(255) Real-world identification of hepatically adjusted Trikafta dosing trends at Atrium Health

Background: Novel CFTR modulator, ELX/TZA/IVA (Trikafta) has significantly improved the quality of life for patients with eligible CF related genetic mutations. While highly desired, this medication does not exist without limitations. Elevated transaminases and hepatic injury have been discovered with the use of ELX/TZA/IVA. We sought to identify hepatic injury trends in relation to current and past modulator use to aid in modulator dosing strategies.

Methods: A retrospective medical record review was conducted for patients from Atrium Health’s adult and pediatric CF clinics, who were identified with preexisting liver disease, transaminitis incidental to prior CFTR modulator use, or requiring ELX/TZA/IVA hepatic dose adjustment for transaminitis discovered on quarterly/annual monitoring lab draws.

Results: Patients at both the adult and pediatric CF clinics required hepatically adjusted dosing of ELX/TZA/IVA. Dosing strategies ranged based on patient tolerability. We identified 13 adults (18yo+) with preexisting liver disease, 5 (38%) who had transaminitis on Trikafta. We also identified 11 children with preexisting liver disease, 5 (45%) who had transaminitis on Trikafta. There were 4 adults and 3 children who had transaminitis on Trikafta without preexisting diagnosed liver disease. Despite a prior history of intolerance to CFTR modulators, the majority of patients with pre-existing liver disease were able to tolerate a modified dose of ELX/TZA/IVA. There were 7 (54%) adults and 4 (36%) children with preexisting liver disease who tolerated full dose ELX/TZA/IVA. There were also 3 adults without known pre-existing liver disease that tolerated previous CFTR modulators but required dose reduction of ELX/TZA/IVA due to transaminitis. Out of 153 patients on ELX/TZA/IVA, a total of 6 (4%) patients had ALT/AST x3 ULN (upper limit of normal), 3 (2%) patients had ALT/AST x5 ULN, 1 (< 1%) patient had ALT/AST x 8 ULN, and 8 (5%) patients had Total bilirubin greater than 2x ULN. Both clinics had at least 1 patient who had to discontinue therapy due to hepatic livery injury.

Conclusions: Having preexisting liver disease did not always preclude use of ELX/TZA/IVA for the management of CF. However, the incidence of transaminitis in the Atrium Health CF clinics was more prevalent than found in phase 3 clinical trials and required intervention with frequent monitoring. Dosing adjustments should be individualized and tailored to the patient’s hepatic response. The results from this detailed review will be used to create a standard process for modulator initiation and dose adjustments. Further studies should be completed to evaluate the efficacy of reduced hepatic dose adjustments and mechanism of hepatic toxicity.

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