Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype

Abstract

Cystic fibrosis (CF) is a life‐shortening disease arising as a consequence of mutations within the CFTR gene. Novel therapeutics for CF are emerging that target CF transmembrane conductance regulator protein (CFTR) defects resulting from specific CFTR variants. Ivacaftor is a drug that potentiates CFTR gating function and is specifically indicated for CF patients with a particular CFTR variant, G551D‐CFTR (rs75527207). Here, we provide therapeutic recommendations for ivacaftor based on preemptive CFTR genotype results. Clinical Pharmacology & Therapeutics (2014); 95 6, 592–597. doi:

PharmGKB summary

“…It is one of the variants in a recommended panel for newborn screening of CF by the American College of Medical Genetics [21]. Global allele frequencies are calculated at 0.02 in Caucasian, 0.025 in African, 0.004 in Mexican, 0.003 in South American, 0.002 in Mediterranean and 0.001 in Middle Eastern CF patients (see CPIC CFTR -ivacaftor guideline supplement for individual references) [37]. …”

“…It was originally indicated in CF patients 6 years and older who have at least one G551D variant (rs75527207 genotype AA or GA) [37]. Ivacaftor targets the gating defect of G551D-CFTR to enhance activity; in vitro studies show it enhances open channel probability and increases chloride transport of G551D-CFTR expressing cells [38–43].…”

“…In Ashkenazis from Israel the W1282X-CFTR (c.3846G>A, rs77010898) variant is more common than F508del-CFTR [14]. Global frequencies are estimated at 0.66 in Caucasian, 0.48 in Mediterranean, 0.44 in Mexican, 0.42 in African, 0.39 in South American, and 0.21 in Middle Eastern CF patients (see CPIC CFTR -ivacaftor guideline supplement for individual references) [37]. …”

“…Currently, ivacaftor monotherapy is not recommended in CF patients homozygous for the F508del-CFTR variant (rs113993960 or rs199826652 genotype del/del) [37, 54]. This may be due to ivacaftor’s mechanism of action as a potentiator (Table 1).…”

Ivacaftor: a guide to its use in cystic fibrosis

“…Patients with an unknown CFTR genotype should be tested by an approved method; Clinical Pharmacogenetics Implementation Consortium guidelines [6] are available to aid interpretation of CFTR genotypes…”