TY - JOUR
T1 - Stepwise Introduction of Elexacaftor-Tezacaftor-Ivacaftor in Patients With Cystic Fibrosis and Liver Cirrhosis Child-Pugh A or B Using Clinical and Therapeutic Drug Monitoring
T2 - A Case Series
AU - Vonk, Steffie E. M.
AU - Lub, Rianne
AU - Weersink, Els J. M.
AU - Amsterdam mucociliary clearance disease research group
AU - Beuers, Ulrich
AU - Mathôt, Ron A. A.
AU - Kemper, E. Marleen
AU - Altenburg, Josje
N1 - Funding Information: The authors would like to thank the patients for their approval to share their clinical data and contribution to this case report. The authors would like to thank Marloes Vos-van der Meer, Dennis van der Laan, and Miranda Seegers for their specific contributions to the laboratory analysis of this study. SV, RL, EW, RM, MK and JA contributed to the design of the study. Data collection and analysis was carried out by SV, RL and JA. SV created the figure. SV, RM, MK, UB and JA interpreted the data. All authors drafted and revised the work critically and finally approved the version to be published. Publisher Copyright: © 2023 The Author(s)
PY - 2023
Y1 - 2023
N2 - Purpose: Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and affecting multiple organs, including the lungs and liver. Almost 90% of people affected carry at least 1 Phe508del CFTR mutation. Medical treatment with the CFTR-modulating drug elexacaftor-tezacaftor-ivacaftor (ETI) has been proven to be efficacious in carriers of at least 1 Phe508del CFTR mutation. Use of ETI in patients with CF (pwCF) and liver cirrhosis is still controversial. Therefore, stepwise introduction of ETI in pwCF and liver cirrhosis Child-Pugh A or B was evaluated using clinical and therapeutic drug monitoring. Methods: Seven consecutive pwCF received ETI. Four dosing steps were defined, at each of which the patients underwent clinical examination, routine blood tests, and therapeutic drug monitoring. Exposure of elexacaftor, tezacaftor, and ivacaftor was assessed by means of determination of AUC. Findings: ETI was successfully introduced and maintained in all pwCF. In those with Child-Pugh B cirrhosis (n = 2), diminishment of the dose as recommended by the label resulted in AUC values that were lower than the mean AUC values in pwCF without hepatic impairment, as reported previously. Implications: Despite the limitations of this small case series, stepwise elevation of ETI dose did not induce clinical adverse effects or increases in serum liver test results under strict clinical follow-up and therapeutic drug monitoring, and may allow tolerable introduction of this therapy in pwCF and cirrhosis Child-Pugh A and possibly B.
AB - Purpose: Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and affecting multiple organs, including the lungs and liver. Almost 90% of people affected carry at least 1 Phe508del CFTR mutation. Medical treatment with the CFTR-modulating drug elexacaftor-tezacaftor-ivacaftor (ETI) has been proven to be efficacious in carriers of at least 1 Phe508del CFTR mutation. Use of ETI in patients with CF (pwCF) and liver cirrhosis is still controversial. Therefore, stepwise introduction of ETI in pwCF and liver cirrhosis Child-Pugh A or B was evaluated using clinical and therapeutic drug monitoring. Methods: Seven consecutive pwCF received ETI. Four dosing steps were defined, at each of which the patients underwent clinical examination, routine blood tests, and therapeutic drug monitoring. Exposure of elexacaftor, tezacaftor, and ivacaftor was assessed by means of determination of AUC. Findings: ETI was successfully introduced and maintained in all pwCF. In those with Child-Pugh B cirrhosis (n = 2), diminishment of the dose as recommended by the label resulted in AUC values that were lower than the mean AUC values in pwCF without hepatic impairment, as reported previously. Implications: Despite the limitations of this small case series, stepwise elevation of ETI dose did not induce clinical adverse effects or increases in serum liver test results under strict clinical follow-up and therapeutic drug monitoring, and may allow tolerable introduction of this therapy in pwCF and cirrhosis Child-Pugh A and possibly B.
KW - Child-Pugh A and B
KW - elexacaftor-tezacaftor-ivacaftor
KW - hepatic impairment
KW - liver cirrhosis
KW - therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=85178636470&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.clinthera.2023.11.003
DO - https://doi.org/10.1016/j.clinthera.2023.11.003
M3 - Article
C2 - 38042631
SN - 0149-2918
JO - Clinical therapeutics
JF - Clinical therapeutics
ER -