Inter-Subject Variability in Clinical Response to Elexacaftor/Tezacaftor/Ivacaftor Therapy: The Role of Therapeutic Drug Monitoring

The combination therapy elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA) (ETI), collectively known as CFTR modulators, marks a significant advancement in cystic fibrosis (CF) treatment by partially restoring CFTR protein function. However, ETI pharmacokinetics (PK) show marked inter-patient variability, are influenced by altered PK in specific populations, and are affected by drug-drug interactions due to hepatic metabolism. The relationships between PK parameters, clinical outcomes, and optimal TDM strategies remain unclear. This thesis aimed to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for ETI quantification, establish a clinical database linking ETI plasma levels to clinical outcomes, and analyze ETI metabolites using liquid chromatography-high resolution mass spectrometry (LC-HRMS). The LC-MS/MS method, validated per international guidelines, was applied to 62 pre-dose (Ctrough) plasma samples, alongside assessments of lung function (FEV1), sweat chloride, and laboratory markers (ALT, AST, bilirubin, CK). No significant correlations were found between Ctrough ETI levels and efficacy or toxicity laboratory parameters. LC-HRMS profiling identified known metabolites (ELX-M23, TEZ-M1, TEZ-M2, TEZ-M6, IVA-M1, IVA-M6) and two novel metabolites (IVA-M+16 and IVA-M+32). The metabolite-to-parent ratios (MPR) was quantified and notably, MPR for TEZ/TEZ-M1 correlated with bilirubin levels (P = 0.0030), warranting further study. Findings suggest Ctrough may not be the ideal TDM timepoint, emphasizing the need for further PK research targeting Cmax. The validated methods provide robust tools for PK studies and enzyme phenotyping, paving the way for individualized TDM protocols for CFTR modulators.