Towards personalized medicine in cystic fibrosis Focusing on clinical pharmacology of CFTR modulators

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.