{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:59:29Z","timestamp":1785488369079,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JST SPRING","award":["JPMJSP2127"],"award-info":[{"award-number":["JPMJSP2127"]}]},{"name":"JSPS Grant-in-Aid for Scientific Research","award":["26K02629"],"award-info":[{"award-number":["26K02629"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Pemetrexed\u2013platinum chemotherapy is a key treatment option for non-squamous non-small cell lung cancer (NSCLC); however, its use is often limited by hematologic toxicity, particularly neutropenia. We aimed to develop a model-informed framework for assessing neutrophil dynamics using routinely available clinical data and pemetrexed exposure. Methods: This real-world investigation included 86 patients with NSCLC who received pemetrexed\u2013platinum chemotherapy for model development, and 83 patients who received the same chemotherapy plus pembrolizumab or bevacizumab for validation. We developed a nonlinear mixed-effects model to predict neutrophil dynamics during the first cycle following pemetrexed\u2013platinum chemotherapy, using patient-specific clinical data collected before chemotherapy initiation and pemetrexed pharmacokinetic parameters derived from physiologically based pharmacokinetic (PBPK) modeling. Results: The final model suggested that the area under the curve (AUC)0\u201324 &gt;175 \u03bcg\u00b7h\/mL for pemetrexed, blood urea nitrogen, and concomitant use of renin\u2013angiotensin system inhibitors influenced neutrophil suppression and delayed recovery. The receiver operating characteristic curve (AUROC) for identifying patients with a neutrophil count &lt;1500\/\u03bcL immediately before the anticipated next treatment cycle was 0.768 (95% CI: 0.639\u20130.898) in the development cohort, and 0.718 (95% CI: 0.545\u20130.891) in the validation cohort. Conclusions: This model-informed framework, based on PBPK-derived pemetrexed exposure and routinely available clinical factors, may help identify patients at risk of clinically relevant neutropenia that could delay the initiation of the next treatment cycle.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080946","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:20:18Z","timestamp":1785486018000},"page":"946","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Risk Assessment of Neutropenia Based on Exposure Information Without Plasma Concentration Measurement in Pemetrexed\u2013Platinum-Based Chemotherapy: A Modeling Approach Using Real-World Clinical Data"],"prefix":"10.3390","volume":"18","author":[{"given":"Kazunori","family":"Morita","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto 861-4193, Japan"},{"name":"Clinical Research Center, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto 861-4193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Shigetome","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"},{"name":"Department of Psychiatry, School of Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsugagun 321-0293, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Narise","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"},{"name":"Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Soejima","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8452-7971","authenticated-orcid":false,"given":"Ryota","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Oita University Hospital, 1-1 Idaigaoka, Hasama-machi, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Jono","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan"},{"name":"Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0322-9356","authenticated-orcid":false,"given":"Hiroki","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Oita University Hospital, 1-1 Idaigaoka, Hasama-machi, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5166-7145","authenticated-orcid":false,"given":"Daisuke","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7525-8094","authenticated-orcid":false,"given":"Koki","family":"Tokunaga","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto 861-4193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akitomo","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto 861-4193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harumi","family":"Tanoue","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto 861-4193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Ichikado","sequence":"additional","affiliation":[{"name":"Clinical Research Center, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto 861-4193, Japan"},{"name":"Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto 861-4193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayami","family":"Kajiwara-Morita","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5926-7151","authenticated-orcid":false,"given":"Kentaro","family":"Oniki","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6266-1347","authenticated-orcid":false,"given":"Junji","family":"Saruwatari","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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