Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model
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 re...
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2024-09-01
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| author | Laura Ben Olivo Pricilla de Oliveira Henz Sophia Wermann Bruna Bernar Dias Gabriel Osorio Porto Amanda Valle Pinhatti Manoela Domingues Martins Lauro José Gregianin Teresa Dalla Costa Bibiana Verlindo de Araújo |
| author_facet | Laura Ben Olivo Pricilla de Oliveira Henz Sophia Wermann Bruna Bernar Dias Gabriel Osorio Porto Amanda Valle Pinhatti Manoela Domingues Martins Lauro José Gregianin Teresa Dalla Costa Bibiana Verlindo de Araújo |
| author_sort | Laura Ben Olivo |
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| description | 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<sup>®</sup>) 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/m<sup>2</sup> 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. |
| format | Article |
| id | doaj-art-fe1672f985444cfeb943911188a273ee |
| institution | OA Journals |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-fe1672f985444cfeb943911188a273ee2025-08-20T01:55:46ZengMDPI AGPharmaceutics1999-49232024-09-01169118010.3390/pharmaceutics16091180Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic ModelLaura Ben Olivo0Pricilla de Oliveira Henz1Sophia Wermann2Bruna Bernar Dias3Gabriel Osorio Porto4Amanda Valle Pinhatti5Manoela Domingues Martins6Lauro José Gregianin7Teresa Dalla Costa8Bibiana Verlindo de Araújo9Pharmacokinetics 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, BrazilPharmacokinetics 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, BrazilPharmacokinetics 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, BrazilPharmacokinetics 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, BrazilPharmacokinetics 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, BrazilMedical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, RS, BrazilFaculty of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, RS, BrazilPediatric Oncology Service, Hospital de Clínicas de Porto Alegre, Department of Pediatrics, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, RS, BrazilPharmacokinetics 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, BrazilPharmacokinetics 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, BrazilMethotrexate (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<sup>®</sup>) 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/m<sup>2</sup> 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.https://www.mdpi.com/1999-4923/16/9/1180methotrexateosteosarcomapharmacokinetic modelBrazilian pediatric patients |
| spellingShingle | Laura Ben Olivo Pricilla de Oliveira Henz Sophia Wermann Bruna Bernar Dias Gabriel Osorio Porto Amanda Valle Pinhatti Manoela Domingues Martins Lauro José Gregianin Teresa Dalla Costa Bibiana Verlindo de Araújo Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model Pharmaceutics methotrexate osteosarcoma pharmacokinetic model Brazilian pediatric patients |
| title | Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model |
| title_full | Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model |
| title_fullStr | Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model |
| title_full_unstemmed | Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model |
| title_short | Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model |
| title_sort | anticipating leucovorin rescue therapy in patients with osteosarcoma through methotrexate population pharmacokinetic model |
| topic | methotrexate osteosarcoma pharmacokinetic model Brazilian pediatric patients |
| url | https://www.mdpi.com/1999-4923/16/9/1180 |
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