Worse capecitabine treatment outcome in patients with a low skeletal muscle mass is not explained by altered pharmacokinetics
Molenaar-Kuijsten, Laura; Jacobs, Bart Albertus Wilhelmus; Kurk, Sophie Alberdine; May, Anne Maria; Dorlo, Thomas Petrus Catharina; Beijnen, Jacob Hendrik; Steeghs, Neeltje; Huitema, Alwin Dagmar Redmar
(2021) Cancer Medicine, volume 10, issue 14, pp. 4781 - 4789
(Article)
Abstract
Background: 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-fluorouracil (5-FU). Capecitabine and its metabolites are highly water-soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patients with
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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. Methods: 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)-scans were available. SMM was measured on CT-scans, by single slice evaluation at the third lumbar vertebra, using the Slice-o-Matic 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. Results: 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-FU. SMM only correlated with the PK of the, most hydrophilic, but inactive and non-toxic, metabolite α-fluoro-β-alanine (FBAL). Patients with a low SMM had a smaller apparent volume of distribution and lower apparent clearance of FBAL. Conclusions: No alterations in PK of capecitabine and the active and toxic metabolite 5-FU 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.
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Keywords: body composition, capecitabine, pharmacokinetics, skeletal muscle mass, Humans, Middle Aged, Neoplasms/drug therapy, Fluorouracil/pharmacokinetics, Male, Tomography, X-Ray Computed, Treatment Outcome, Prodrugs/administration & dosage, beta-Alanine/analogs & derivatives, Capecitabine/administration & dosage, Sex Factors, Adult, Female, Aged, Muscle, Skeletal/diagnostic imaging, Antimetabolites, Antineoplastic/administration & dosage, Oncology, Radiology Nuclear Medicine and imaging, Cancer Research, Journal Article
ISSN: 2045-7634
Publisher: John Wiley & Sons Inc.
Note: Funding Information: J.H. Beijnen (partly) holds a patent on oral taxane formulations and is a (part time) employee and stockholder of Modra Pharmaceuticals, a spin‐out company developing oral taxanes. Not related to the manuscript. N. Steeghs provided consultation or attended advisory boards for AIMM Therapeutics, Boehringer Ingelheim, Ellipses Pharma. N. Steeghs received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol‐Myers Squibb, Cantargia, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, InteRNA, Lilly, Merck Sharp & Dohme, Merus, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho, Takeda (outside the submitted work). The other authors indicated no financial disclosures. Publisher Copyright: © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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