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Population Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia: Treatment Phase Dependency and Predictivity in Case of Missing Data

G. Würthwein, C. Lanvers-Kaminsky, C. Siebel, J. Gerß, A. Möricke, M. Zimmermann, J. Stary, P. Smisek, M. Schrappe, C. Rizzari, M. Zucchetti, G. Hempel, SG. Wicha, J. Boos, AIEOP-BFM ALL 2009 Asparaginase Working Party

. 2021 ; 46 (2) : 289-300. [pub] 20210217

Language English Country France

Document type Clinical Trial, Journal Article, Multicenter Study, Validation Study

Persistent link   https://www.medvik.cz/link/bmc22004574

BACKGROUND AND OBJECTIVES: The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance. METHODS: In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m2 intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia. ASNase activity levels were monitored weekly. A PopPK model was used for covariate modeling and external validation. The predictivity of the model in case of missing data was tested for observations, as well as for the derived parameters of the area under the concentration time curve (AUC0-∞) and time above different thresholds. RESULTS: Compared to the first administration in induction (1374 patients, 6069 samples), the initial clearance and volume of distribution decreased by 11.0% and 15.9%, respectively, during the second administration during induction and by 41.2% and 28.4% during reinduction. Furthermore, the initial clearance linearly increased for children aged > 8 years and was 7.1% lower for females. The model was successfully externally validated (1253 patients, 5523 samples). In case of missing data, > 52% of the predictions for observations and > 82% for derived parameters were within ± 20% of the nominal value. CONCLUSION: A PopPK model that describes the complex pharmacokinetics of PEG-ASNase was successfully externally validated. AUC0-∞ or time above different thresholds, which are parameters describing dose intensity, can be estimated with high predictivity, despite missing data. ( www.clinicaltrials.gov , NCT01117441, first submitted date: May 3, 2010).

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$a BACKGROUND AND OBJECTIVES: The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance. METHODS: In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m2 intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia. ASNase activity levels were monitored weekly. A PopPK model was used for covariate modeling and external validation. The predictivity of the model in case of missing data was tested for observations, as well as for the derived parameters of the area under the concentration time curve (AUC0-∞) and time above different thresholds. RESULTS: Compared to the first administration in induction (1374 patients, 6069 samples), the initial clearance and volume of distribution decreased by 11.0% and 15.9%, respectively, during the second administration during induction and by 41.2% and 28.4% during reinduction. Furthermore, the initial clearance linearly increased for children aged > 8 years and was 7.1% lower for females. The model was successfully externally validated (1253 patients, 5523 samples). In case of missing data, > 52% of the predictions for observations and > 82% for derived parameters were within ± 20% of the nominal value. CONCLUSION: A PopPK model that describes the complex pharmacokinetics of PEG-ASNase was successfully externally validated. AUC0-∞ or time above different thresholds, which are parameters describing dose intensity, can be estimated with high predictivity, despite missing data. ( www.clinicaltrials.gov , NCT01117441, first submitted date: May 3, 2010).
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$a Lanvers-Kaminsky, Claudia $u Department of Pediatric Hematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany
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$a Siebel, Christian $u Department of Pediatric Hematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany
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$a Gerß, Joachim $u Institute of Biostatistics and Clinical Research, University Münster, Münster, Germany
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$a Möricke, Anja $u Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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$a Zimmermann, Martin $u Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
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$a Smisek, Petr $u Department of Pediatric Hematology and Oncology, Charles University and University Hospital, Motol, Prague, Czech Republic
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$a Schrappe, Martin $u Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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$a Rizzari, Carmelo $u Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of Milano-Bicocca, MBBM Foundation, ASST-Monza, Monza, Italy
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$a Zucchetti, Massimo $u Department of Oncology, Laboratory of Cancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
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$a Hempel, Georg $u Department of Pharmaceutical and Medical Chemistry-Clinical Pharmacy, Münster, Germany
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