Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model
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
Affiliations
Laura Ben Olivo
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
Pricilla de Oliveira Henz
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
Sophia Wermann
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
Bruna Bernar Dias
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
Gabriel Osorio Porto
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
Amanda Valle Pinhatti
Medical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, RS, Brazil
Manoela Domingues Martins
Faculty of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, RS, Brazil
Lauro José Gregianin
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
Teresa Dalla Costa
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
Bibiana Verlindo de Araújo
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
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.
