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.

Objective: This study aims to evaluate free vancomycin concentrations in tissues of septic patients that received empirical doses. Methods: A PBPK model was built in PK-Sim to simulate vancomycin concentrations in healthy volunteers and septic patients. Literature data were used to validate the model. A strain of MRSA (methicillin-resistant Staphylococcus aureus) was evaluated through time-kill curves. Based on the information obtained from the time-kill study, a PD model, including adaptive resistance, was developed using NONMEM. The PBPK and PD models were combined to evaluate the vancomycin effect in plasma and tissues against MRSA. Results: A PBPK model was successfully built for both healthy volunteers and septic patients. The tissue concentrations were found to be significantly lower than plasma concentrations. The studied strain of MRSA was found to have an MIC of 2 µg/mL, and the PD model described the EC50 as 1.05 µg/mL. The PBPK and PD models were successfully combined, and septic patients infected with MRSA strains with MIC of 2 µg/mL had effective treatment response. However, septic patients infected with MRSA strains with MICs of 4 µg/mL and 8 µg/mL did not have adequate response to vancomycin treatment. Conclusions: In septic patients, response was limited against resistant MRSA strains. These findings should be considered hypothesis-generating and interpreted with caution, underscoring the need for individualized approaches and rigorous monitoring.

Objectives: Investigating how nanoparticle systems interact in whole blood (WB) is critical to evaluating the effectiveness of malaria therapy. Methods: We decided to establish a pharmacokinetic/pharmacodynamic (PK/PD) model of the quinine population in WB using Plasmodium berghei-infected mice, with a subsequent model comparison for nanocapsules coated with polysorbate (NCP80) or prepared with Eudragit^® RS (NCEUD). The WB quinine population pharmacokinetic model in rats was developed using plasma and partition coefficients for rat erythrocytes. Mouse WB quinine population PK/PD modeling was developed using allometrically scaled literature-free mouse quinine pharmacokinetic data and covariate values to obtain a WB population pharmacokinetic model for quinine and nanocapsules in mice. This allowed for PK/PD modeling of the quinine population with the WB concentration and parasitemia data in mice. All models were built in NONMEN. Results: The WB quinine concentration profiles in rats were characterized using a two-compartment model. Nanoencapsulation reduced clearance and central compartment volume and increased peripherical compartimental volume. A maximum effect model described the PK/PD of the quinine WB population in mice, demonstrating that NCEUD enhances the antimalarial effect. Conclusions: Quinine WB is a good surrogate for describing the response to exposure in malaria. NCEUD outperformed NCP80 and free quinine, suggesting that cationic surfaces improve the potential for treating malaria.