Drug/Small Molecule:
ivacaftor

last updated 05/06/2014

CPIC Dosing Guideline for ivacaftor and CFTR

Summary

Ivacaftor treatment is recommended only in cystic fibrosis (CF) patients that are either homozygous or heterozygous for certain CFTR variants. See full guideline for disclaimers, further details and supporting evidence.

Annotation

April 2014 Update on PharmGKB

March 2014

Accepted article preview online March 2014; Advance online publication March 2014.

Table 1: Recommended therapeutic use of ivacaftor based on CFTR genotype

Adapted from Table 2 of the 2014 guideline manuscript (April 2014 Update on PharmGKB). Variants have been added to the table below that are not in the published 2014 guideline or supplement; specifically, variants other than G551D and F508del.

CFTR Genotype Examples of diplotypes Implications for ivacaftor effects Recommendations for ivacaftor therapy Classification of recommendation for ivacaftor therapy c
Homozygous or Heterozygous G551D-CFTR, rs75527207 genotype AA or AG G551D/ F508del, G551D/ G551D Significant improvement in lung function, weight, risk of pulmonary exacerbation, patient reported outcomes, and reduction in sweat chloride concentrations through enhanced CFTR channel activity (increase probability of open channel). Use ivacaftor according to the product label (e.g., 150 mg every 12 hours for patients age 6 and older without other diseases; modify dose in patients with hepatic impairment) Strong
Homozygous for F508del-CFTR, rs113993960 or rs199826652 genotype del/del F508del/F508del No significant reduction in sweat chloride concentrations; no changes in other clinical measurements including spirometric measurements, pulmonary exacerbations, or body weight b. Unlikely to respond to treatment. Ivacaftor is not recommended a Moderate b
Homozygous or heterozygous for one of the following CFTR variants that affect gating: G1244E (rs267606723 genotype AA or AG), G1349D (rs193922525 genotype AA or AG), G178R (rs80282562 genotype AA or AG), G551S (rs121909013 genotype AA or AG), S1251N (rs74503330 genotype AA or AG), S1255P (rs121909041 genotype CC or CT), S549N (rs121908755 genotype AA or AG), S549R (rs121909005 genotype GG or GT, rs121908757 genotype CC or CA) d F508del/S549N Significantly enhanced channel open probability in vitro [Article:22293084]. In vitro assays with CFBEo- cells expressing S549N-CFTR showed ivacaftor potentiated chloride channel function [Article:23027855], and a case study showed improved lung function after ivacaftor treatment in a 12-year-old girl with CF with a copy of the S549N variant [Article:24081349]. Use ivacaftor according to the product label (e.g., 150 mg every 12 hours for patients age 6 and older without other diseases; modify dose in patients with hepatic impairment) Moderate

a These recommendations are based on treatment of CF patients with ivacaftor alone and current evidence. Clinical trials are currently underway to investigate ivacaftor alone or in combination with other drugs to treat CF patients with CFTR variants other than G551D, therefore there is potential that ivacaftor may be effective in these patients. See the 2014 guidelines for further details.
b The recommendation for patients with the F508del/F508del genotype is based on ivacaftor mechanism of action and clinical observational data. The clinical study however was a safety study and was not powered to detect a difference in efficacy [Article:22383668].
c Rating scheme described in the 2014 supplement.
d Variants listed in this table include those added to the amended drug label for ivacaftor which was approved by the FDA on February 21, 2014. The modifications to this table were made after the acceptance of publication of the 2014 CPIC Ivacaftor-CFTR guideline [Article:24598717] and are not reflected in the PDFs of the CPIC guideline main manuscript or supplement.

Figure 1: Treatment algorithm for clinical use of Ivacaftor for cystic fibrosis patients based on CFTR genotype.

Adapted from Figure 1 of the 2014 guideline manuscript (April 2014 Update on PharmGKB). Variants have been added to this figure that are not in the published 2014 guideline or supplement; specifically, variants other than G551D and F508del.

e Ivacaftor is not recommended for CF patients with other CFTR variants or in patients homozygous for the F508del variant (see 2014 guideline for further details, supporting evidence and disclaimers). Future clinical trials for other CFTR variants are ongoing.


PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.



last updated 03/05/2014

FDA Label for ivacaftor and CFTR

This label is on the FDA Biomarker List
Genetic testing required

Summary

Ivacaftor is indicated in patients with cystic fibrosis (CF) who have one of the following variants in the CFTR gene: G551D (rs75527207), G1244E (rs267606723), G1349D (rs193922525), G178R (rs80282562), G551S (rs121909013), S1251N (rs74503330), S1255P (rs121909041), S549N (rs121908755) or S549R (rs121908757 and rs121909005). Genetic testing is required prior to initiating treatment with Ivacaftor if a patient's CFTR genotype is not known. The label also states that ivacaftor is not effective in patients homozygous for the F508del variant (rs113993960 and rs199826652).

Annotation

The FDA recommends genetic testing prior to initiating treatment with Ivacaftor if a patient's CFTR genotype is not known. The drug is indicated in cystic fibrosis (CF) patients who have at least one of the following variants in the CFTR gene: G551D (rs75527207), G1244E (rs267606723), G1349D (rs193922525), G178R (rs80282562), G551S (rs121909013), S1251N (rs74503330), S1255P (rs121909041), S549N (rs121908755) or S549R (rs121908757 and rs121909005).

The FDA label also contains information regarding metabolism of ivacaftor by CYP3A enzymes, therefore concomitant use with strong CYP3A inhibitors is not recommended or adjustments to dose are required. Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's Wort) substantially decreases exposure of ivacaftor which may diminish effectiveness.

Excerpts from the ivacaftor (Kalydeco) label:

KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bidirectional sequencing when recommended by the mutation test instructions for use.


Limitations of Use:

  • Not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the ivacaftor (Kalydeco) drug label. This label was amended and approved by the FDA on Feb/21/2014. One amendment includes the addition of CFTR variants to the indication (ivacaftor was originally indicated for use in CF patients with the G551D variant).

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Cystic Fibrosis
    • Indications & usage section, Information for patients section, Clinical studies section, Use in specific populations section
    • source: FDA Label
  • CFTR
    • Indications & usage section, Information for patients section, Clinical pharmacology section, Clinical studies section, Pharmacodynamics section, Use in specific populations section, efficacy
    • source: FDA Label
  • CYP3A4
    • Dosage & administration section, Drug interactions section, Pharmacokinetics section, Warnings and precautions section, dosage
    • source: FDA Label
  • CYP3A5
    • Dosage & administration section, Drug interactions section, Pharmacokinetics section, Warnings and precautions section, dosage
    • source: FDA Label

last updated 10/27/2013

European Medicines Agency (EMA) Label for ivacaftor and CFTR

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) contains pharmacogenetic information regarding the indication of ivacaftor (Kalydeco) in cystic fibrosis patients who have one of the following variants in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R. Treatment in patients who do not have one of these variants is not recommended, and if a patient's genotype is not known, testing should be carried out before treatment.

Annotation

Update Oct/22/2014: The EPAR originally contained information regarding indication in patients with the CFTR-G551D variant. It is now contains information regarding the indication of ivacaftor in patients with one of nine CFTR variants.

Excerpts from the ivacaftor (Kalydeco) EPAR:

Kalydeco is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R (see sections 4.4 and 5.1).


Kalydeco should only be prescribed by physicians with experience in the treatment of cystic fibrosis. If the patient's genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of one of the above-listed gating (class III) mutations in at least one allele of the CFTR gene before starting treatment.

The EPAR also contains information regarding the role of CYP3A4 and CYP3A5 in the metabolism of ivacaftor, and that if taken concomitantly with inhibitors or inducers of these enzymes, ivacaftor may require dose adjustments.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the ivacaftor EMA drug label.

*Disclaimer: The contents of this page have not been endorsed by the EMA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • CFTR
    • Information for patients section, Pharmacodynamics section, efficacy
    • source: European Medicines Agency (EMA) Label
  • CYP3A4
    • Drug interactions section, Warnings and precautions section, metabolism/PK
    • source: European Medicines Agency (EMA) Label
  • CYP3A5
    • Drug interactions section, Warnings and precautions section, metabolism/PK
    • source: European Medicines Agency (EMA) Label

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?
LabCorp Cystic Fibrosis (CF) Gene Sequencing CFTR Sequencing of CFTR gene
ARUP Lab CFTR 32 mutations (PCR,oligonucleotide ligation, fragment analysis) rs113993960 , rs75527207 , CFTR F508del , CFTR I507del , CFTR G542X , CFTR G551D , CFTR W1282X , CFTR N1303K , CFTR R553X , CFTR 621+1GT , CFTR R117H , CFTR 1717-1GA , CFTR A455E , CFTR R560T , CFTR R1162X , CFTR G85E , CFTR R334W , CFTR R347P , CFTR 711+1GT , CFTR 1898+1GA , CFTR 2184delA , CFTR 1078delT , CFTR 3849+10kbCT , CFTR 2789+5GA , CFTR 3659delC , CFTR 2183delAA>G , CFTR 3120+1GA , CFTR R347H , CFTR V520F , CFTR S549N , CFTR S549R , CFTR 3905insT , CFTR 3876del , CFTR 394delTT
23andme.com rs113993960 , rs75527207 , CFTR 1898+1G>A , CFTR N1303K , CFTR R347H , CFTR 2789+5G>A , CFTR 711-+1G>T , CFTR S549N , CFTR 3849+10kb C>T , CFTR R334W , CFTR S549R , CFTR A455E , CFTR 1717-1G>A , CFTR V520F , CFTR R1162X , CFTR W1282X , CFTR 394deITT , CFTR R560T , CFTR R117H , CFTR 3876deIA , CFTR 3120+1G>A , CFTR 621+1G>T , CFTR 3905insT , CFTR 3659delC , CFTR R347P , CFTR G551D , CFTR R553X , CFTR 1078delT , CFTR G85E , CFTR 2184delA , CFTR G542X , CFTR deltaI507 , CFTR deltaF508 , CFTR F508C
Ambry Genetics Cystic Fibrosis (pyrosequencing) rs113993960 , rs75527207 , CFTR deltaI507 , CFTR deltaF508 , CFTR A455E , CFTR E60X , CFTR G542X , CFTR G551D , CFTR G85E , CFTR N1303K , CFTR R117H , CFTR R334W , CFTR R347P , CFTR R553X , CFTR R560T , CFTR R1066C , CFTR R1162X , CFTR S492F , CFTR S549N , CFTR W1282X , CFTR 394delTT , CFTR 406-1G>A , CFTR 621+1G>T , CFTR 711+1G>T , CFTR 1717-1G>A , CFTR 1898+1G>A , CFTR 2055del9>A , CFTR 2105-2117del13insAGAAA , CFTR 2184delA , CFTR 2789+5G>A , CFTR 3120+1G>A , CFTR 3849+10kbC>T , CFTR 3659delC , CFTR 3876delA
Medical Diagnostic Laboratories Cystic Fibrosis Gene Carrier Screening (PCR, Bio-Plex liquid microarray analysis) rs113993960 , rs75527207 , CFTR F508 , CFTR A455E , CFTR 2789+5G>A , CFTR G85V , CFTR I507 , CFTR R560T , CFTR 3659delC , CFTR R347L , CFTR G542X , CFTR R1162X , CFTR 3120+1G>A , CFTR G551D , CFTR G85E , CFTR W1282C , CFTR W1282X , CFTR R334W , CFTR R553G , CFTR N1303K , CFTR R347P , CFTR R117L , CFTR R553X , CFTR 711+1G>T , CFTR R117P , CFTR 621+1G>T , CFTR 1898+1G>A , CFTR 1898+1G>T , CFTR R117H , CFTR 2184delA , CFTR K684K , CFTR 1717-1G>A , CFTR 3849+10kbC>T , CFTR R560K
Abbott Molecular Cystic Fibrosis Genotyping Assay (PCR, oligonucleotide ligation assay) rs113993960 , rs75527207 , CFTR 1898+1G>A , CFTR N1303K , CFTR R347H , CFTR 2789+5G>A , CFTR 711-+1G>T , CFTR S549N , CFTR 3849+10kb C>T , CFTR R334W , CFTR S549R , CFTR A455E , CFTR 1717-1G>A , CFTR V520F , CFTR R1162X , CFTR W1282X , CFTR 394deITT , CFTR R560T , CFTR R117H , CFTR 3876deIA , CFTR 3120+1G>A , CFTR 621+1G>T , CFTR 3905insT , CFTR 3659delC , CFTR R347P , CFTR 2183AA>G , CFTR G551D , CFTR R553X , CFTR 1078delT , CFTR G85E , CFTR 2184delA , CFTR G542X , CFTR deltaI507 , CFTR deltaF508 , CFTR F508C
Quest Diagnostics Cystic Fibrosis Screen (PCR, oligonucleotide ligation assay) rs113993960 , rs75527207 , CFTR 621+1G>T , CFTR 3120+1G>A , CFTR G85E , CFTR R347P , CFTR 5T/7T/9Ta , CFTR 711+1G>T , CFTR 3659delC , CFTR G542X , CFTR R553X , CFTR ¿506V , CFTR 1717-1G>A , CFTR 3849+10kbC>T , CFTR G551D , CFTR R560T , CFTR ¿507V , CFTR 1898+1G>A , CFTR A455E , CFTR N1303K , CFTR R1162X , CFTR 2184delA , CFTR deltaI507 , CFTR R117H , CFTR W1282X , CFTR 2789+5G>A , CFTR deltaF508 , CFTR R334W , CFTR 1078delT , CFTR 2183AA>G , CFTR 3876delA , CFTR 3905insT , CFTR 394delTT , CFTR R347H , CFTR S549N , CFTR S549R , CFTR V520F
Mayo Medical Laboratories Cystic Fibrosis Mutation Analysis, 106-Mutation Panel (multiplex PCR, sequenom mass array) rs113993960 , rs75527207 , CFTR deltaF508 , CFTR deltaI507 , CFTR G542X , CFTR G85E , CFTR R117H , CFTR W1282X , CFTR 621+1 G->T , CFTR 711+1 G->T N1303K (C->A and C->G) , CFTR R334W , CFTR R347P , CFTR A455E , CFTR 1717-1 G->A , CFTR R553X , CFTR R560T , CFTR G551D , CFTR 1898+1 G->A , CFTR 2184delA , CFTR 2789+5 G->A , CFTR 3120+1 G->A , CFTR R1162X , CFTR 3659delC , CFTR and 3849+10kb C->T) as well as the deletion exons 2-3 , CFTR 296+2 T->A , CFTR E60X , CFTR R75X , CFTR 394delTT , CFTR 405+1 G->A , CFTR 406-1 G->A , CFTR E92X , CFTR 444delA , CFTR 457TAT->G , CFTR R117C , CFTR Y122X , CFTR 574delA , CFTR 663delT , CFTR G178R , CFTR 711+5 G->A , CFTR 712-1 G->T , CFTR H199Y , CFTR P205S , CFTR L206W , CFTR 852del22 , CFTR 935delA , CFTR 936delTA , CFTR deltaF311 , CFTR 1078delT , CFTR G330X , CFTR T338I , CFTR R347H , CFTR R352Q , CFTR Q359K , CFTR T360K , CFTR 1288insTA , CFTR S466X (C->A) , CFTR S466X (C->G) , CFTR G480C , CFTR Q493X , CFTR 1677delTA , CFTR C524X , CFTR S549N , CFTR S549R , CFTR Q552X , CFTR A559T , CFTR 1811+1.6kb A->G , CFTR 1812-1 G->A , CFTR 1898+1 G->T , CFTR 1898+1 G->C , CFTR 1898+5G->T , CFTR P574H , CFTR 1949del84 , CFTR 2043delG , CFTR 2055del9->A , CFTR 2105del13ins5 , CFTR 2108delA , CFTR 2143delT , CFTR 2183AA->G , CFTR 2184insA , CFTR R709X , CFTR K710X , CFTR 2307insA , CFTR R764X , CFTR Q890X , CFTR 2869insG , CFTR 3171delC , CFTR 3199del6 , CFTR R1066C , CFTR W1089X , CFTR Y1092X (C->G) , CFTR Y1092X (C->A) , CFTR M1101K , CFTR M1101R , CFTR D1152H , CFTR R1158X , CFTR 3667del4 , CFTR S1196X , CFTR W1204X , CFTR 3791delC , CFTR Q1238X , CFTR 3876delA , CFTR S1251N , CFTR S1255X , CFTR 3905insT , CFTR 4016insT

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
rs113993960 117559592_117559594delCTT, 1521_1523delCTT, 1845_1847delCTT, 55052813_55052815delCTT, 98809_98811delCTT, F508del, Phe508del, Phe616del, c.1521_1523delCTT, deltaF508, p.Phe508del, rs199826652
CTT > -
Not Available
No VIP available CA VA
rs121908755 117587800G>A, 117587800G>T, 127017G>A, 127017G>T, 1646G>A, 1646G>T, 1970G>A, 1970G>T, 55081021G>A, 55081021G>T, S549N, Ser549Asn, Ser549Ile, Ser657Asn, Ser657Ile, c.1646G>A, p.Ser549Asn
G > T
G > A
Not Available
Ser657Ile
Ser657Asn
No VIP available CA VA
rs121908757 117587799A>C, 127016A>C, 1645A>C, 1969A>C, 55081020A>C, S549R, Ser549Arg, Ser657Arg, c.1645A>C, p.Ser549Arg
A > C
Not Available
Ser657Arg
No VIP available CA VA
rs121909005 117587801T>G, 127018T>G, 1647T>G, 1971T>G, 55081022T>G, S549R, Ser549Arg, Ser657Arg, c.1647T>G, p.Ser549Arg
T > G
Not Available
Ser657Arg
No VIP available CA VA
rs121909013 G551S, c.1651G>A, p.Gly551Ser
G > A
Not Available
Gly551Ser
No VIP available CA VA
rs121909041 117642483T>C, 181700T>C, 3763T>C, 4087T>C, 55135704T>C, S1255P, Ser1255Pro, Ser1363Pro, c.3763T>C, p.Ser1255Pro
T > C
Not Available
Ser1363Pro
No VIP available CA VA
rs193922525 117664770G>A, 203987G>A, 4046G>A, 4370G>A, 55157991G>A, G1349D, Gly1349Asp, Gly1457Asp, c.4046G>A, p.Gly1349Asp
G > A
Not Available
Gly1457Asp
No VIP available CA VA
rs267606723 117642451G>A, 117642451G>T, 181668G>A, 181668G>T, 3731G>A, 3731G>T, 4055G>A, 4055G>T, 55135672G>A, 55135672G>T, G1244E, Gly1244Glu, Gly1244Val, Gly1352Glu, Gly1352Val, c.3731G>A, p.Gly1244Glu
G > T
G > A
Not Available
Gly1352Glu
Gly1352Val
No VIP available CA VA
rs74503330 117282526G>A, 167510G>A, 55315369G>A, S1251N, c.3752G>A, p.Ser1251Asn
G > A
Not Available
Ser1251Asn
rs75527207 117587806G>A, 127023G>A, 1652G>A, 1976G>A, 55081027G>A, G551D, Gly551Asp, Gly659Asp, c.1652G>A, p.Gly551Asp
G > A
Not Available
Gly659Asp
No VIP available CA VA
rs80282562 117534318G>A, 532G>A, 55027539G>A, 73535G>A, 856G>A, G178R, Gly178Arg, Gly286Arg, c.532G>A, p.Gly178Arg
G > A
Not Available
Gly286Arg
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • ivacaftor
  • vx-770
Trade Names
  • Kalydeco
Brand Mixture Names

PharmGKB Accession Id:
PA165950341

Description

Ivacaftor (also known as Kalydeco or VX-770) is a drug for the treatment of cystic fibrosis, developed by Vertex Pharmaceuticals and the Cystic Fibrosis Foundation.

Source: Drug Bank

Indication

For the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the CFTR gene.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Cystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator, which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. The defect, which is caused by a mutation in the individual's DNA, can be in any of several locations along the protein, each of which interferes with a different function of the protein. One mutation, G551D, lets the CFTR protein reach the epithelial cell surface, but doesn't let it transport chloride through the ion channel. Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the G551D-CFTR protein.

Source: Drug Bank

Pharmacology

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR). In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.

Source: Drug Bank

Protein Binding

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells.

Source: Drug Bank

Half-Life

12 hours following a single dose

Source: Drug Bank

Toxicity

There have been no reports of overdose with Ivacaftor. The highest single dose used in a clinical study was 800 mg in a solution formulation without any treatment-related adverse events.

Source: Drug Bank

Clearance

The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.

Source: Drug Bank

Route of Elimination

Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent.

Source: Drug Bank

Volume of Distribution

The mean apparent volume of distribution (Vz/F) of ivacaftor after a single dose of 275 mg of Ivacaftor in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.

Source: Drug Bank

Chemical Properties

Chemical Formula

C24H28N2O3

Source: Drug Bank

C24H28N2O3

Source: PubChem Compound

Canonical SMILES

CC(C)(C)C1=CC(=C(O)C=C1NC(=O)C1=CNC2=CC=CC=C2C1=O)C(C)(C)C

Source: Drug Bank

CC(C)(C)C1=CC(=C(C=C1NC(=O)C2=CNC3=CC=CC=C3C2=O)O)C(C)(C)C

Source: PubChem Compound

Average Molecular Weight

392.4907

Source: Drug Bank

392.49072

Source: PubChem Compound

Monoisotopic Molecular Weight

392.209992772

Source: Drug Bank

392.209993

Source: PubChem Compound

IUPAC Names

  • N-(2,4-ditert-butyl-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
CFTR
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
CYP3A4
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
CYP3A5
No related drugs are available.

Curated Information ?

EvidenceDisease
No Dosing Guideline available DL CA VA No VIP available No VIP available
Cystic Fibrosis

Publications related to ivacaftor: 29

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2014. Sheikh Shahid I, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. The Lancet. Respiratory medicine. 2014. Boyle Michael P, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis: Toward personalized therapies. The international journal of biochemistry & cell biology. 2014. Ikpa Pauline T, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls. Pharmacology & therapeutics. 2014. Bell Scott C, et al. PubMed
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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype. Clinical pharmacology and therapeutics. 2014. Clancy John P, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. PloS one. 2014. Char Jessica E, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest. 2013. McGarry Meghan E, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Ivacaftor in a G551D homozygote with cystic fibrosis. The New England journal of medicine. 2013. Harrison Michael J, et al. PubMed
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Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harbor perspectives in medicine. 2013. Rowe Steven M, et al. PubMed
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Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2013. Van Goor Fredrick, et al. PubMed
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Effect of VX-770 (Ivacaftor) and OAG on Ca(2+) influx and CFTR activity in G551D and F508del-CFTR expressing cells. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2013. Vachel Laura, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2013. Hebestreit Helge, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation. American journal of respiratory and critical care medicine. 2013. Davies Jane C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013. Durmowicz Anthony G, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis therapeutics: the road ahead. Chest. 2013. Hoffman Lucas R, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The use of ivacaftor in an adult with severe lung disease due to cystic fibrosis (deltaF508/G551D). Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2013. Polenakovik Hari M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A young Hispanic with c.1646G>A mutation exhibits severe cystic fibrosis lung disease: is ivacaftor an option for therapy?. American journal of respiratory and critical care medicine. 2012. Yarlagadda Sunitha, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy. Clinical biochemistry. 2012. Lubamba Bob, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. The Journal of biological chemistry. 2012. Eckford Paul D W, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012. Flume Patrick A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Ivacaftor potentiation of multiple CFTR channels with gating mutations. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2012. Yu Haihui, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease. PloS one. 2012. Sloane Peter A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment. The Annals of pharmacotherapy. 2012. Pettit Rebecca S. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. The New England journal of medicine. 2011. Ramsey Bonnie W, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators. American journal of physiology. Lung cellular and molecular physiology. 2011. Pyle Louise C, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Probing conformational rescue induced by a chemical corrector of F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutant. The Journal of biological chemistry. 2011. Yu Wilson, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. The New England journal of medicine. 2010. Accurso Frank J, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proceedings of the National Academy of Sciences of the United States of America. 2009. Van Goor Fredrick, et al. PubMed

LinkOuts

DrugBank:
DB08820
PubChem Compound:
16220172

Clinical Trials

These are trials that mention ivacaftor and are related to either pharmacogenetics or pharmacogenomics.

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.