@article{StraubVollmerLametal.2022, author = {Straub, Anton and Vollmer, Andreas and L{\^a}m, Thi{\^e}n-Tr{\´i} and Brands, Roman C. and Stapf, Maximilian and Scherf-Clavel, Oliver and Bittrich, Max and Fuchs, Andreas and K{\"u}bler, Alexander C. and Hartmann, Stefan}, title = {Evaluation of advanced platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam}, series = {Clinical Oral Investigations}, volume = {26}, journal = {Clinical Oral Investigations}, number = {12}, doi = {10.1007/s00784-022-04663-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324515}, pages = {7033-7044}, year = {2022}, abstract = {Objectives Mechanisms of wound healing are often impaired in patients with osteonecrosis of the jaw (ONJ). According to the guidelines for the treatment of this disease, early surgical intervention is indicated. However, surgery often faces complications such as wound healing disorders. The application of platelet-rich fibrin (PRF) after necrosectomy between bone and mucosa may constitute a promising approach to improve surgical results. An aspect that was not investigated until now is that PRF acts as a "bio-carrier" for antibiotics previously applied intravenously. Materials and methods We investigated the antimicrobial properties of PRF in 24 patients presenting ONJ undergoing systemic antibiosis with ampicillin/sulbactam. We measured the concentration of ampicillin/sulbactam in plasma and PRF and performed agar diffusion tests. Ampicillin/sulbactam was applied intravenously to the patient 10 minutes for blood sampling for PRF. No further incorporation of patients' blood or PRF product with antibiotic drugs was obtained. Four healthy patients served as controls. Results Our results revealed that PRF is highly enriched with ampicillin/sulbactam that is released to the environment. The antibiotic concentration in PRF was comparable to the plasma concentration of ampicillin/sulbactam. The inhibition zone (IZ) of PRF was comparable to the standard ampicillin/sulbactam discs used in sensitivity testing. Conclusions The results of our study demonstrated that PRF is a reliable bio-carrier for systemic applied antibiotics and exhibits a large antimicrobial effect. Clinical relevance We describe a clinically useful feature of PRF as a bio-carrier for antibiotics. Especially when applied to poorly perfused tissues and bone such as in ONJ, the local release of antibiotics can reduce wound healing disorders like infections.}, 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{IsbernerGesierichBalakirouchenaneetal.2022, author = {Isberner, Nora and Gesierich, Anja and Balakirouchenane, David and Schilling, Bastian and Aghai-Trommeschlaeger, Fatemeh and Zimmermann, Sebastian and Kurlbaum, Max and Puszkiel, Alicja and Blanchet, Benoit and Klinker, Hartwig and Scherf-Clavel, Oliver}, title = {Monitoring of dabrafenib and trametinib in serum and self-sampled capillary blood in patients with BRAFV600-mutant melanoma}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers14194566}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288109}, year = {2022}, abstract = {Simple Summary In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary blood concentrations to serum concentrations was developed. (Hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or AE. Co-medication with P-glycoprotein inducers was associated with lower trough concentrations of trametinib but not (hydroxy-)dabrafenib. The applicability of the self-sampling of capillary blood was demonstrated. Our conversion model was adequate for estimating serum exposure from micro-samples. The monitoring of dabrafenib and trametinib may be useful for dose modification and can be optimized by at-home sampling and our new conversion model. Abstract Patients treated with dabrafenib and trametinib for BRAF\(^{V600}\)-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.}, language = {en} } @article{IsbernerKrausGrigoleitetal.2021, author = {Isberner, Nora and Kraus, Sabrina and Grigoleit, G{\"o}tz Ulrich and Aghai, Fatemeh and Kurlbaum, Max and Zimmermann, Sebastian and Klinker, Hartwig and Scherf-Clavel, Oliver}, title = {Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial}, series = {Cancer Chemotherapy and Pharmacology}, volume = {88}, journal = {Cancer Chemotherapy and Pharmacology}, number = {6}, issn = {1432-0843}, doi = {10.1007/s00280-021-04351-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266476}, pages = {973-983}, year = {2021}, abstract = {Purpose Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. Methods 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. Results Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50\%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15\% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). Conclusion Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.}, language = {en} } @article{AghaiZimmermannKurlbaumetal.2021, author = {Aghai, Fatemeh and Zimmermann, Sebastian and Kurlbaum, Max and Jung, Pius and Pelzer, Theo and Klinker, Hartwig and Isberner, Nora and Scherf-Clavel, Oliver}, title = {Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma}, series = {Analytical and Bioanalytical Chemistry}, volume = {413}, journal = {Analytical and Bioanalytical Chemistry}, issn = {1618-2642}, doi = {10.1007/s00216-020-03031-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231925}, pages = {599-612}, year = {2021}, abstract = {A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2-500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6-1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients.}, language = {en} }