Advancing therapeutic drug monitoring of CYP3A4-metabolized drugs: analytical innovations and clinical applications

Zibold, Kajetan (2026): Advancing therapeutic drug monitoring of CYP3A4-metabolized drugs: analytical innovations and clinical applications. Dissertation, LMU München: Faculty of Medicine

Abstract

Therapeutic drug monitoring has become a cornerstone of individualized pharmacotherapy, particularly for drugs with a narrow therapeutic range and strong inter- and intraindividual variability. This dissertation focuses on two complementary projects that illustrate both methodological innovation and clinical application of TDM. In the first study, an offline SPE-LC-MS/MS method was successfully developed and validated for the simultaneous quantification of tacrolimus, cyclosporine A, creatinine, tryptophan, and kynurenine from VAMS. Validation according to EMA and FDA guidelines confirmed the clinical applicability of the method through precise and robust quantification of all analytes. Additionally, matrix effects were effectively compensated using isotope-labeled internal standards. The inclusion of creatinine in the assay enabled the parallel monitoring of kidney function, while kynurenine/tryptophan ratio was measured as potential biomarker of immune activation. A correlation analysis of VAMS capillary blood samples and matched venous whole blood samples from transplant recipients demonstrated methodological agreement, confirming the clinical applicability of the method. In conclusion, the developed method has the potential to facilitate patient-centric sampling of VAMS samples for decentralized TDM, thereby reducing the burden of frequent clinic visits. The second study evaluated TDM of mirtazapine in a naturalistic clinical setting by applying established TDM tools. Data from 326 patients showed that almost half did not have mirtazapine serum concentrations within the established TRR, with 38% falling below and 8% exceeding the recommended values. Significant sex- and age-related pharmacokinetic differences were observed, as women exhibited higher C/D ratios than men, and elderly patients (>65 years) showed higher C/D ratios compared to younger individuals. DRC values deviated from guideline expectations, likely reflecting real-world factors such as higher prescribed doses, polypharmacy, and inter-individual variability. Analysis of the MR further highlighted variability in CYP3A4 metabolism, with about 4% of samples falling outside the expected MR range. Altogether, the study demonstrates that the combined use of TRR, C/D ratio, DRC, and MR may support routine practice by facilitating the detection of non-adherence, drug interactions, and patient subgroups whose pharmacokinetics deviate from the expected cohort, thereby enabling the potential for individualized dose adjustments. In conclusion, these studies demonstrate distinct but complementary aspects of modern TDM. They provide technological innovation through multiplex LC-MS/MS combined with a novel microsampling device for immunosuppressants, and the clinical utility of established TDM tools for tailoring antidepressant therapy. Both approaches highlight how TDM can enhance individualized medicine by improving drug safety, efficacy, and patient-centered care in transplantation medicine and psychiatry.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 10. June 2026
• 1. Referee: Schwarz, Markus
• Signature of the printed copy: 0700/UMD 22868