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3. 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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17. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study

Author

Buunk, Annemarie, Goossens, Hanneke, Baas, Gert, Algera, Maartje, Schuil-Vlassak, Evelyn, Ambagts, Thijs, De Hoog-Schouten, Leonie, Musaafir, Sara, Bosch, Roelof, Tjong, Carol, Steeman, Sanne, Van der Plas, Martine, Baldew, Glenn, Den Hollander, Iris, De Waal, Zacharias, Heijn, Aurele, Nelemans, Leen, Kouwen-Lubbers, Kirsten, Van Leeuwen, Maartje, Hoogenboom, Sacha, Van Doremalen, Jacobine, Ton, Célin, Beetstra, Bastien, Meijs, Veronique, Dikken, Jan, Dubero, Dasha, Slager, Mark, Houben, Tom, Kanis, Thomas, Overmars, Wietske, Nijenhuis, Marga, Steffens, Michael, Bergs, Ingmar, Karamperis, Kariofyllis, Siamoglou, Stavroula, Ivantsik, Ouliana, Samiou, Georgia-Chryssa, Kordou, Zoe, Tsermpini, Evira, Ferentinos, Panagiotis, Karaivazoglou, Aikaterini, Rigas, George, Gerasimou, Harilaos, Voukelatou, Georgia, Georgila, Eleni, Tsermpini, Evangelia Eirini, Mendrinou, Efrossyni, Chalikiopoulou, Konstantina, Kolliopoulou, Alexandra, Mitropoulos, Konstantinos, Stratopoulos, Apostolos, Liopetas, Ioannis, Tsikrika, Athina, Barba, Evangelia, Emmanouil, Georgia, Stamopoulou, Theano, Stathoulias, Andreas, Giannopoulos, Panagiotis, Kanellakis, Filippos, Bartsakoulia, Marina, Katsila, Theodora, Douzenis, Athanassios, Gourzis, Filippos, Assimakopoulos, Konstantinos, Bignucolo, Alessia, Dal Cin, Lisa, Comello, Francesco, Mezzalira, Silvia, Puglisi, Fabio, Spina, Michele, Foltran, Luisa, Guardascione, Michela, Buonadonna, Angela, Bartoletti, Michele, Corsetti, Serena, Ongaro, Elena, Da Ros, Lucia, Bolzonello, Silvia, Spazzapan, Simon, Freschi, Andrea, Di Nardo, Paola, Palazzari, Elisa, Navarria, Federico, Innocente, Roberto, Berretta, Massimiliano, D'Andrea, Mario, Angelini, Francesco, Diraimo, Tania, Favaretto, Adolfo, Dávila-Fajardo, Cristina Lucía, Díaz-Villamarín, Xando, Martínez-González, Luis Javier, Antúnez-Rodríguez, Alba, Moreno-Escobar, Eduardo, Fernández-Gómez, Ana Estefanía, García-Navas, Paloma, Bautista-Pavés, Alicia Bautista Pavés, Burillo-Gómez, Francisco, Villegas-Rodríguez, Inmaculada, Sánchez-Ramos, Jesús Gabriel, Antolinos-Pérez, Mª José, Rivera, Ricardo, Martínez-Huertas, Susana, Thomas-Carazo, Jesús, Yañez-Sanchez, Jose Julio, Blancas-López-Barajas, Mª Isabel, García-Orta, Rocío, González-Astorga, Beatriz, Rodríguez-González, Carlos José, Ruiz-Carazo, Francisco Javier, Pérez-Campos, Manuel, Cano-Herrera, Irene, Herrera, Rosa, Gil-Jiménez, Teresa, Delgado-Ureña, Mª Teresa, Triviño-Juarez, Jose Matías, Campos-Velázquez, Salustiano, Alcántara- Espadafor, Silvia, Moreno Aguilar, Maria Rosario, Ontiveros- Ortega, Maria Carmen, Carnerero-Córdoba, Lidia, Guerrero-Jiménez, Margarita, Legeren- Álvarez, Marta, Yélamos-Vargas, Marisol, Castillo-Pérez, Isabel, Aomar-Millán, Ismael, Anguita-Romero, Manuel, Sánchez-García, María José, Sequero-Lopez, Silvia, Faro-Miguez, Naya, López-Fernández, Silvia, Leyva-Ferrer, Rosario Nieves, Herrera-Gómez, Norberto, Pertejo-Manzano, Laura, Pérez-Gutierrez, Eva Mª, Martín-de la Higuera, Antonio J., Plaza-Carrera, Jose, Baena-Garzón, Flor, Toledo-Frías, Pablo, Cruz-Valero, Inés, Chacón-McWeeny, Verónica, Gallardo- Sánchez, Isabel, Arrebola, Antonio, Guillén-Zafra, Lucía, Ceballos-Torres, Ángel, Guardia-Mancilla, Plácido, Guirao-Arrabal, Emilio, Canterero-Hinojosa, Jesús, Velasco-Fuentes, Sara, Sánchez- Cano, Daniel, Aguilar-Jaldo, Mª del Pilar, Caballero-Borrego, Juan, Praznik, Monika, Slapšak, Urška, Voncina, Blaz, Rajter, Branka, Škrinjar, Andrej, Marjetic Ulcakar, Angelika, Zidanšek, Anja, Stegne Ignjatvic, Tea, Mazej Poredoš, Barbara, Vivod Pecnik, Živka, Poplas Susic, Tonka, Juteršek, Milojka, Klen, Jasna, Skoporc, Janja, Kotar, Tjaša, Petek Šter, Marija, Zvezdana Dernovšk, Mojca, Mlinšek, Gregor, Miklavcic, Petra, Plemenitaš Ilješ, Anja, Grašic Kuhar, Cvetka, Oblak, Irena, Stražišar, Branka, Štrbac, Danijela, Matos, Erika, Mencinger, Marina, Vrbnjak, Marko, Saje, Marko, Radovanovic, Mirjana, Jeras, Katja, Bukovec, Lucija, Terzic, Tea, Minichmayr, Iris, Nanah, Abdulaziz, Nielsen, Elisabet, Zou, Yuanxi, Lauschke, Volker, Johansson, Inger, Zhou, Yitian, Nordling, Åsa, Aigner, Christof, Dames-Ludwig, Marlies, Monteforte, Rossella, Sunder-Plassmann, Raute, Steinhauser, Corinna, Sengoelge, Guerkan, Winnicki, Wolfgang, Schmidt, Alice, Vasileios, Fragoulakis, Fontana, Vanessa, Hanson, Anita, Little, Margaret, Hornby, Rachael, Dello Russo, Cinzia, French, Stephanie, Hampson, Jamie, Gumustekin, Mukaddes, Anyfantis, George, Hampson, Lucy, Lewis, David, Westhead, Ruth, Prince, Clare, Rajasingam, Arjunan, Swen, Jesse J, van der Wouden, Cathelijne H, Manson, Lisanne EN, Abdullah-Koolmees, Heshu, Blagec, Kathrin, Blagus, Tanja, Böhringer, Stefan, Cambon-Thomsen, Anne, Cecchin, Erika, Cheung, Ka-Chun, Deneer, Vera HM, Dupui, Mathilde, Ingelman-Sundberg, Magnus, Jonsson, Siv, Joefield-Roka, Candace, Just, Katja S, Karlsson, Mats O, Konta, Lidija, Koopmann, Rudolf, Kriek, Marjolein, Lehr, Thorsten, Mitropoulou, Christina, Rial-Sebbag, Emmanuelle, Rollinson, Victoria, Roncato, Rossana, Samwald, Matthias, Schaeffeler, Elke, Skokou, Maria, Schwab, Matthias, Steinberger, Daniela, Stingl, Julia C, Tremmel, Roman, Turner, Richard M, van Rhenen, Mandy H, Dávila Fajardo, Cristina L, Dolžan, Vita, Patrinos, George P, Pirmohamed, Munir, Sunder-Plassmann, Gere, Toffoli, Giuseppe, and Guchelaar, Henk-Jan

Published
2023
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18. Correction: Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction between UGT1A1 and irinotecan

Author

Hulshof, Emma C., Deenen, Maarten J., Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J., Buunk, Anne-Marie, Houwink, Elisa J. F., Risselada, Arne, Rongen, Gerard A. P. J. M., van Schaik, Ron H. N., Touw, Daan J., van der Weide, Jan, van Westrhenen, Roos, Deneer, Vera H. M., Guchelaar, Henk-Jan, and Swen, Jesse J.

Published
2023
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19. Mapping the Pharmacogenetic Landscape in a Ugandan Population: Implications for Personalized Medicine in an Underrepresented Population.

Author

Samarasinghe, Sumudu Rangika, Lee, Seung‐been, Corpas, Manuel, Fatumo, Segun, Guchelaar, Henk‐Jan, and Nagaraj, Shivashankar H.

Subjects
WHOLE genome sequencing, GENETIC profile, HAPLOTYPES, COMMUNICABLE diseases, INDIVIDUALIZED medicine
Abstract

Africans are extremely underrepresented in global genomic research. African populations face high burdens of communicable and non‐communicable diseases and experience widespread polypharmacy. As population‐specific genetic studies are crucial to understanding unique genetic profiles and optimizing treatments to reduce medication‐related complications in this diverse population, the present study aims to characterize the pharmacogenomics profile of a rural Ugandan population. We analyzed low‐pass whole genome sequencing data from 1998 Ugandans to investigate 18 clinically actionable pharmacogenes in this population. We utilized PyPGx to identify star alleles (haplotype patterns) and compared allele frequencies across populations using the Pharmacogenomics Knowledgebase PharmGKB. Clinical interpretations of the identified alleles were conducted following established dosing guidelines. Over 99% of participants displayed actionable phenotypes across the 18 pharmacogenes, averaging 3.5 actionable genotypes per individual. Several variant alleles known to affect drug metabolism (i.e., CYP3A5*1, CYP2B6*9, CYP3A5*6, CYP2D6*17, CYP2D6*29, and TMPT*3C)—which are generally more prevalent in African individuals—were notably enriched in the Ugandan cohort, beyond reported frequencies in other African peoples. More than half of the cohort exhibited a predicted impaired drug response associated with CFTR, IFNL3, CYP2B6, and CYP2C19, and approximately 31% predicted altered CYP2D6 metabolism. Potentially impaired CYP2C9, SLCO1B1, TPMT, and DPYD metabolic phenotypes were also enriched in Ugandans compared with other African populations. Ugandans exhibit distinct allele profiles that could impact drug efficacy and safety. Our findings have important implications for pharmacogenomics in Uganda, particularly with respect to the treatment of prevalent communicable and non‐communicable diseases, and they emphasize the potential of pharmacogenomics‐guided therapies to optimize healthcare outcomes and precision medicine in Uganda. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Dutch pharmacogenetics working group guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate

Author

van der Pol, Karel H, Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J, Buunk, Anne Marie, Guchelaar, Henk-Jan, Risselada, Arne, van Schaik, Ron H N, Swen, Jesse J, Touw, Daan, van der Weide, Jan, van Westrhenen, Roos, Deneer, Vera H M, Houwink, Elisa J F, Rongen, Gerard A, van der Pol, Karel H, Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J, Buunk, Anne Marie, Guchelaar, Henk-Jan, Risselada, Arne, van Schaik, Ron H N, Swen, Jesse J, Touw, Daan, van der Weide, Jan, van Westrhenen, Roos, Deneer, Vera H M, Houwink, Elisa J F, and Rongen, Gerard A

Abstract

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.

Published
2024

28. Dutch pharmacogenetics working group guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate

Author

Apotheek Klinische Farmacie, van der Pol, Karel H., Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J., Buunk, Anne Marie, Guchelaar, Henk Jan, Risselada, Arne, van Schaik, Ron H.N., Swen, Jesse J., Touw, Daan, van der Weide, Jan, van Westrhenen, Roos, Deneer, Vera H.M., Houwink, Elisa J.F., Rongen, Gerard A., Apotheek Klinische Farmacie, van der Pol, Karel H., Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J., Buunk, Anne Marie, Guchelaar, Henk Jan, Risselada, Arne, van Schaik, Ron H.N., Swen, Jesse J., Touw, Daan, van der Weide, Jan, van Westrhenen, Roos, Deneer, Vera H.M., Houwink, Elisa J.F., and Rongen, Gerard A.

Published
2024

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

Author

MS Medische Oncologie, Cancer, 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, Swen, Jesse J., MS Medische Oncologie, Cancer, 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

30. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs

Author

Apotheek Klinische Farmacie, Manson, Lisanne E.N., Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J., Buunk, Anne Marie, Houwink, Elisa J.F., Risselada, Arne, Rongen, Gerard A.P.J.M., van Schaik, Ron H.N., Swen, Jesse J., Touw, Daan J., van Westrhenen, Roos, Deneer, Vera H.M., Guchelaar, Henk Jan, Apotheek Klinische Farmacie, Manson, Lisanne E.N., Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J., Buunk, Anne Marie, Houwink, Elisa J.F., Risselada, Arne, Rongen, Gerard A.P.J.M., van Schaik, Ron H.N., Swen, Jesse J., Touw, Daan J., van Westrhenen, Roos, Deneer, Vera H.M., and Guchelaar, Henk Jan

Published
2024

31. Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort

Author

Mc Laughlin, Anna M., Helland, Thomas, Klima, Fenja, Koolen, Stijn L.W., van Schaik, Ron H.N., Mathijssen, Ron H.J., Neven, Patrick, Swen, Jesse J., Guchelaar, Henk Jan, Dalenc, Florence, White-Koning, Melanie, Michelet, Robin, Mikus, Gerd, Schroth, Werner, Mürdter, Thomas, Brauch, Hiltrud, Schwab, Matthias, Søiland, Håvard, Mellgren, Gunnar, Thomas, Fabienne, Kloft, Charlotte, Hertz, Daniel L., Mc Laughlin, Anna M., Helland, Thomas, Klima, Fenja, Koolen, Stijn L.W., van Schaik, Ron H.N., Mathijssen, Ron H.J., Neven, Patrick, Swen, Jesse J., Guchelaar, Henk Jan, Dalenc, Florence, White-Koning, Melanie, Michelet, Robin, Mikus, Gerd, Schroth, Werner, Mürdter, Thomas, Brauch, Hiltrud, Schwab, Matthias, Søiland, Håvard, Mellgren, Gunnar, Thomas, Fabienne, Kloft, Charlotte, and Hertz, Daniel L.

Abstract

Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z-endoxifen concentration and tamoxifen treatment outcomes, and identify a Z-endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed-effect (NLME) model for tamoxifen and Z-endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z-endoxifen. The final parent-metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co-medication with CYP2D6 inhibitors, on Z-endoxifen pharmacokinetics. Future work will use the model to simulate Z-endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long-term survival to identify the Z-endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor-positive breast cancer.

Published
2024

32. 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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33. Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan

Author

Moes, Dirk J.A.R., Hendrikx, Jeroen J.M.A., Guchelaar, Henk Jan, Mathijssen, Ron H.J., Bakker, J. L., Dezentjé, Vincent O., de Rouw, Nikki, van Erp, Nielka P., Smit, Egbert F., van den Heuvel, Michel M., Munnink, Thijs H.Oude, van Kats, Maartje, Croes, Sander, Kroep, Judith R., Zwaveling, Juliette, ter Heine, Rob, Moes, Dirk J.A.R., Hendrikx, Jeroen J.M.A., Guchelaar, Henk Jan, Mathijssen, Ron H.J., Bakker, J. L., Dezentjé, Vincent O., de Rouw, Nikki, van Erp, Nielka P., Smit, Egbert F., van den Heuvel, Michel M., Munnink, Thijs H.Oude, van Kats, Maartje, Croes, Sander, Kroep, Judith R., Zwaveling, Juliette, and ter Heine, Rob

Abstract

Background: The antibody–drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality. Objective: The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access. Patients and Methods: Exposure equivalent dosing strategies were developed based on pharmacokinetic modeling and simulation by using the published pharmacokinetic model developed by the license holder. The alternative dose was based on the principle of using complete vials to prevent spillage and on the established non-linear relationship between body weight and systemic exposure. Equivalent exposure compared to the approved dosing regimen of 10 mg/kg was aimed for. Equivalent exposure was conservatively defined as calculated geometric mean ratios within the 0.9–1.11 boundaries for area under the concentration–time curve (AUC), trough concentration (Ctrough) and maximum concentration (Cmax) of the alternative dosing regimen compared to the approved dosing regimen. Since different vial sizes are available for the European Union (EU) and United States (US) market, because body weight distributions differ between these populations, we performed our analysis for both scenarios. Results: Dosing regimens of sacituzumab govitecan for the EU (< 50 kg: 400 mg, 50–80 kg: 600 mg, and > 80 kg: 800 mg) and US population (< 40 kg: 360 mg, 40–65 kg: 540 mg, 65–90 kg: 720 mg, and > 90 kg: 900 mg) were developed, based on weight bands. The geometric mean ratios for all pharmacokinetic outcomes were within the predefined equivalence boundaries, while the quantity of drug used was 21.5% and

Published
2024

34. Dutch pharmacogenetics working group guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate

Author

Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, PECP – Centre for Clinical Therapeutics, van der Pol, Karel H, Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J, Buunk, Anne Marie, Guchelaar, Henk-Jan, Risselada, Arne, van Schaik, Ron H N, Swen, Jesse J, Touw, Daan, van der Weide, Jan, van Westrhenen, Roos, Deneer, Vera H M, Houwink, Elisa J F, Rongen, Gerard A, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, PECP – Centre for Clinical Therapeutics, van der Pol, Karel H, Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J, Buunk, Anne Marie, Guchelaar, Henk-Jan, Risselada, Arne, van Schaik, Ron H N, Swen, Jesse J, Touw, Daan, van der Weide, Jan, van Westrhenen, Roos, Deneer, Vera H M, Houwink, Elisa J F, and Rongen, Gerard A

Published
2024

35. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics

Author

Apotheek Klinische Farmacie, Beunk, Lianne, Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J, Buunk, Anne-Marie, Guchelaar, Henk Jan, Houwink, Elisa J F, Risselada, Arne, Rongen, Gerard A P J M, van Schaik, Ron H N, Swen, Jesse J, Touw, Daan, van Westrhenen, Roos, Deneer, Vera H M, van der Weide, Jan, Apotheek Klinische Farmacie, Beunk, Lianne, Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J, Buunk, Anne-Marie, Guchelaar, Henk Jan, Houwink, Elisa J F, Risselada, Arne, Rongen, Gerard A P J M, van Schaik, Ron H N, Swen, Jesse J, Touw, Daan, van Westrhenen, Roos, Deneer, Vera H M, and van der Weide, Jan

Published
2024

36. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics

Author

Afd Pharmacoepi & Clinical Pharmacology, PECP – Centre for Clinical Therapeutics, Pharmacoepidemiology and Clinical Pharmacology, Beunk, Lianne, Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J, Buunk, Anne-Marie, Guchelaar, Henk Jan, Houwink, Elisa J F, Risselada, Arne, Rongen, Gerard A P J M, van Schaik, Ron H N, Swen, Jesse J, Touw, Daan, van Westrhenen, Roos, Deneer, Vera H M, van der Weide, Jan, Afd Pharmacoepi & Clinical Pharmacology, PECP – Centre for Clinical Therapeutics, Pharmacoepidemiology and Clinical Pharmacology, Beunk, Lianne, Nijenhuis, Marga, Soree, Bianca, de Boer-Veger, Nienke J, Buunk, Anne-Marie, Guchelaar, Henk Jan, Houwink, Elisa J F, Risselada, Arne, Rongen, Gerard A P J M, van Schaik, Ron H N, Swen, Jesse J, Touw, Daan, van Westrhenen, Roos, Deneer, Vera H M, and van der Weide, Jan

Published
2024

37. Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole.

Author

Klomp, Sylvia D., Veringa, Anette, Alffenaar, Jan‐Willem C., de Boer, Mark G. J., Span, Lambert F. R., Guchelaar, Henk‐Jan, and Swen, Jesse J.

Subjects
CYTOCHROME P-450 CYP2C19, VORICONAZOLE, GENOTYPES, INFLAMMATION, MYCOSES
Abstract

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype‐predicted‐phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose‐corrected voriconazole plasma concentration and C‐reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype‐predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose‐corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose‐corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes. [ABSTRACT FROM AUTHOR]

Published
2024
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38. A Genome‐Wide Association Study of Endoxifen Serum Concentrations and Adjuvant Tamoxifen Efficacy in Early‐Stage Breast Cancer Patients.

Author

Sanchez‐Spitman, Anabel Beatriz, Böhringer, Stefan, Dezentjé, Vincent Olaf, Gelderblom, Hans, Swen, Jesse Joachim, and Guchelaar, Henk‐Jan

Subjects
GENOME-wide association studies, TAMOXIFEN, BREAST cancer, CYTOCHROME P-450 CYP2D6, ADJUVANT treatment of cancer
Abstract

Tamoxifen is part of the standard of care of endocrine therapy for adjuvant treatment of breast cancer. However, survival outcomes with tamoxifen are highly variable. The concentration of endoxifen, the 30–100 times more potent metabolite of tamoxifen and bioactivated by the CYP2D6 enzyme, has been described as the most relevant metabolite of tamoxifen metabolism. A genome‐wide association study (GWAS) was performed with the objective to identify genetic polymorphisms associated with endoxifen serum concentration levels and clinical outcome in early‐stage breast cancer patients receiving tamoxifen. A GWAS was conducted in 608 women of the CYPTAM study (NTR1509/PMID: 30120701). Germline DNA and clinical and survival characteristics were readily available. Genotyping was performed on Infinium Global Screening Array (686,082 markers) and single nucleotide polymorphism (SNP) imputation by using 1000 Genomes. Relapse‐free survival during tamoxifen (RFSt) was defined the primary clinical outcome. Endoxifen serum concentration was analyzed as a continuous variable. Several genetic variants reached genome‐wide significance (P value: ≤5 × 10−8). Endoxifen concentrations analysis identified 430 variants, located in TCF20 and WBP2NL genes (chromosome 22), which are in strong linkage disequilibrium with CYP2D6 variants. In the RFSt analysis, several SNP were identified (LPP gene: rs77693286, HR 18.3, 95% CI: 15.2–21.1; rs6790761, OR 18.2, 95% CI: 15.5–21.1). Endoxifen concentrations have a strong association with the chromosome 22, which contains the CYP2D6 gene. [ABSTRACT FROM AUTHOR]

Published
2024
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40. 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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43. Population Pharmacokinetic and Pharmacogenetic Analysis of Mitotane in Patients with Adrenocortical Carcinoma: Towards Individualized Dosing

Author

Yin, Anyue, Ettaieb, Madeleine H. T., Swen, Jesse J., van Deun, Liselotte, Kerkhofs, Thomas M. A., van der Straaten, Robert J. H. M., Corssmit, Eleonora P. M., Gelderblom, Hans, Kerstens, Michiel N., Feelders, Richard A., Eekhoff, Marelise, Timmers, Henri J. L. M., D’Avolio, Antonio, Cusato, Jessica, Guchelaar, Henk-Jan, Haak, Harm R., and Moes, Dirk Jan A. R.

Published
2021
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