{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:07:11Z","timestamp":1790104031657,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PEG-ASPase product (medac GmBH, Sigma-Tau, Baxalta, Shire and Servier)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Asparaginase (ASPase) plays an important role in the therapy of acute lymphoblastic leukemia (ALL). Serum ASPase activity (SAA) can be modified and even abolished by host immune responses; therefore, current treatment guidelines recommend to monitor SAA during treatment administration. The SAA monitoring schedule needs to be carefully planned to reduce the number of samples without hampering the possibility of measuring pharmacokinetics (PK) parameters in individual patients. Complex modelling approaches, not easily applicable in common practice, have been applied in previous studies to estimate ASPase PK parameters. This study aimed to estimate PK parameters by using a simplified approach suitable for real-world settings with limited sampling. Methods: Our study was based on 434 patients treated in Italy within the AIEOP-BFM ALL 2009 trial. During the induction phase, patients received two doses of pegylated ASPase and were monitored with blood sampling at five time points, including time 0. PK parameters were estimated by using the individually available SAA measurements with simple modifications of the classical non-compartmental PK analysis. We also took the opportunity to develop and validate a series of limited sampling models to predict ASPase exposure. Results: During the induction phase, average ASPase activity at day 7 was 1380 IU\/L after the first dose and 1948 IU\/L after the second dose; therapeutic SAA levels (&gt;100 IU\/L) were maintained until day 33 in 90.1% of patients. The average AUC and clearance were 46,937 IU\/L \u00d7 day and 0.114 L\/day\/m2, respectively. The database was analyzed for possible associations of PK parameters with biological characteristics of the patients, finding only a limited dependence on sex, age and risk score; however, these differences were not sufficient to allow any dose or schedule adjustments. Thereafter the possibility of further sampling reduction by using simple linear models to estimate the AUC was also explored. The most simple model required only two samplings 7 days after each ASPase dose, with the AUC being proportional to the sum of the two measured activities A(7) and A(21), calculated by the formula AUC = 14.1 \u00d7 [A(7) + A(21)]. This model predicts the AUC with 6% average error and 35% maximum error compared to the AUC estimated with all available measures. Conclusions: Our study demonstrates the feasibility of a direct estimation of PK parameters in a real-life situation with limited and variable blood sampling schedules and also offers a simplified method and formulae easily applicable in clinical practice while maintaining a reliable pharmacokinetic monitoring.<\/jats:p>","DOI":"10.3390\/pharmaceutics17070915","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T13:00:51Z","timestamp":1752757251000},"page":"915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacokinetics of Pegaspargase with a Limited Sampling Strategy for Asparaginase Activity Monitoring in Children with Acute Lymphoblastic Leukemia"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8910-1104","authenticated-orcid":false,"given":"Cristina","family":"Matteo","sequence":"first","affiliation":[{"name":"Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Colombini","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9963-4457","authenticated-orcid":false,"given":"Marta","family":"Cancelliere","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Ceruti","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Fuso Nerini","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Porcu","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5427-052X","authenticated-orcid":false,"given":"Massimo","family":"Zucchetti","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Silvestri","sequence":"additional","affiliation":[{"name":"Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5574-3504","authenticated-orcid":false,"given":"Maria Grazia","family":"Valsecchi","sequence":"additional","affiliation":[{"name":"Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"},{"name":"School of Medicine and Surgery, University of Milan-Bicocca, 20126 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3350-5286","authenticated-orcid":false,"given":"Rosanna","family":"Parasole","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia, Ematologia e Terapie Cellulari, AORN Santobono-Pausilipon, 80122 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2803-992X","authenticated-orcid":false,"given":"Luciana","family":"Vinti","sequence":"additional","affiliation":[{"name":"Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica, Ospedale Pediatrico Bambino Ges\u00f9, 00050 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Bertorello","sequence":"additional","affiliation":[{"name":"Oncoematologia Pediatrica, Ospedale Infantile Regina Margherita, Citt\u00e0 della Salute e della Scienza, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Onofrillo","sequence":"additional","affiliation":[{"name":"Oncoematologia Pediatrica, Dipartimento di Oncologia e Ematologia, Ospedale Civile Spirito Santo, 65100 Pescara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Provenzi","sequence":"additional","affiliation":[{"name":"Oncologia Pediatrica, Ospedale Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Chiocca","sequence":"additional","affiliation":[{"name":"Department of Hematology-Oncology, Meyer Children\u2019s Hospital IRCCS, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2480-1799","authenticated-orcid":false,"given":"Luca","family":"Lo Nigro","sequence":"additional","affiliation":[{"name":"Centro di Ematologia ed Oncologia Pediatrica, Azienda Ospedaliero Universitaria, Policlinico \u201cG. Rodolico-San Marco\u201d, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Rachele","family":"Bettini","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"},{"name":"Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Gotti","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bungaro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schrappe","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Christian-Albrechts-University Kiel and University Medical Centre Schleswig-Holstein, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0412-9891","authenticated-orcid":false,"given":"Paolo","family":"Ubezio","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelo","family":"Rizzari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s40265-019-01120-1","article-title":"Pegaspargase: A Review in Acute Lymphoblastic Leukaemia","volume":"79","author":"Heo","year":"2019","journal-title":"Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s00280-016-3236-y","article-title":"Asparaginase Pharmacology: Challenges Still to Be Faced","volume":"79","year":"2017","journal-title":"Cancer Chemother. 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