a potential delay in therapeutic effects had genetic testing not been performed.

CFTR genetic testing does not completely rule out the risk for taking ivacaftor nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefits and minimizing harm.

The links below provide access to important articles and information relative to glimepiride. The links are to external websites and will be checked regularly for consistency.

• Ivacaftor Prescribing Information
• Ivacaftor Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Ivacaftor

Genetics Home Reference [Internet]. Bethesda (MD): Department of Health and Human Services; 2017 Jan 24; CFTR gene; [2017 Jan 26]; [about 3 screens]. Available from: https://ghr.nlm.nih.gov/gene/CFTR#

Kalydeco [package insert on the Internet]. Cambridge (MA): Vertex Pharmaceuticals Incorporated; 2012 Jan [updated 2012 Jan; cited 2016 Feb]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203188lbl.pdf.

Lexicomp [Internet]. Hudson (OH): Wolters Kluwer. Ivacaftor; [2016 Dec 14; 2017 Jan 26]; [about 19 screens]. Available from: http://www.crlonline.com/lco/action/doc/retrieve/docid/patch_f/3636103.

Wainwright CE, Elborn JS, Ramsey BW, et al. Lumcaftor-ivacaftor in patients with cystic fibrosis homozygous for the Phe508del CFTR. N Engl J Med. 2015 Jul 16;373:220-31.

Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012 Oct;92(4):414-7.