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Pharmaceutics
Volume 16
Issue 9
10.3390/pharmaceutics16091180
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model

by
Laura Ben Olivo
1,
Pricilla de Oliveira Henz
1,
Sophia Wermann
1,
Bruna Bernar Dias
1,
Gabriel Osorio Porto
1,
Amanda Valle Pinhatti
2,3,
Manoela Domingues Martins
3,
Lauro José Gregianin
4,
Teresa Dalla Costa
1 and
Bibiana Verlindo de Araújo
1,2,*
1
Pharmacokinetics and PK/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, 2752 Ipiranga Ave., Santana, Porto Alegre 90610-000, RS, Brazil
2
Medical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, RS, Brazil
3
Faculty of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, RS, Brazil
4
Pediatric Oncology Service, Hospital de Clínicas de Porto Alegre, Department of Pediatrics, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, RS, Brazil
*
Author to whom correspondence should be addressed.
Pharmaceutics 2024, 16(9), 1180; https://doi.org/10.3390/pharmaceutics16091180
Submission received: 30 June 2024 / Revised: 26 August 2024 / Accepted: 1 September 2024 / Published: 6 September 2024
(This article belongs to the Special Issue Optimizing Drug Safety and Efficacy: Pharmacokinetic Modeling)
Review Reports Versions Notes

Abstract

Methotrexate (MTX), which presents high inter-individual variability, is part of the Brazilian Osteosarcoma Treatment Group (BOTG) protocol. This work aimed to develop a MTX population pharmacokinetic model (POPPK) for Brazilian children with osteosarcoma (OS) following the BOTG protocol to guide rescue therapy and avoid toxicity. The model was developed in NONMEM 7.4 (Icon®) using retrospective sparse data from MTX therapeutic drug monitoring of children attending a southern Brazilian public reference hospital. Data were described by a two-compartment model using 216 MTX cycles from 32 patients (5–18 y.o.) with OS who received 12 g/m2 dose/cycle. To explain inter-individual and inter-occasion variability in clearance and peripheral volume, covariates from demographic and biochemical data were evaluated. Serum creatinine was a significant covariate of MTX clearance (14.8 L/h), and the body surface area (BSA) was significant for central compartment volume (82.5 L). Inter-compartmental clearance and volume of peripheral compartment were 0.178 L/h and 5.72 L, respectively. The model adequately describes MTX exposure in Brazilian children with OS. Successful simulations were performed to predict MTX concentrations in pediatric patients above five years old with acute kidney injury and anticipate rescue therapy adjustments.
Keywords: methotrexate; osteosarcoma; pharmacokinetic model; Brazilian pediatric patients methotrexate; osteosarcoma; pharmacokinetic model; Brazilian pediatric patients

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MDPI and ACS Style

Olivo, L.B.; de Oliveira Henz, P.; Wermann, S.; Dias, B.B.; Porto, G.O.; Pinhatti, A.V.; Martins, M.D.; Gregianin, L.J.; Dalla Costa, T.; de Araújo, B.V. Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model. Pharmaceutics 2024, 16, 1180. https://doi.org/10.3390/pharmaceutics16091180

AMA Style

Olivo LB, de Oliveira Henz P, Wermann S, Dias BB, Porto GO, Pinhatti AV, Martins MD, Gregianin LJ, Dalla Costa T, de Araújo BV. Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model. Pharmaceutics. 2024; 16(9):1180. https://doi.org/10.3390/pharmaceutics16091180

Chicago/Turabian Style

Olivo, Laura Ben, Pricilla de Oliveira Henz, Sophia Wermann, Bruna Bernar Dias, Gabriel Osorio Porto, Amanda Valle Pinhatti, Manoela Domingues Martins, Lauro José Gregianin, Teresa Dalla Costa, and Bibiana Verlindo de Araújo. 2024. "Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model" Pharmaceutics 16, no. 9: 1180. https://doi.org/10.3390/pharmaceutics16091180

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