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 protein alters electrolyte homeostasis, which changes cell potentials and can lead to organ damage in CF patients. 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 one month 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 use1,2. A list of CF mutations indicated for the treatment of CF in patients one month of age and older are provided in the following list.
List of CFTR Gene Mutations that Produce Protein and are Responsive to Kalydeco
- 711+3A→G*
- F311del
- I148T
- R75Q
- S589N
- 2789+5G→A*
- F311L
- I175V
- R117C*
- S737F
- 3272-26A→G*
- F508C
- I807M
- R117G
- S945L*
- 3849+10kbC→T*
- F508C;S1251N†
- I1027T
- R117H*
- S977F*
- A120T
- F1052V
- I1139V
- R117L
- S1159F
- A234D
- F1074L
- K1060T
- R117P
- S1159P
- A349V
- G178E
- L206W*
- R170H
- S1251N*
- A455E*
- G178R*
- L320V
- R347H*
- S1255P*
- A1067T
- G194R
- L967S
- R347L
- T338I
- D110E
- G314E
- L997F
- R352Q*
- T1053I
- D110H
- G551D*
- L1480P
- R553Q
- V232D
- D192G
- G551S*
- M152V
- R668C
- V562I
- D579G*
- G576A
- M952I
- R792G
- V754M
- D924N
- G970D
- M952T
- R933G
- V1293G
- D1152H*
- G1069R
- P67L*
- R1070Q
- W1282R
- D1270N
- G1244E*
- Q237E
- R1070W*
- Y1014C
- E56K
- G1249R
- Q237H
- R1162L
- Y1032C
- E193K
- G1349D*
- Q359R
- R1283M
- E822K
- H939R
- Q1291R
- S549N*
- E831X*
- H1375P
- R74W
- S549R*
Legend
- * = Clinical data exists for these mutations.
- † = 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.
A combination product containing lumacaftor and ivacaftor (Orkambi) is approved for use in patients one year 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, stability (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 based on in vitro data and/or clinical evidence. 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 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 increases CFTR quantity and function at the cell surface and increases chloride transport, resulting in clinical benefit1,4,6,7. CFTR mutations that are responsive to Symdeko are listed in the list below.
CFTR Mutations that Produce CFTR Protein and Are Responsive to Symdeko
- 546insCTA
- E92K
- G576A
- L346P
- R117G
- S589N
- 711+3A→G*
- E116K
- G576A:R668C†
- L967S
- R117H
- S737F
- 2789+5G→A*
- E193K
- G622D
- L997F
- R117L
- S912L
- 3272-26A→G*
- E403D
- G970D
- L1324P
- R117P
- S945L*
- 3849+10kbC→T*
- E588V
- G1069R
- L1335P
- R170H
- S977F*
- A120T
- E822K
- G1244E
- L1480P
- R258G
- S1159F
- A234D
- E831X
- G1249R
- M152V
- R334L
- S1159P
- A349V
- F191V
- G1349D
- M265R
- R334Q
- S1251N
- A455E*
- F311del
- H939R
- M952I
- R347H*
- S1255P
- A554E
- F311L
- H1054D
- M952T
- R347L
- T338I
- A1006E
- F508C
- H1375P
- P5L
- R347P
- T1036N
- A1067T
- F508C;S1251N†
- I148T
- P67L*
- R352Q*
- T1053I
- D110E
- F508del‡
- I175V
- P205S
- R352W
- V201M
- D110H*
- F575Y
- I336K
- Q98R
- R553Q
- V232D
- D192G
- F1016S
- I601F
- Q237E
- R668C
- V562I
- D443Y
- F1052V
- I618T
- Q237H
- R751L
- V754M
- D443Y;G576A;R668C†
- F1074L
- I807M
- Q359R
- R792G
- V1153E
- D579G*
- F1099L
- I980K
- Q1291R
- R933G
- V1240G
- D614G
- G126D
- I1027T
- R31L
- R1066H
- V1293G
- D836Y
- G178E
- I1139V
- R74Q
- R1070Q
- W1282R
- D924N
- G178R
- I1269N
- R74W
- R1070W*
- Y109N
- D979V
- G194R
- I1366N
- R74W;D1270N†
- R1162L
- Y161S
- D1152H*
- G194V
- K1060T
- R74W;V201M†
- R1283M
- Y1014C
- D1270N
- G314E
- L15P
- R74W;V201M;D1270N†
- R1283S
- Y1032C
- E56K
- G551D
- L206W*
- R75Q
- S549N
- E60K
- G551S
- L320V
- R117C*
- S549R
Legend:
- * = Clinical data for these mutations appear in sections 14.1 and 14.2 of the Prescribing Information.
- † = 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.
- ‡ = A patient must have two copies of the F508del mutation or at least one copy of a responsive mutation listed above in this table to be indicated for Symdeko.
Trikafta is a combination product of elexacaftor, tezacaftor, and ivacaftor that is FDA approved for the treatment of cystic fibrosis patients two 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 mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data1,5.
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 increases CFTR quantity and function at the cell surface, increases chloride transport, and results in clinical benefit1,5-7. A list of CFTR gene mutations that are responsive to Trikafta therapy are listed in the following list.
List of CFTR Gene Mutations that are Responsive to Trikafta
- 3141del9
- E822K
- G1069R
- L967S
- R117L
- S912L
- 546insCTA
- F191V
- G1244E
- L997F
- R117P
- S945L
- A46D
- F311del
- G1249R
- L1077P
- R170H
- S977F
- A120T
- F311L
- G1349D
- L1324P
- R258G
- S1159F
- A234D
- F508C
- H139R
- L1335P
- R334L
- S1159P
- A349V
- F508C;S1251N*
- H199Y
- L1480P
- R334Q
- S1251N
- A455E
- F508del†
- H939R
- M152V
- R347H
- S1255P
- A554E
- F575Y
- H1054D
- M265R
- R347L
- T338I
- A1006E
- F1016S
- H1085P
- M952I
- R347P
- T1036N
- A1067T
- F1052V
- H1085R
- M952T
- R352Q
- T1053I
- D110E
- F1074L
- H1375P
- M1101K
- R352W
- V201M
- D110H
- F1099L
- I148T
- P5L
- R553Q
- V232D
- D192G
- G27R
- I175V
- P67L
- R668C
- V456A
- D443Y
- G85E
- I336K
- P205S
- R751L
- V456F
- D443Y;G576A;R668C*
- G126D
- I502T
- P574H
- R792G
- V562I
- D579G
- G178E
- I601F
- Q98R
- R933G
- V754M
- D614G
- G178R
- I618T
- Q237E
- R1066H
- V1153E
- D836Y
- G194R
- I807M
- Q237H
- R1070Q
- V1240G
- D924N
- G194V
- I980K
- Q359R
- R1070W
- V1293G
- D979V
- G314E
- I1027T
- Q1291R
- R1162L
- W361R
- D1152H
- G463V
- I1139V
- R31L
- R1283M
- W1098C
- D1270N
- G480C
- I1269N
- R74Q
- R1283S
- W1282R
- E56K
- G551D
- I1366N
- R74W
- S13F
- Y109N
- E60K
- G551S
- K1060T
- R74W;D1270N*
- S341P
- Y161D
- E92K
- G576A
- L15P
- R74W;V201M*
- S364P
- Y161S
- E116K
- G576A;R668C*
- L165S
- R74W;V201M;D1270N*
- S492F
- Y563N
- E193K
- G622D
- L206W
- R75Q
- S549N
- Y1014C
- E403D
- G628R
- L320V
- R117C
- S549R
- Y1032C
- E474K
- G970D
- L346P
- R117G
- S589N
- E588V
- G1061R
- L453S
- R117H
- S737F
Legend:
- * = 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
- † = F508del is a responsive CFTR mutation based on both clinical and in vitro data