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2. Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology – an analysis of the closed cohorts of a multicentre prospective study

Author

van der Kleij, Maud B. A., Guchelaar, Niels A. D., Meertens, Marinda, Westerdijk, Kim, Giraud, Eline L., Bleckman, Roos F., Groenland, Stefanie L., van Eerden, Ruben A. G., Imholz, Alex L. T., Vulink, Annelie J. E., Otten, Hans-Martin, Fiebrich-Westra, Helle-Brit, Lubberman, Floor J. E., Desar, Ingrid M. E., Moes, Dirk-Jan A. R., Touw, Daan J., Koolen, Stijn L. W., Gelderblom, Hans, Reyners, An K. L., van Erp, Nielka P., Mathijssen, Ron H. J., Huitema, Alwin D. R., and Steeghs, Neeltje

Published
2024
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3. Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort

Author

Meertens, Marinda, Giraud, Eline L., van der Kleij, Maud B. A., Westerdijk, Kim, Guchelaar, Niels A. D., Bleckman, Roos F., Rieborn, Amy, Imholz, Alex L. T, Otten, Hans-Martin, Vulink, Annelie, Los, Maartje, Hamberg, Paul, van der Graaf, Winette T. A., Gelderblom, Hans, Moes, Dirk Jan A. R., Broekman, K. Esther, Touw, Daan J., Koolen, Stijn L. W., Mathijssen, Ron H. J., Huitema, Alwin D. R., van Erp, Nielka P., Desar, Ingrid M. E., and Steeghs, Neeltje

Published
2024
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4. The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study

Author

Guchelaar, Niels A. D., Buck, Stefan A. J., van Doorn, Leni, Hussaarts, Koen G. A. M., Sandberg, Yorick, van der Padt-Pruijsten, Annemieke, van Alphen, Robbert J., Poppe-Manenschijn, Laura, Vleut, Isolde, de Bruijn, Peter, van Leeuwen, Roelof W. F., Mostert, Bianca, Eskens, Ferry A. L. M., Oomen-de Hoop, Esther, Koolen, Stijn L. W., and Mathijssen, Ron H. J.

Published
2024
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6. Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD

Author

Knikman, Jonathan E., Zhai, Qinglian, Lunenburg, Carin A. T. C., Henricks, Linda M., Böhringer, Stefan, van der Lee, Maaike, de Man, Femke M., Offer, Steven M., Shrestha, Shikshya, Creemers, Geert-Jan, Baars, Arnold, Dezentjé, Vincent O., Imholz, Alexander L. T., Jeurissen, Frank J. F., Portielje, Johanna E. A., Jansen, Rob L. H., Hamberg, Paul, Droogendijk, Helga J., Koopman, Miriam, Nieboer, Peter, van de Poel, Marlène H. W., Mandigers, Caroline M. P. W., van Schaik, Ron H. N., Gelderblom, Hans, Mathijssen, Ron H. J., Schellens, Jan H. M., Cats, Annemieke, Guchelaar, Henk-Jan, and Swen, Jesse J.

Published
2024
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13. CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients

Author

van Eerden, Ruben A. G., IJzerman, Nikki S., van Meekeren, Milan, Oomen-de Hoop, Esther, Guchelaar, Niels A. D., Visser, Andrea M. W., Matic, Maja, van Schaik, Ron H. N., de Bruijn, Peter, Moes, Dirk-Jan A. R., Jobse, Pieter A., Gelderblom, Hans, Huitema, Alwin D. R., Steeghs, Neeltje, Mathijssen, Ron H. J., and Koolen, Stijn L. W.

Published
2023
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14. Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies

Author

Guchelaar, Niels A. D., Noordman, Bo J., Koolen, Stijn L. W., Mostert, Bianca, Madsen, Eva V. E., Burger, Jacobus W. A., Brandt-Kerkhof, Alexandra R. M., Creemers, Geert-Jan, de Hingh, Ignace H. J. T., Luyer, Misha, Bins, Sander, van Meerten, Esther, Lagarde, Sjoerd M., Verhoef, Cornelis, Wijnhoven, Bas P. L., and Mathijssen, Ron. H. J.

Published
2023
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18. Influence of Darolutamide on Cabazitaxel Systemic Exposure

Author

Buck, Stefan A. J., Guchelaar, Niels A. D., de Bruijn, Peter, Ghobadi Moghaddam-Helmantel, Inge M., Oomen-de Hoop, Esther, Westgeest, Hans M., Hamberg, Paul, Mathijssen-van Stein, Danielle, Lolkema, Martijn P., Koolen, Stijn L. W., de Wit, Ronald, and Mathijssen, Ron H. J.

Published
2022
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19. Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer

Author

Braal, C. Louwrens, Jager, Agnes, Hoop, Esther Oomen-de, Westenberg, Justin D., Lommen, Koen M. W. T., de Bruijn, Peter, Vastbinder, Mijntje B., van Rossum-Schornagel, Quirine C., Thijs-Visser, Martine F., van Alphen, Robbert J., Struik, Liesbeth E. M., Zuetenhorst, Hanneke J. M., Mathijssen, Ron H. J., and Koolen, Stijn L. W.

Published
2022
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22. Levels of circulating tumor DNA correlate with tumor volume in gastro‐intestinal stromal tumors: an exploratory long‐term follow‐up study.

Author

Bleckman, Roos F., Haag, Charlotte M. S. C., Rifaela, Naomi, Beukema, Gerrieke, Mathijssen, Ron H. J., Steeghs, Neeltje, Gelderblom, Hans, Desar, Ingrid M. E., Cleven, Arjen, ter Elst, Arja, Schuuring, Ed, and Reyners, Anna K. L.

Abstract

Patients with gastro‐intestinal stromal tumors (GISTs) undergoing tyrosine kinase inhibitor therapy are monitored with regular computed tomography (CT) scans, exposing patients to cumulative radiation. This exploratory study aimed to evaluate circulating tumor DNA (ctDNA) testing to monitor treatment response and compare changes in ctDNA levels with RECIST 1.1 and total tumor volume measurements. Between 2014 and 2021, six patients with KIT proto‐oncogene, receptor tyrosine kinase (KIT) exon‐11‐mutated GIST from whom long‐term plasma samples were collected prospectively were included in the study. ctDNA levels of relevant plasma samples were determined using the KIT exon 11 digital droplet PCR drop‐off assay. Tumor volume measurements were performed using a semi‐automated approach. In total, 94 of 130 clinically relevant ctDNA samples were analyzed. Upon successful treatment response, ctDNA became undetectable in all patients. At progressive disease, ctDNA was detectable in five out of six patients. Higher levels of ctDNA correlated with larger tumor volumes. Undetectable ctDNA at the time of progressive disease on imaging was consistent with lower tumor volumes compared to those with detectable ctDNA. In summary, ctDNA levels seem to correlate with total tumor volume at the time of progressive disease. Our exploratory study shows promise for including ctDNA testing in treatment follow‐up. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Darolutamide does not interfere with OATP‐mediated uptake of docetaxel

Author

Buck, Stefan A. J., primary, Talebi, Zahra, additional, Drabison, Thomas, additional, Jin, Yan, additional, Gibson, Alice A., additional, Hu, Peng, additional, de Bruijn, Peter, additional, de Ridder, Corrina M. A., additional, Stuurman, Debra, additional, Hu, Shuiying, additional, van Weerden, Wytske M., additional, Koolen, Stijn L. W., additional, de Wit, Ronald, additional, Sparreboom, Alex, additional, Mathijssen, Ron H. J., additional, and Eisenmann, Eric D., additional

Published
2024
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26. Therapeutic Drug Monitoring of Oral Oncology Drugs: Finding the Right Nails

Author

MS Medische Oncologie, Apotheek O&O&O, Cancer, Guchelaar, Niels A D, Institute, Erasmus, Steeghs, Neeltje, Huitema, Alwin D R, Mathijssen, Ron H J, Koolen, Stijn L W, MS Medische Oncologie, Apotheek O&O&O, Cancer, Guchelaar, Niels A D, Institute, Erasmus, Steeghs, Neeltje, Huitema, Alwin D R, Mathijssen, Ron H J, and Koolen, Stijn L W

Published
2024

27. The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine:A Crossover Pharmacokinetic Study

Author

Guchelaar, Niels A. D., Buck, Stefan A. J., van Doorn, Leni, Hussaarts, Koen G. A. M., Sandberg, Yorick, van der Padt-pruijsten, Annemieke, van Alphen, Robbert J., Poppe-Manenschijn, Laura, Vleut, Isolde, de Bruijn, Peter, van Leeuwen, Roelof W. F., Mostert, Bianca, Eskens, Ferry A. L. M., Oomen-de Hoop, Esther, Koolen, Stijn L. W., Mathijssen, Ron H. J., Guchelaar, Niels A. D., Buck, Stefan A. J., van Doorn, Leni, Hussaarts, Koen G. A. M., Sandberg, Yorick, van der Padt-pruijsten, Annemieke, van Alphen, Robbert J., Poppe-Manenschijn, Laura, Vleut, Isolde, de Bruijn, Peter, van Leeuwen, Roelof W. F., Mostert, Bianca, Eskens, Ferry A. L. M., Oomen-de Hoop, Esther, Koolen, Stijn L. W., and Mathijssen, Ron H. J.

Abstract

Background and Objectives: Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug–drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine. Methods: In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction. Results: Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (− 12.6%; 97.5% confidence interval − 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil. Conclusions: Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure. Clinical Trial Registration: NL8067 (registered 04-10-2019).

Published
2024

28. Quantitative modeling of tumor dynamics and development of drug resistance in non-small cell lung cancer patients treated with erlotinib

Author

Yin, Anyue, Veerman, G. D. Marijn, van Hasselt, Johan G. C., Steendam, Christi M. J., Dubbink, Hendrikus Jan, Guchelaar, Henk-Jan, Friberg, Lena E., Dingemans, Anne-Marie C., Mathijssen, Ron H. J., Moes, Dirk Jan A. R., Yin, Anyue, Veerman, G. D. Marijn, van Hasselt, Johan G. C., Steendam, Christi M. J., Dubbink, Hendrikus Jan, Guchelaar, Henk-Jan, Friberg, Lena E., Dingemans, Anne-Marie C., Mathijssen, Ron H. J., and Moes, Dirk Jan A. R.

Abstract

Insight into the development of treatment resistance can support the optimization of anticancer treatments. This study aims to characterize the tumor dynamics and development of drug resistance in patients with non-small cell lung cancer treated with erlotinib, and investigate the relationship between baseline circulating tumor DNA (ctDNA) data and tumor dynamics. Data obtained for the analysis included (1) intensively sampled erlotinib concentrations from 29 patients from two previous pharmacokinetic (PK) studies, and (2) tumor sizes, ctDNA measurements, and sparsely sampled erlotinib concentrations from 18 patients from the START-TKI study. A two-compartment population PK model was first developed which well-described the PK data. The PK model was subsequently applied to investigate the exposure-tumor dynamics relationship. To characterize the tumor dynamics, models accounting for intra-tumor heterogeneity and acquired resistance with or without primary resistance were investigated. Eventually, the model assumed acquired resistance only resulted in an adequate fit. Additionally, models with or without exposure-dependent treatment effect were explored, and no significant exposure-response relationship for erlotinib was identified within the observed exposure range. Subsequently, the correlation of baseline ctDNA data on EGFR and TP53 variants with tumor dynamics' parameters was explored. The analysis indicated that higher baseline plasma EGFR mutation levels correlated with increased tumor growth rates, and the inclusion of ctDNA measurements improved model fit. This result suggests that quantitative ctDNA measurements at baseline have the potential to be a predictor of anticancer treatment response. The developed model can potentially be applied to design optimal treatment regimens that better overcome resistance.

Published
2024
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29. Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology - an analysis of the closed cohorts of a multicentre prospective study

Author

Apotheek O&O&O, Cancer, MS Medische Oncologie, van der Kleij, Maud B A, Guchelaar, Niels A D, Meertens, Marinda, Westerdijk, Kim, Giraud, Eline L, Bleckman, Roos F, Groenland, Stefanie L, van Eerden, Ruben A G, Imholz, Alex L T, Vulink, Annelie J E, Otten, Hans-Martin, Fiebrich-Westra, Helle-Brit, Lubberman, Floor J E, Desar, Ingrid M E, Moes, Dirk-Jan A R, Touw, Daan J, Koolen, Stijn L W, Gelderblom, Hans, Reyners, An K L, van Erp, Nielka P, Mathijssen, Ron H J, Huitema, Alwin D R, Steeghs, Neeltje, Dutch Pharmacology Oncology Group (DPOG), Apotheek O&O&O, Cancer, MS Medische Oncologie, van der Kleij, Maud B A, Guchelaar, Niels A D, Meertens, Marinda, Westerdijk, Kim, Giraud, Eline L, Bleckman, Roos F, Groenland, Stefanie L, van Eerden, Ruben A G, Imholz, Alex L T, Vulink, Annelie J E, Otten, Hans-Martin, Fiebrich-Westra, Helle-Brit, Lubberman, Floor J E, Desar, Ingrid M E, Moes, Dirk-Jan A R, Touw, Daan J, Koolen, Stijn L W, Gelderblom, Hans, Reyners, An K L, van Erp, Nielka P, Mathijssen, Ron H J, Huitema, Alwin D R, Steeghs, Neeltje, and Dutch Pharmacology Oncology Group (DPOG)

Published
2024

30. Early Identification of Patients at Risk of Cabazitaxel-induced Severe Neutropenia

Author

Agema, Bram C, Buck, Stefan A J, Viskil, Mano, Isebia, Khrystany T, de Neijs, Micha J, Sassen, Sebastiaan D T, Koch, Birgit C P, Joerger, Markus, de Wit, Ronald, Koolen, Stijn L W, Mathijssen, Ron H J, Agema, Bram C, Buck, Stefan A J, Viskil, Mano, Isebia, Khrystany T, de Neijs, Micha J, Sassen, Sebastiaan D T, Koch, Birgit C P, Joerger, Markus, de Wit, Ronald, Koolen, Stijn L W, and Mathijssen, Ron H J

Abstract

BACKGROUND: Cabazitaxel frequently causes severe neutropenia. A higher cabazitaxel systemic exposure is related to a lower nadir absolute neutrophil count (ANC).OBJECTIVE: To describe the effect of cabazitaxel systemic exposure on ANC by a population pharmacokinetic/pharmacodynamic (POP-PK/PD) model, and to identify patients at risk of severe neutropenia early in their treatment course using a PK threshold.DESIGN, SETTING, AND PARTICIPANTS: Data from five clinical studies were pooled to develop a POP-PK/PD model using NONMEM, linking both patient characteristics and cabazitaxel systemic exposure directly to ANC.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A PK threshold, predictive of severe neutropenia (grade ≥3), was determined using a receiver operating characteristic curve.RESULTS AND LIMITATIONS: Ninety-six patients were included with a total of 1726 PK samples and 1081 ANCs. The POP-PK/PD model described both cabazitaxel PK and ANC accurately. A cabazitaxel plasma concentration of >4.96 ng/ml at 6 h after the start of infusion was found to be predictive of severe neutropenia, with a sensitivity of 76% and a specificity of 65%.CONCLUSIONS: Early cabazitaxel plasma levels are predictive of severe neutropenia. Implementation of the proposed PK threshold results in early identification of almost 76% of all severe neutropenias. If prospectively validated, patients at risk could benefit from prophylactic administration of granulocyte colony stimulating factors, preventing severe neutropenia in an early phase of treatment. Implementation of this threshold permits a less restricted use of the 25 mg/m2 dose, potentially increasing the therapeutic benefit.PATIENT SUMMARY: Treatment with cabazitaxel chemotherapy often causes neutropenia, leading to susceptibility to infections, which might be life threatening. We found that a systemic cabazitaxel concentration above 4.96 ng/ml 6 h after the start of infusion is predictive

Published
2024

32. Population pharmacokinetics of intraperitoneal irinotecan and SN‐38 in patients with peritoneal metastases from colorectal origin.

Author

Rietveld, Pascale C. S., Sassen, Sebastiaan D. T., Guchelaar, Niels A. D., van Eerden, Ruben A. G., de Boer, Nadine L., van den Heuvel, Teun B. M., Burger, Jacobus W. A., Mathijssen, Ron H. J., Koch, Birgit C. P., and Koolen, Stijn L. W.

Subjects
IRINOTECAN, BEVACIZUMAB, HYPERTHERMIC intraperitoneal chemotherapy, BLOOD volume, PHARMACOKINETICS, CYTOREDUCTIVE surgery
Abstract

Peritoneal metastases (PM) are common in patients with colorectal cancer. Patients with PM have a poor prognosis, and for those who are not eligible for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), palliative chemotherapy is currently the only option. Recently, we conducted a phase I trial (INTERACT) in which irinotecan was administered intraperitoneally (IP) to 18 patients ineligible for CRS‐HIPEC. The primary objective was to evaluate covariates influencing the PK profile of irinotecan and SN‐38 after IP administration. Secondly, a population PK model was developed to support the further development of IP irinotecan by improving dosing in patients with PM. Patients were treated with IP irinotecan every 2 weeks in combination with systemic FOLFOX‐bevacizumab. Irinotecan and SN‐38 were measured in plasma (588 samples) and SN‐38 was measured in peritoneal fluid (267 samples). Concentration‐Time data were log‐transformed and analyzed using NONMEM version 7.5 using FOCE+I estimation. An additive error model described the residual error, with inter‐individual variability in PK parameters modeled exponentially. The final structural model consisted of five compartments. Weight was identified as a covariate influencing the SN‐38 plasma volume of distribution and GGT was found to influence the SN‐38 plasma clearance. This population PK model adequately described the irinotecan and SN‐38 in plasma after IP administration, with weight and GGT as predictive factors. Irinotecan is converted intraperitoneal to SN‐38 by carboxylesterases and the plasma bioavailability of irinotecan is low. This model will be used for the further clinical development of IP irinotecan by providing dosing strategies. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Fibrotic activity quantified in serum by measurements of type III collagen pro-peptides can be used for prognosis across different solid tumor types

Author

Willumsen, Nicholas, Jensen, Christina, Green, George, Nissen, Neel I., Neely, Jaclyn, Nelson, David M., Pedersen, Rasmus S., Frederiksen, Peder, Chen, Inna M., Boisen, Mogens K., Johansen, Astrid Z., Madsen, Daniel H., Svane, Inge Marie, Lipton, Allan, Leitzel, Kim, Ali, Suhail M., Erler, Janine T., Hurkmans, Daan P., Mathijssen, Ron H. J., Aerts, Joachim, Eslam, Mohammed, George, Jacob, Christiansen, Claus, Bissel, Mina J., and Karsdal, Morten A.

Published
2022
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36. Quantitative modeling of tumor dynamics and development of drug resistance in non‐small cell lung cancer patients treated with erlotinib

Author

Yin, Anyue, primary, Veerman, G. D. Marijn, additional, van Hasselt, Johan G. C., additional, Steendam, Christi M. J., additional, Dubbink, Hendrikus Jan, additional, Guchelaar, Henk‐Jan, additional, Friberg, Lena E., additional, Dingemans, Anne‐Marie C., additional, Mathijssen, Ron H. J., additional, and Moes, Dirk Jan A. R., additional

Published
2024
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38. Influence of Cow’s Milk and Esomeprazole on the Absorption of Erlotinib: A Randomized, Crossover Pharmacokinetic Study in Lung Cancer Patients

Author

Veerman, G. D. Marijn, Hussaarts, Koen G. A. M., Peric, Robert, Oomen-de Hoop, Esther, Landa, Kersten D., van der Leest, Cor H., Broerse, Suzanna D., Rutten, Hugo B., Belderbos, Huub N. A., Steendam, Christi M. J., Paats, Marthe S., Koolen, Stijn L. W., Dingemans, Anne-Marie C., van Gelder, Teun, van Leeuwen, Roelof W. F., Aerts, Joachim G. J. V., and Mathijssen, Ron H. J.

Published
2021
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39. Individualized Dosing Patterns in the Treatment of Older Patients with Gastrointestinal Stromal Tumors: Results of a Registry-Based Observational National Cohort Study Including 871 Patients

Author

Bleckman, Roos F., primary, Broekman, K. Esther, additional, Roets, Evelyne, additional, Mohammadi, Mohammed, additional, Desar, Ingrid M. E., additional, Gelderblom, Hans, additional, Mathijssen, Ron H. J., additional, Steeghs, Neeltje, additional, de Graeff, Pauline, additional, and Reyners, Anna K. L., additional

Published
2023
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41. Influence of green tea consumption on endoxifen steady-state concentration in breast cancer patients treated with tamoxifen

Author

Braal, C. Louwrens, Hussaarts, Koen G. A. M., Seuren, Lieke, Oomen-de Hoop, Esther, de Bruijn, Peter, Buck, Stefan A. J., Bos, Monique E. M. M., Thijs-Visser, Martine F., Zuetenhorst, Hanneke J. M., Mathijssen-van Stein, Daniëlle, Vastbinder, Mijntje B., van Leeuwen, Roelof W. F., van Gelder, Teun, Koolen, Stijn L. W., Jager, Agnes, and Mathijssen, Ron H. J.

Published
2020
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45. Model‐Based Prediction of Irinotecan‐Induced Grade 4 Neutropenia in Cancer Patients: Influence of Incorporating Germline Genetic Factors in the Model.

Author

Karas, Spinel, Mathijssen, Ron H. J., van Schaik, Ron H. N., Forrest, Alan, Wiltshire, Tim, Bies, Robert R., and Innocenti, Federico

Subjects
NEUTROPENIA, GENETIC models, RECEIVER operating characteristic curves, PROGRESSION-free survival, GERM cells, CANCER patients
Abstract

Neutropenia is the major dose‐limiting toxicity of irinotecan‐based therapy. The objective of this study was to assess whether inclusion of germline genetic variants into a population pharmacokinetic/pharmacodynamic model can improve prediction of irinotecan‐induced grade 4 neutropenia and identify novel variants of clinical value. A semimechanistic population pharmacokinetic/pharmacodynamic model was used to predict neutrophil response over time in 197 patients receiving irinotecan. Covariate analysis was performed for demographic/clinical factors and 4,781 genetic variants in 84 drug response‐ and toxicity‐related genes to identify covariates associated with neutrophil response. We evaluated the predictive value of the model for grade 4 neutropenia reflecting different clinical scenarios of available data on identified demographic/clinical covariates, baseline and post‐treatment absolute neutrophil counts (ANCs), individual pharmacokinetics, and germline genetic variation. Adding 8 genetic identified covariates (rs10929302 (UGT1A1), rs1042482 (DPYD), rs2859101 (HLA‐DQB3), rs61754806 (NR3C1), rs9266271 (HLA‐B), rs7294 (VKORC1), rs1051713 (ALOX5), and ABCB1 rare variant burden) to a model using only baseline ANCs improved prediction of irinotecan‐induced grade 4 neutropenia from area under the receiver operating characteristic curve (AUC‐ROC) of 50–64% (95% confidence interval (CI), 54–74%). Individual pharmacokinetics further improved the prediction to 74% (95% CI, 64–84%). When weekly ANC was available, the identified covariates and individual pharmacokinetics yielded no additional contribution to the prediction. The model including only ANCs at baseline and at week 1 achieved an AUC‐ROC of 78% (95% CI, 69–88%). Germline DNA genetic variants may contribute to the prediction of irinotecan‐induced grade 4 neutropenia when incorporated into a population pharmacokinetic/pharmacodynamic model. This approach is generalizable to drugs that induce neutropenia and ultimately allows for personalized intervention to enhance patient safety. [ABSTRACT FROM AUTHOR]

Published
2024
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46. Darolutamide added to docetaxel augments antitumor effect in models of prostate cancer through cell cycle arrest at the G1-S transition

Author

Buck, Stefan A.J., primary, Van Hemelryk, Annelies, additional, de Ridder, Corrina, additional, Stuurman, Debra, additional, Erkens-Schulze, Sigrun, additional, Van 't Geloof, Sem, additional, Teubel, Wilma J., additional, Koolen, Stijn L.W., additional, Martens-Uzunova, Elena S., additional, van Royen, Martin E., additional, de Wit, Ronald, additional, Mathijssen, Ron H. J., additional, and van Weerden, Wytske M., additional

Published
2023
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47. Exploring the impact of patient‐specific clinical features on osimertinib effectiveness in a real‐world cohort of patients with EGFR mutated non‐small cell lung cancer

Author

van Veelen, Ard, primary, Veerman, G. D. Marijn, additional, Verschueren, Marjon V., additional, Gulikers, Judith L., additional, Steendam, Christi M. J., additional, Brouns, Anita J. W. M., additional, Dursun, Safiye, additional, Paats, Marthe S., additional, Tjan‐Heijnen, Vivianne C. G., additional, van der Leest, Cor, additional, Dingemans, Anne‐Marie C., additional, Mathijssen, Ron H. J., additional, van de Garde, Ewoudt M. W., additional, Souverein, Patrick, additional, Driessen, Johanna H. M., additional, Hendriks, Lizza E. L., additional, van Geel, Robin M. J. M., additional, and Croes, Sander, additional

Published
2023
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48. Pharmacokinetic boosting of olaparib: a randomised, cross-over study (PROACTIVE-study)

Author

Overbeek, Joanneke K, primary, Guchelaar, Niels A D, additional, Ali, Ma Ida Mohmaed, additional, Ottevanger, Petronella B, additional, Bloemendal, Haiko J, additional, Koolen, Stijn L W, additional, Mathijssen, Ron H J, additional, Boere, Ingrid A, additional, Hamberg, Paul, additional, Huitema, Alwin D R, additional, Sonke, Gabe S, additional, Opdam, Frans L, additional, ter Heine, Rob, additional, and van Erp, Nielka P, additional

Published
2023
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