Personalized Dosing of ELE/TEZ/IVA in Cystic Fibrosis: integrating pharmacokinetics and pharmacogenetics for Improved Outcomes

<bold>Rationale:</bold> Elexacaftor-tezacaftor-ivacaftor (ELE-TEZ-IVA) is effective for CF patients with ≥1 F508del mutation, but interindividual variability in response and adverse drug reactions (ADRs) necessitate better understanding of pharmacokinetics (PK) and pharmacogenetics (PG). <bold>Objectives:</bold> This study explores PK/PG variability and its impact on ELE-TEZ-IVA efficacy and ADRs. <bold>Methods:</bold> Fourteen CF adults underwent therapeutic drug monitoring at trough concentration and PG analysis after at least three months of TEZ/ELX/IVA. Concomitant treatments, hepatic, renal function, and ADRs were documented. <bold>Results:</bold> 14 CF adults underwent therapeutic drug monitoring (trough concentrations) and PG analysis after ≥3 months of ELE-TEZ-IVA. Neuropsychiatric ADRs occurred in 4 patients. Median concentrations (mg/L) in ADR vs. non-ADR groups were: TEZ (3.3 vs. 3.3), TEZ-M1 (4.3 vs. 6.7), ELE (7.6 vs. 5.7), IVA (1.7 vs. 1.3), and IVA-M1 (3.1 vs. 1.7) (Fig 1). <fig><object-id>erj;66/suppl_69/PA3978/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>No significant correlation was found between C0 or C0/dose and ADRs, though a trend toward IVA-M1 and TEZ-M1 overexposure was noted in ADR patients. CYP3A4/3A5 polymorphisms showed no significant impact. <bold>Conclusions:</bold> A larger cohort is yet ongoing to clarify exposure-response relationships and genetic variability’s role in ADRs, with emerging trends for specific molecules/metabolites.