@article{MuellerSchoellGroenlandScherfClaveletal.2020,
  author    = {Mueller-Schoell, Anna and Groenland, Stefanie L. and Scherf-Clavel, Oliver and van Dyk, Madele and Huisinga, Wilhelm and Michelet, Robin and Jaehde, Ulrich and Steeghs, Neeltje and Huitema, Alwin D. R. and Kloft, Charlotte},
  title     = {Therapeutic drug monitoring of oral targeted antineoplastic drugs},
  series = {European journal of clinical pharmacology},
  volume    = {77},
  journal   = {European journal of clinical pharmacology},
  number    = {4},
  publisher = {Springer},
  address   = {Heidelberg},
  issn      = {0031-6970},
  doi       = {10.1007/s00228-020-03014-8},
  pages     = {441 -- 464},
  year      = {2020},
  abstract  = {Purpose This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.},
  language  = {en}
}
@article{HenrichJoergerKraffetal.2017,
  author    = {Henrich, Andrea and Joerger, Markus and Kraff, Stefanie and Jaehde, Ulrich and Huisinga, Wilhelm and Kloft, Charlotte and Parra-Guillen, Zinnia Patricia},
  title     = {Semimechanistic Bone Marrow Exhaustion Pharmacokinetic/Pharmacodynamic Model for Chemotherapy-Induced Cumulative Neutropenia},
  series = {Journal of Pharmacology and Experimental Therapeutics},
  volume    = {362},
  journal   = {Journal of Pharmacology and Experimental Therapeutics},
  number    = {2},
  publisher = {American Society for Pharmacology and Experimental Therapeutics},
  address   = {Bethesda},
  issn      = {0022-3565},
  doi       = {10.1124/jpet.117.240309},
  pages     = {347 -- 358},
  year      = {2017},
  abstract  = {Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. Joerger et al. (2016) developed a dose individualization algorithm based on a pharmacokinetic (PK)/pharmacodynamic (PD) model describing paclitaxel and neutrophil concentrations. Furthermore, the algorithm was prospectively compared in a clinical trial against standard dosing (Central European Society for Anticancer Drug Research Study of Paclitaxel Therapeutic Drug Monitoring; 365 patients, 720 cycles) but did not substantially improve neutropenia. This might be caused by misspecifications in the PK/PD model underlying the algorithm, especially without consideration of the observed cumulative pattern of neutropenia or the platinum-based combination therapy, both impacting neutropenia. This work aimed to externally evaluate the original PK/PD model for potential misspecifications and to refine the PK/PD model while considering the cumulative neutropenia pattern and the combination therapy. An underprediction was observed for the PK (658 samples), the PK parameters, and these parameters were re-estimated using the original estimates as prior information. Neutrophil concentrations (3274 samples) were over-predicted by the PK/PD model, especially for later treatment cycles when the cumulative pattern aggravated neutropenia. Three different modeling approaches (two from the literature and one newly developed) were investigated. The newly developed model, which implemented the bone marrow hypothesis semiphysiologically, was superior. This model further included an additive effect for toxicity of carboplatin combination therapy. Overall, a physiologically plausible PK/PD model was developed that can be used for dose adaptation simulations and prospective studies to further improve paclitaxel/ carboplatin combination therapy.},
  language  = {en}
}