1. Dosage

Ivacaftor is categorized as a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. Cystic fibrosis (CF) occurs because of CFTR genetic mutations causing mucosal obstruction of the distal lung airway and submucosal glands.  Malfunction of the CFTR alters electrolyte homeostasis, which changes cell potentials and can lead to organ damage in CF patients. Patient genotyping shows that approximately 4% of the 30,000 CF patients in America are believed to have a G551D-CFTR mutation. Kalydeco® (Ivacaftor) targets multi-organ chloride channels at the surface of epithelial cells to enhance the opening of the CFTR protein.

Kalydeco® (ivacaftor) is FDA approved for use in patients 4 months or older who have one mutation in the CFTR gene that is responsive to ivacaftor therapy based on clinical and/ or in vitro assay data. If the patient’s genotype is unknown then an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use 1,2,4. A list of CF mutations indicated for the treatment of CF in patients 4 months of age and older are provided in the list below.

List of CFTR Gene Mutations that Produce Protein and are Responsive to Kalydeco®

  • 711+3A→G*
  • 2789+5G→A*
  • 3272-26A→G*
  • 3849+10kbC→T*
  • A120T
  • A234D
  • A349V
  • A455E*
  • A1067T
  • D110E
  • D110H
  • D192G
  • D579G*
  • D924N
  • D1152H*
  • D1270N
  • E56K
  • E193K
  • E822K
  • E831X*
  • F311del
  • F311L
  • F508C
  • F508C;S1251N†
  • F1052V
  • F1074L
  • G178E
  • G178R*
  • G194R
  • G314E
  • G551D*
  • G551S*
  • G576A
  • G970D
  • G1069R
  • G1244E*
  • G1249R
  • G1349D*
  • H939R
  • H1375P
  • I148T
  • I175V
  • I807M
  • I1027T
  • I1139V
  • K1060T
  • L206W*
  • L320V
  • L967S
  • L997F
  • L1480P
  • M152V
  • M952I
  • M952T
  • P67L*
  • Q237E
  • Q237H
  • Q359R
  • Q1291R
  • R74W
  • R75Q
  • R117C*
  • R117G
  • R117H*
  • R117L
  • R117P
  • R170H
  • R347H*
  • R347L
  • R352Q*
  • R553Q
  • R668C
  • R792G
  • R933G
  • R1070Q
  • R1070W*
  • R1162L
  • R1283M
  • S549N*
  • S549R*
  • S589N
  • S737F
  • S945L*
  • S977F*
  • S1159F
  • S1159P
  • S1251N*
  • S1255P*
  • T338I
  • T1053I
  • V232D
  • V562I
  • V754M
  • V1293G
  • W1282R
  • Y1014C
  • Y1032C

Legend

  • * Clinical data exists for these mutations.
  • † Complex/compound mutations. Most people with CF have 2 CF mutations, 1 on each copy of the CF gene. However, in rare instances, 1 copy of the CF gene can have more than 1 mutation. This is called a compound, or complex, mutation.

A combination product containing lumacaftor and ivacaftor (Orkambi®) was approved in July 2015 for use in patients 2 years and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, then an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. The F508del mutation is the most common cause of CF, with approximately half of the CF population in the U.S. being homozygous for the mutation. The combined effect of lumacaftor and ivacaftor increases the quantity (lumacaftor) and function (ivacaftor) of the F508del-CFTR ion channel, resulting in improved channel function and clinical benefit. The efficacy and safety of lumacaftor and ivacaftor combination therapy has not been established in patients with cystic fibrosis other than those homozygous for the F508del mutation1-3.

Tezacaftor/ivacaftor (Symdeko®) combination therapy is FDA-approved for CF in patients six years of age and older homozygous for the F508del mutation or who have at least one mutation in the CFTR gene responsive to tezacaftor/ivacaftor. If the patient’s genotype is unknown, then an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. Tezacaftor increases the amount of mature CFTR at the cell surface by expediting cellular processing and trafficking of normal and select mutant forms of CFTR, while ivacaftor enhances channel-opening probability of CFTR proteins at the cell surface. Combined therapy improves CFTR function at the cell surface and increases chloride transport, resulting in clinical benefit1-3, 7. All CFTR protein producing CFTR mutations that are responsive to Symdeko® are listed in the following list8 .

CFTR Mutations that Produce CFTR Protein and Are Responsive to Symdeko®

  • 546insCTA§
  • 711+3A→G*
  • 2789+5G→A*
  • 3272-26A→G*
  • 3849+10kbC→T*
  • A120T§
  • A234D§
  • A349V§
  • A455E*
  • A554E§
  • A1006E§
  • A1067T
  • D110E
  • D110H*
  • D192G§
  • D443Y§
  • D443Y;G576A;R668C‡§
  • D579G*
  • D614G§
  • D836Y§
  • D924N§
  • D979V§
  • D1152H*
  • D1270N
  • E56K
  • E60K§
  • E92K§
  • E116K§
  • E193K
  • E403D§
  • E588V§
  • E822K§
  • E831X
  • F191V§
  • F311del§
  • F311L§
  • F508C§
  • F508C;S1251N‡§
  • F508del†
  • F575Y§
  • F1016S§
  • F1052V
  • F1074L
  • F1099L§
  • G126D§
  • G178E§
  • G178R§
  • G194R§
  • G194V§
  • G314E§
  • G551D§
  • G551S§
  • G576A§
  • G576A;R668C‡§
  • G622D§
  • G970D§
  • G1069R§
  • G1244E§
  • G1249R§
  • G1349D§
  • H939R§
  • H1054D§
  • H1375P§
  • I148T§
  • I175V§
  • I336K§
  • I601F§
  • I618T§
  • I807M§
  • I980K§
  • I1027T§
  • I1139V§
  • I1269N§
  • I1366N§
  • K1060T
  • L15P§
  • L206W*
  • L320V§
  • L346P§
  • L967S§
  • L997F§
  • L1324P§
  • L1335P§
  • L1480P§
  • M152V§
  • M265R§
  • M952I§
  • M952T§
  • P5L§
  • P67L*
  • P205S§
  • Q98R§
  • Q237E§
  • Q237H§
  • Q359R§
  • Q1291R§
  • R31L§
  • R74Q§
  • R74W
  • R74W; D1270N‡§
  • R74W;V201M‡§
  • R74W;V201M;D1270N‡§
  • R75Q§
  • R117C*§
  • R117G§
  • R117H§
  • R117L§
  • R117P§
  • R170H§
  • R258G§
  • R334L§
  • R334Q§
  • R347H*§
  • R347L§
  • R347P§
  • R352Q*§
  • R352W§
  • R553Q§
  • R668C§
  • R751L§
  • R792G§
  • R933G§
  • R1066H§
  • R1070Q§
  • R1070W*
  • R1162L§
  • R1283M§
  • R1283S§
  • S549N§
  • S549R§
  • S589N§
  • S737F§
  • S912L§
  • S945L*
  • S977F*
  • S1159F§
  • S1159P§
  • S1251N§
  • S1255P§
  • T338I§
  • T1036N§
  • T1053I§
  • V201M§
  • V232D§
  • V562I§
  • V754M§
  • V1153E§
  • V1240G§
  • V1293G§
  • W1282R§
  • Y109N§
  • Y161S§
  • Y1014C§
  • Y1032C§

Legend:

  • § = Mutations approved in December 2020
  • * = Clinical data for these mutations appear in sections 14.1 and 14.2 of the Prescribing Information.
  • † = A patient must have 2 copies of the F508del mutation or at least 1 copy of a responsive mutation listed above in this table to be indicated for Symdeko®.
  • ‡ = Complex/compound mutations in which a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.

Trikafta® is a combination product of elexacaftor, tezacaftor, and ivacaftor that is FDA approved for the treatment of cystic fibrosis patients 6 years of age and older who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data. If the patient’s genotype is unknown, then an FDA-cleared cystic fibrosis test should be used to confirm the presence of at least one F508del mutation or a responsive mutation based on in vitro data1,2,10.

Both elexacaftor and tezacaftor increase the amount of mature CFTR at the cell surface by facilitating cellular processing and trafficking of normal and select mutant forms of CFTR, while ivacaftor enhances channel-opening probability of CFTR proteins at the cell surface. Combined therapy improves CFTR function at the cell surface, increases chloride transport, and results in clinical benefit1-3, 7-9. A list of CFTR gene mutations that are responsive to Trikafta® therapy are listed below10.

List of CFTR Gene Mutations that are Responsive to Trikafta®

  • 3141del9   
  • 546insCTA 
  • A46D 
  • A120T 
  • A234D 
  • A349V 
  • A455E 
  • A554E 
  • A1006E 
  • A1067T 
  • D110E 
  • D110H 
  • D192G 
  • D443Y 
  • D443Y;G576A;R668C†  
  • D579G 
  • D614G 
  • D836Y 
  • D924N 
  • D979V   
  • D1152H 
  • D1270N 
  • E56K 
  • E60K 
  • E92K 
  • E116K 
  • E193K   
  • E403D  
  • E474K 
  • E588V 
  • E822K
  • F191V 
  • F311del 
  • F311L 
  • F508C 
  • F508C;S1251N† 
  • F508del* 
  • F575Y 
  • F1016S 
  • F1052V 
  • F1074L 
  • F1099L 
  • G27R 
  • G85E  
  • G126D
  • G178E 
  • G178R 
  • G194R 
  • G194V 
  • G314E
  • G463V 
  • G480C 
  • G551D 
  • G551S 
  • G576A 
  • G576A;R668C† 
  • G622D
  • G628R 
  • G970D 
  • G1061R 
  • G1069R
  • G1244E 
  • G1249R 
  • G1349D 
  • H139R 
  • H199Y 
  • H939R 
  • H1054D 
  • H1085P 
  • H1085R 
  • H1375P 
  • I148T 
  • I175V 
  • I336K
  • I502T 
  • I601F 
  • I618T 
  • I807M 
  • I980K 
  • I1027T
  • I1139V 
  • I1269N 
  • I1366N  
  • K1060T 
  • L15P 
  • L165S 
  • L206W
  • L320V
  • L346P  
  • L453S 
  • L967S
  • L997F 
  • L1077P 
  • L1324P 
  • L1335P 
  • L1480P 
  • M152V 
  • M265R 
  • M952I 
  • M952T 
  • M1101K 
  • P5L 
  • P67L 
  • P205S 
  • P574H 
  • Q98R 
  • Q237E 
  • Q237H 
  • Q359R  
  • Q1291R 
  • R31L 
  • R74Q 
  • R74W
  • R74W;D1270N†
  • R74W;V201M†
  • R74W;V201M;D1270N†
  • R75Q 
  • R117C  
  • R117G
  • R117H 
  • R117L
  • R117P 
  • R170H 
  • R258G 
  • R334L 
  • R334Q 
  • R347H 
  • R347L
  • R347P 
  • R352Q
  • R352W 
  • R553Q 
  • R668C 
  • R751L 
  • R792G 
  • R933G 
  • R1066H 
  • R1070Q 
  • R1070W
  • R1162L 
  • R1283M 
  • R1283S 
  • S13F
  • S341P 
  • S364P 
  • S492F 
  • S549N 
  • S549R
  • S589N
  • S737F
  • S912L
  • S945L
  • S977F
  • S1159F
  • S1159P
  • S1251N
  • S1255P
  • T338I
  • T1036N
  • T1053I
  • V201M
  • V232D
  • V456A
  • V456F
  • V562I
  • V754M
  • V1153E
  • V1240G
  • V1293G
  • W361R
  • W1098C
  • W1282R
  •  Y109N
  • Y161D
  • Y161S
  • Y563N
  • Y1014C
  • Y1032C

Legend:

  • * = F508del is a responsive CFTR mutation based on both clinical and in vitro data.
  • † = Complex/ compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.