{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:47:35Z","timestamp":1787730455744,"version":"build-2784847793"},"reference-count":42,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T00:00:00Z","timestamp":1583193600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100010434","name":"\u201cla Caixa\u201d Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Busulfan and treosulfan are cytotoxic agents used in the conditioning regime prior to paediatric haematopoietic stem cell transplantation (HSCT). These agents cause suppression of myeloid cells leaving patients severely immunocompromised in the early post\u2010HSCT period. The main objectives were: (i) to establish a mechanistic pharmacokinetic\u2013pharmacodynamic (PKPD) model for the treatment and engraftment effects on neutrophil counts comparing busulfan and treosulfan\u2010based conditioning, and (ii) to explore current dosing schedules with respect to time to HSCT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data on 126 patients, 72 receiving busulfan (7 months\u201318 years, 5.1\u201347.0 kg) and 54 treosulfan (4 months\u201317 years, 3.8\u201335.8 kg), were collected. In total, 8935 neutrophil count observations were recorded during the study period in addition to drug concentrations to develop a mechanistic PKPD model. Absolute neutrophil count profiles were modelled semimechanistically, accounting for transplant effects and differing set points pre\u2010 and post\u2010transplant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PK were best described by 2\u2010compartment models for both drugs. The Friberg semimechanistic neutropenia model was applied with a linear model for busulfan and a maximum efficacy model for treosulfan describing drug effects at various stages of neutrophil maturation. System parameters were consistent across both drugs. The HSCT was represented by an amount of progenitor cells enhancing the neutrophils' proliferation and maturation compartments. Alemtuzumab was found to enhance the proliferative rate under which the absolute neutrophil count begin to grow after HSCT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A semimechanistic PKPD model linking exposure to either busulfan or treosulfan to the neutrophil reconstitution dynamics was successfully built. Alemtuzumab coadministration enhanced the neutrophil proliferative rate after HSCT. Treosulfan administration was suggested to be delayed with respect to time to HSCT, leaving less time between the end of the administration and stem cell infusion.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14260","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T05:30:12Z","timestamp":1582176612000},"page":"1537-1549","source":"Crossref","is-referenced-by-count":7,"title":["Modelling of neutrophil dynamics in children receiving busulfan or treosulfan for haematopoietic stem cell transplant conditioning"],"prefix":"10.1111","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4621-5480","authenticated-orcid":false,"given":"Bel\u00e9n P.","family":"Solans","sequence":"first","affiliation":[{"name":"Pharmacometrics and Systems Pharmacology, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition University of Navarra  Pamplona Spain"},{"name":"IdiSNA Navarra Institute for Health Research  Pamplona 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