@phdthesis{Gerner2023,
  author    = {Gerner, Bettina},
  title     = {Improvement of oral antineoplastic therapy by means of pharmacometric approaches \& therapeutic drug monitoring},
  doi       = {10.25972/OPUS-32196},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321966},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Oral antineoplastic drugs are an important component in the treatment of solid tumour diseases, haematological and immunological malignancies. Oral drug administration is associated with positive features (e.g., non-invasive drug administration, outpatient care with a high level of independence for the patient and reduced costs for the health care system). The systemic exposure after oral intake however is prone to high IIV as it strongly depends on gastrointestinal absorption processes, which are per se characterized by high inter-and intraindividual variability. Disease and patient-specific characteristics (e.g., disease state, concomitant diseases, concomitant medication, patient demographics) may additionally contribute to variability in plasma concentrations between individual patients. In addition, many oral antineoplastic drugs show complex PK, which has not yet been fully investigated and elucidated for all substances. All this may increase the risk of suboptimal plasma exposure (either subtherapeutic or toxic), which may ultimately jeopardise the success of therapy, either through a loss of efficacy or through increased, intolerable adverse drug reactions. TDM can be used to detect suboptimal plasma levels and prevent permanent under- or overexposure. It is essential in the treatment of ACC with mitotane, a substance with unfavourable PK and high IIV. In the current work a HPLC-UV method for the TDM of mitotane using VAMS was developed. A low sample volume (20 µl) of capillary blood was used in the developed method, which facilitates dense sampling e.g., at treatment initiation. However, no reference ranges for measurements from capillary blood are established so far and a simple conversion from capillary concentrations to plasma concentrations was not possible. To date the therapeutic range is established only for plasma concentrations and observed capillary concentrations could not be reliable interpretated.The multi-kinase inhibitor cabozantinib is also used for the treatment of ACC. However, not all PK properties, like the characteristic second peak in the cabozantinib concentration-time profile have been fully understood so far. To gain a mechanistic understanding of the compound, a PBPK model was developed and various theories for modelling the second peak were explored, revealing that EHC of the compound is most plausible. Cabozantinib is mainly metabolized via CYP3A4 and susceptible to DDI with e.g., CYP3A4 inducers. The DDI between cabozantinib and rifampin was investigated with the developed PBPK model and revealed a reduced cabozantinib exposure (AUC) by 77\%. Hence, the combination of cabozantinib with strong CYP inducers should be avoided. If this is not possible, co administration should be monitored using TDM. The model was also used to simulate cabozantinib plasma concentrations at different stages of liver injury. This showed a 64\% and 50\% increase in total exposure for mild and moderate liver injury, respectively.Ruxolitinib is used, among others, for patients with acute and chronic GvHD. These patients often also receive posaconazole for invasive fungal prophylaxis leading to CYP3A4 mediated DDI between both substances. Different dosing recommendations from the FDA and EMA on the use of ruxolitinib in combination with posaconazole complicate clinical use. To simulate the effect of this relevant DDI, two separate PBPK models for ruxolitinib and posaconazole were developed and combined. Predicted ruxolitinib exposure was compared to observed plasma concentrations obtained in GvHD patients. The model simulations showed that the observed ruxolitinib concentrations in these patients were generally higher than the simulated concentrations in healthy individuals, with standard dosing present in both scenarios. According to the developed model, EMA recommended RUX dose reduction seems to be plausible as due to the complexity of the disease and intake of extensive co-medication, RUX plasma concentration can be higher than expected.},
  subject      = {Arzneimittel{\"u}berwachung},
  language  = {en}
}
@article{GernerAghaiTrommeschlaegerKrausetal.2022,
  author    = {Gerner, Bettina and Aghai-Trommeschlaeger, Fatemeh and Kraus, Sabrina and Grigoleit, G{\"o}tz Ulrich and Zimmermann, Sebastian and Kurlbaum, Max and Klinker, Hartwig and Isberner, Nora and Scherf-Clavel, Oliver},
  title     = {A physiologically-based pharmacokinetic model of ruxolitinib and posaconazole to predict CYP3A4-mediated drug-drug interaction frequently observed in graft versus host disease patients},
  series = {Pharmaceutics},
  volume    = {14},
  journal   = {Pharmaceutics},
  number    = {12},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics14122556},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297261},
  year      = {2022},
  abstract  = {Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug-drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.},
  language  = {en}
}
@article{GernerScherfClavel2021,
  author    = {Gerner, Bettina and Scherf-Clavel, Oliver},
  title     = {Physiologically based pharmacokinetic modelling of Cabozantinib to simulate enterohepatic recirculation, drug-drug interaction with Rifampin and liver impairment},
  series = {Pharmaceutics},
  volume    = {13},
  journal   = {Pharmaceutics},
  number    = {6},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics13060778},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239661},
  year      = {2021},
  abstract  = {Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug-drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (C\(_{max}\)) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9-1.2 for AUC and 0.8-1.1 for C\(_{max}\)). DDI with Rifampin led to a reduction in predicted AUC by 77\%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.},
  language  = {en}
}