P301 Step-wise introduction of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and liver cirrhosis Child-Pugh A or B using clinical- and therapeutic drug monitoring: a case series

Serum liver test abnormalities are described as a common adverse effect of elexacaftor-tezacaftor-ivacator (ETI) in patients with Cystic Fibrosis (pwCF). In the phase I registration studies the PK of ETI have been compared between non-CF people with hepatic impairment and healthy individuals. In the former group exposure of ETI was increased and therefore a reduced dose in pwCF and cirrhosis Child-Pugh B is recommended. To our knowledge, there are no data on the exposure of ETI in pwCF and cirrhosis Child-Pugh A or B. In this case series we describe seven pwCF and cirrhosis Child-Pugh A or B where ETI was gradually introduced using clinical and therapeutic drug monitoring (TDM). Four dosing steps were defined at which patients underwent clinical examination, routine blood tests and TDM. Exposure of ETI was assessed by determination of the area under the plasma concentration versus time curve (AUC). The decision to proceed with the next dosing step was at the discretion of the treating pulmonologist, taking into account the presence or absence of liver test abnormalities, other side effects, the TDM advice by the pharmacist and the clinical effectiveness of ETI. In all patients ETI was successfully introduced and maintained. All patients improved in respiratory symptoms, ppFEV1, and BMI. Four patients reported side effects, which resolved in most cases. In pwCF with Child-Pugh B cirrhosis (n = 2) diminishment of the dose as recommended by the label resulted in AUCs that were lower than previously reported mean AUC values in pwCF without hepatic impairment. Therefore, the dose was further increased under careful monitoring. Stepwise elevation of ETI dose did not induce clinical side effects or increase in serum liver tests under strict clinical and biochemical follow-up and TDM, and may allow safe introduction of this therapy in pwCF and hepatic impairment.