This thesis aimed to improve understanding of the clinical pharmacology of CFTR modulators in children with cystic fibrosis (CF) using real-world data, thereby supporting progress towards personalized medicine.To enable pharmacokinetic analyses, two bioanalytical LC-MS/MS methods were developed and validated: one for plasma and sputum samples, and one using dried blood spots. The latter allows minimally invasive, home-based sampling, facilitating therapeutic drug monitoring in children. All methods demonstrated good accuracy, stability, and clinical applicability.These methods were subsequently applied in clinical studies. Population pharmacokinetic (popPK) models for elexacaftor-tezacaftor-ivacaftor (ETI) and tezacaftor-ivacaftor were developed in pediatric patients. Considerable inter- and intra-patient variability in drug exposure was observed, though all children achieved concentrations within or above effective ranges. Exploratory exposure-response analyses did not show a linear correlation between exposure and clinical outcomes. Further clinical applications included case studies in special populations. No relevant drug-drug interaction was observed between clofazimine and tezacaftor-ivacaftor. In patients with liver cirrhosis, careful dose escalation of ETI under close clinical- and therapeutic drug monitoring appeared feasible and safe. Also, a relationship was established between trough concentrations and exposure (area under the curve, AUC), indicating that single-sample monitoring could reliably estimate drug exposure.In conclusion, this work provides validated analytical methods, popPK models, and real-world clinical data supporting individualized CFTR modulator therapy in children and special patient groups. These findings mark important steps toward safe, effective, and patient-friendly personalized treatment strategies in CF
