{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T14:37:43Z","timestamp":1747147063057,"version":"3.40.5"},"reference-count":34,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5\u2010fluorouracil (5\u2010FU). Capecitabine and its metabolites are highly water\u2010soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patients with a low SMM could be changed, for example, by reaching higher maximum plasma concentrations. In this study, we aimed to examine whether the association between a low SMM and increased toxicity and shorter survival could be explained by altered PK of capecitabine and its metabolites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Previously, a population PK model of capecitabine and metabolites in patients with solid tumors was developed. In our analysis, we included patients from this previous analysis for which evaluable abdominal computed tomography (CT)\u2010scans were available. SMM was measured on CT\u2010scans, by single slice evaluation at the third lumbar vertebra, using the Slice\u2010o\u2010Matic software. The previously developed population PK model was extended with SMM as a covariate, to assess the association between SMM and capecitabine and metabolite PK.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PK and SMM data were available from 151 cancer patients with solid tumors. From the included patients, 55% had a low SMM. No relevant relationships were found between SMM and the PK parameters of capecitabine and, the active and toxic metabolite, 5\u2010FU. SMM only correlated with the PK of the, most hydrophilic, but inactive and non\u2010toxic, metabolite \u03b1\u2010fluoro\u2010\u03b2\u2010alanine (FBAL). Patients with a low SMM had a smaller apparent volume of distribution and lower apparent clearance of FBAL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>No alterations in PK of capecitabine and the active and toxic metabolite 5\u2010FU were observed in patients with a low SMM. Therefore, the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by changes in pharmacokinetic characteristics of capecitabine and metabolites.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.4038","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T08:23:30Z","timestamp":1623659010000},"page":"4781-4789","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Worse capecitabine treatment outcome in patients with a low skeletal muscle mass is not explained by altered pharmacokinetics"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5389-463X","authenticated-orcid":false,"given":"Laura","family":"Molenaar\u2010Kuijsten","sequence":"first","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute \u2010 Antoni van Leeuwenhoek Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart Albertus Wilhelmus","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute \u2010 Antoni van Leeuwenhoek Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8948-5937","authenticated-orcid":false,"given":"Sophie Alberdine","family":"Kurk","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University Medical Center Utrecht Utrecht University Utrecht The Netherlands"},{"name":"Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht University Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne Maria","family":"May","sequence":"additional","affiliation":[{"name":"Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht University Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas Petrus Catharina","family":"Dorlo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute \u2010 Antoni van Leeuwenhoek Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob Hendrik","family":"Beijnen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute \u2010 Antoni van Leeuwenhoek Amsterdam The Netherlands"},{"name":"Department of Pharmaceutical Sciences Utrecht University Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neeltje","family":"Steeghs","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Clinical Pharmacology The Netherlands Cancer Institute \u2010 Antoni van Leeuwenhoek Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alwin Dagmar Redmar","family":"Huitema","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute \u2010 Antoni van Leeuwenhoek Amsterdam The Netherlands"},{"name":"Department of Clinical Pharmacy University Medical Center Utrecht Utrecht University Utrecht The Netherlands"},{"name":"Department of Pharmacology Princess M\u00e1xima Center for Pediatric Oncology Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"European Medicines Agency Committee for Medicinal Products for Human Use (CHMP).Capecitabine European Public Assessment Report [Internet]. 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