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.
April 2014 Update on PharmGKB
- After the submission and review of the CPIC guideline manuscript, the FDA-approved drug label for ivacaftor was updated to include additional variants. In light of these changes, the CPIC guideline annotation on this PharmGKB webpage has been updated to include additional CFTR variants, specifically G1244E (rs267606723), G1349D (rs193922525), G178R (rs80282562), G551S (rs121909013), S1251N (rs74503330), S1255P (rs121909041), S549N (rs121908755) and S549R (rs121908757 and rs121909005) (see Table 1 and Figure 1, below). These variants are not discussed in the 2014 guideline publication.
Accepted article preview online March 2014; Advance online publication March 2014.
- Guidelines regarding the use of pharmacogenomic tests in determining whether ivacaftor treatment should be undertaken have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
- These guidelines are applicable to
- cystic fibrosis patients
- pediatrics, 6 years and older
- Download and read:
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.