ABCMdb

PMID: 24030637

Deeks ED
Ivacaftor: a review of its use in patients with cystic fibrosis.
Drugs. 2013 Sep;73(14):1595-604. doi: 10.1007/s40265-013-0115-2., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCC7 p.Gly551Asp Ivacaftor increases the open probability (i.e. gating) of CFTR channels with the G551D mutation, thus enhancing chloride transport, and is indicated in a number of countries for the treatment of cystic fibrosis in patients aged C6 years who carry this mutation. Login to comment 3 ABCC7 p.Gly551Asp In two 48-week, double-blind, phase III trials in patients aged C12 (STRIVE) or 6-11 (ENVISION) years with cystic fibrosis and the G551D mutation, oral ivacaftor 150 mg every 12 h significantly improved lung function relative to placebo, when used in combination with standard care. Significant improvements in pulmonary exacerbation risk (in STRIVE) as well as bodyweight and some aspects of health-related quality of life (both studies) were also seen with the drug versus placebo. Login to comment 6 ABCC7 p.Gly551Asp Thus, ivacaftor expands the current treatment options for patients with cystic fibrosis who have the G551D mutation. Login to comment 8 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Ivacaftor in cystic fibrosis: a summary First drug that treats an underlying cause of cystic fibrosis to be licensed for use Increases the open probability (i.e. gating) of cystic fibrosis transmembrane conductance regulator channels with the G551D mutation, thus augmenting chloride transport Convenient oral administration Improves lung function and bodyweight parameters when used in combination with standard care in adults, adolescents and children (aged C6 years) with cystic fibrosis and the G551D mutation Generally well tolerated 1 Introduction Cystic fibrosis is a complex, life-limiting, genetic disorder that can affect multiple organs throughout the body, leading to pulmonary disease (most cystic fibrosis-related deaths are due to pulmonary insufficiency), reproductive, hepatic, pancreatic and gastrointestinal dysfunction and malnutrition [1, 2]. Login to comment 17 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg1162* Mutations can be classified on the basis of their functional consequences, which include CFTR protein that is truncated and fails to reach the cell surface (class I) [e.g. R1162X]; is misfolded, improperly processed and defective, little of which reaches the cell surface (class II) [e.g. F508del]; is unable to open and transport chloride properly (class III) [e.g. G551D] or has reduced chloride conductance due to channel narrowing (class IV) [e.g. R117H] but reaches the cell surface; or transports chloride effectively but reaches the cell surface in reduced amounts due to defective transcript splicing (class V) [e.g. 3120?1G?A] [1, 3]. Login to comment 20 ABCC7 p.Gly551Asp The drug potentiates the open probability (i.e. gating) of the CFTR channel, thus enhancing its transport of chloride, and is indicated for the treatment of patients with cystic fibrosis aged C6 years who carry the CFTR gating mutation G551D [9, 10]. Login to comment 23 ABCC7 p.Gly551Asp Data are from in vitro [1116] and ex vivo [17] studies, as well as from double-blind [18-21] or single-blind [22], placebo-controlled trials in patients with cystic fibrosis and the G551D mutation (n = 8-167). Login to comment 28 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp In vitro, ivacaftor increased transepithelial current (a measure of chloride secretion) by approximately fourfold in rodent cells expressing human G551D CFTR (half maximal effective concentration [EC50] 100 nmol/L) and by approximately tenfold in human bronchial epithelial (HBE) cells isolated from a cystic fibrosis patient with both the G551D and F508del mutations (EC50 236 nmol/L) [10, 12]. Login to comment 30 ABCC7 p.Gly551Asp In membrane patches excised from recombinant rodent cells exposed to both PKA and ATP, the open probability of human G551D CFTR and wildtype CFTR increased approximately sixfold and twofold at ivacaftor concentrations of 10 and 1 lmol/L, respectively [12]. Login to comment 32 ABCC7 p.Gly551Asp Such ATP-independent potentiation may help to explain the drug`s benefit in cystic fibrosis patients with the G551D-CFTR mutation (see Sect. 4), which is known to cause disruption of the CFTR binding site usually responsible for ATP-dependent gating [11, 15]. Login to comment 33 ABCC7 p.Gly551Asp Of the two main circulating ivacaftor metabolites, only one (M1; see Sect. 3) is considered to be pharmacologically active, potentiating CFTR-mediated chloride transport with a potency approximately sixfold lower than that of the parent drug in HBE cells expressing G551D/F508del CFTR [5]. Login to comment 34 ABCC7 p.Gly551Asp Ivacaftor may potentiate CFTR channels with gating mutations other than G551D, according to additional in vitro data [13]. Login to comment 35 ABCC7 p.Gly551Asp ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Ser1251Asn ABCC7 p.Ser549Asn ABCC7 p.Gly970Arg ABCC7 p.Gly178Arg For example, in rodent cells expressing G551D/S, G178R, S549N/R, G970R, G1244E, S1251N, S1255P or G1349D CFTR, ivacaftor increased channel open probability from B5 % of normal at baseline to 30-118 % of normal and increased chloride transport C16- fold (EC50 124-594 nmol/L). Login to comment 36 ABCC7 p.Arg117His ABCC7 p.Pro67Leu ABCC7 p.Ser1235Arg ABCC7 p.Asp110His ABCC7 p.Asp110Glu ABCC7 p.Glu56Lys Further in vitro data suggest that other CFTR proteins with residual function may also be potentiated by ivacaftor, including those with mutations that affect conductance (e.g. R117H, D110H), mildly affect CFTR processing (e.g. E56K, P67L) or have uncharacterized effects (e.g. D110E, S1235R) [5, 16]. Login to comment 37 ABCC7 p.Arg334Trp ABCC7 p.Gly542* The in vitro effect of ivacaftor on CFTR mutant proteins with minimal chloride transport, such as those with mutations affecting CFTR synthesis (e.g. G542X) [5] or severely affecting CFTR conductance (e.g. R334W) or processing (e.g. F508del [13]) [5, 16], was minimal [5, 13] or less than its effect on CFTR proteins with mild conductance or processing defects [16]. Login to comment 38 ABCC7 p.Gly551Asp In another in vitro study, transepithelial current was increased with ivacaftor in HBE cultures from three of six patients homozygous for the F508del mutation, although this effect was of lesser magnitude than in HBE cells carrying both the F508del and G551D mutation [12]. Login to comment 39 ABCC7 p.Gly551Asp Notably, the affinity of the drug for F508del CFTR may be higher than for G551D CFTR, as the EC50 of ivacaftor was approximately tenfold lower in homozygous than in heterozygous cells (22 vs. 236 nmol/ L) [12]. Login to comment 41 ABCC7 p.Gly551Asp For example, the excessive absorption of sodium in HBE cells expressing G551D/F508del CFTR was reduced with ivacaftor, with a resultant increase in both apical surface fluid and the beat frequency of cilia [12]. Login to comment 43 ABCC7 p.Gly551Asp 2.2 Studies in Humans Improvements in CFTR function, as measured by the concentration of chloride in sweat, were seen with oral ivacaftor 150 mg every 12 h in patients with cystic fibrosis and the G551D mutation. Login to comment 47 ABCC7 p.Gly551Asp Treatment with ivacaftor 150 mg every 12 h for 28 days generally led to significant (p \ 0.01) reductions in total ventilation defects (assessed by hyperpolarized gas magnetic resonance imaging) [22] and ventilation inhomogeneity (measured by lung clearance index) [18] in patients with cystic fibrosis and the G551D mutation in placebo-controlled, phase II trials. Login to comment 50 ABCC7 p.Gly551Asp In an ex vivo study, the impaired degranulation of secondary and tertiary neutrophil granules in patients with cystic fibrosis and the G551D mutation was corrected following 1 year of treatment with ivacaftor (dosage not specified), with levels of degranulation significantly (p \ 0.05) increasing (by 130 %) to reach those seen in healthy controls [17]. Login to comment 59 ABCC7 p.Gly551Asp Exposure to ivacaftor appears to be related to FEV1 [9, 26] and sweat chloride [26] responses in patients with cystic fibrosis and the G551D mutation, according to population pharmacokinetic/pharmacodynamic modelling of data from phase IIa and III trials. Login to comment 87 ABCC7 p.Gly551Asp 4 Therapeutic Efficacy The potential for oral ivacaftor to be used in the treatment of patients with cystic fibrosis who have a G551D mutation in the CFTR gene was evaluated in a randomized, double-blind, placebo-controlled, dose-ranging (25-250 mg every 12 h) trial (n = 39) [19]. Login to comment 90 ABCC7 p.Gly551Asp These multicentre, phase III studies were conducted to evaluate the clinical efficacy of ivacaftor 150 mg every 12 h in treating cystic fibrosis when used in addition to existing therapy (the exception being inhaled hypertonic saline) in adults and adolescents (aged C12 years; Sect. 4.1) [20, 28] and children (aged 6-11 years; Sect. 4.2) [21, 29] with the G551D mutation. Login to comment 91 ABCC7 p.Gly551Asp Patients eligible for these trials had confirmed cystic fibrosis and the G551D mutation in at least one CFTR allele [28, 29] and were required to have an FEV1 40-90 % of predicted in STRIVE [28] and 40-105 % of predicted in ENVISION [29]. Login to comment 99 ABCC7 p.Gly551Asp Oral ivacaftor 150 mg every 12 h improved lung function when used in combination with standard care in adults and adolescents with cystic fibrosis and the G551D CFTR mutation. Login to comment 113 ABCC7 p.Gly551Asp 4.1.1 Longer-Term Findings The beneficial effects of ivacaftor on lung function, respiratory symptoms and bodyweight in adults and Table 2 Effect of oral ivacaftor 150 mg every 12 h, in addition to standard care, on lung function and respiratory symptoms in patients with cystic fibrosis and the G551D mutation in the CFTR gene. Login to comment 120 ABCC7 p.Gly551Asp Oral ivacaftor 150 mg every 12 h, in combination with standard care, was effective in improving lung function in children aged 6-11 years with cystic fibrosis and the G551D CFTR mutation, according to primary endpoint analysis. Login to comment 135 ABCC7 p.Gly551Asp 5 Tolerability Tolerability data concerning the use of oral ivacaftor in patients aged C6 years with cystic fibrosis who have the G551D CFTR mutation are available from the clinical studies discussed in Sect. 4. Login to comment 137 ABCC7 p.Gly551Asp Treatment with ivacaftor 150 mg every 12 h for up to 48 weeks was generally well tolerated in adults [20], adolescents [20] and children [21] with cystic fibrosis and the G551D CFTR mutation participating in the STRIVE [20] and ENVISION [21] trials. Login to comment 144 ABCC7 p.Gly551Asp In a pooled analysis, the adverse events that occurred most frequently and with at least a 3 % greater incidence with ivacaftor than with placebo among patients aged C6 years with cystic fibrosis and the G551D CFTR mutation included headache, oropharyngeal pain, upper respiratory tract infection (URTI), nasal congestion, abdominal pain, nasopharyngitis, diarrhoea, rash and dizziness (Fig. 2) [10]. Login to comment 158 ABCC7 p.Gly551Asp 0 5 10 15 20 25 30 Dizziness Rash Diarrhoea Nasopharyngitis Abdominal pain Nasal congestion URTI Oropharyngeal pain Headache % of patients Ivacaftor Placebo Fig. 2 Tolerability of oral ivacaftor 150 mg every 12 h in patients (aged 6-53 years) with cystic fibrosis and the G551D CFTR mutation. Login to comment 161 ABCC7 p.Gly551Asp URTI upper respiratory infection 6 Dosage and Administration For the treatment of patients with cystic fibrosis and the G551D CFTR mutation, the recommended dosage of iva- caftorintheUSA[10] andEU[9] is150 mgevery12 h,taken orally with fat-containing food. Login to comment 162 ABCC7 p.Gly551Asp Patients with an unknown genotype should have the presence of the G551D mutation confirmed before being treated with ivacaftor. Login to comment 164 ABCC7 p.Gly551Asp 7 Current Status of Ivacaftor in Cystic Fibrosis Oral ivacaftor is indicated in a number of countries, including the USA [10] and those of the EU [9], for the treatment of cystic fibrosis in patients aged C6 years who have the G551D CFTR mutation and its use is strongly recommended in this patient population in the most recent guidelines of the Pulmonary Clinical Practice Guidelines Committee (established by the Cystic Fibrosis Foundation) [7]. Login to comment 169 ABCC7 p.Gly551Asp The G551D mutation is present in &3 % of patients with cystic fibrosis, making it the third most common mutation of the CFTR gene [3]. Login to comment 176 ABCC7 p.Arg117His A phase III ivacaftor trial in patients with the class IV CFTR mutation, R117H, is also recruiting participants [33]. Login to comment