AIMS: Methotrexate (MTX) is recognized for its potential to induce hepatotoxicity, commonly manifested by elevated alanine aminotransferase (ALT) levels. However, the quantitative relationship between the pharmacokinetics (PK) of MTX and ALT-based hepatotoxicity remains unclear. This study aimed to develop a semimechanistic PK/pharmacodynamic (PD) model to characterize the MTX-induced hepatotoxicity based on ALT in paediatric patients with acute lymphoid leukaemia. METHODS: A retrospective study was conducted on paediatric patients who received high-dose (3-5 g/m2 ) MTX treatment. MTX concentrations were assessed at 24-h intervals until the concentration dropped below 0.1 µmol/L. ALT concentrations were measured both before and after MTX administration. A population PK model was initially developed, which was later connected to a semimechanistic hepatotoxicity model. RESULTS: The PK model was developed using 354 MTX concentrations obtained from 51 patients, while the PD model was constructed using 379 ALT concentrations collected from 48 patients. The optimal PK model for MTX consisted of a 2-compartment structure, where body surface area served as a covariate for clearance and central volume of distribution. An indirect response model coupled to a liver injury signal transduction model was developed to describe the dynamics of ALT after MTX administration. The drug effect was adequately described by a linear model, exhibiting considerable interoccasion variability for each treatment session. No significant covariates were identified to have an impact on the PD parameters. CONCLUSION: A semimechanistic model was developed to describe ALT-based hepatotoxicity of MTX, and it has the potential to serve as a valuable tool for characterizing drug-induced hepatotoxicity.
Chemical and Drug Induced Liver Injury , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Child , Methotrexate/pharmacokinetics , Alanine Transaminase , Retrospective Studies , Chemical and Drug Induced Liver Injury/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
BACKGROUND: Methotrexate (MTX) is a key immunosuppressant for children with acute lymphoid leukemia (ALL), and it has a narrow therapeutic window and relatively high pharmacokinetic variability. Several population pharmacokinetic (PopPK) models of MTX in ALL children have been reported, but the validity of these models for model-informed precision dosing in clinical practice is unclear. This study set out to evaluate the predictive performance of published pediatric PopPK models of MTX using an independent patient cohort. METHODS: A PubMed literature search was performed to identify suitable models for evaluation. Demographics and measurements of the validation dataset were retrospectively collected from the medical records of ALL children who had received intravenous MTX. Predictive performance for each model was assessed by visual comparison of predictions to observations, median and mean predicted error (PE), and relative root mean squared error (RMSE). RESULTS: Six models were identified for external evaluation, carried out on a dataset containing 354 concentrations from 51 pediatrics. Model performance varied considerably from one model to another. Different models had the median PE for population and individual predictions at -33.23% to 442.04% and -25.20% to 6.52%, mean PE for population and individual predictions at -25.51% to 780.87% and 1.33% to 64.44%, and RMSE for population and individual predictions at 62.88% to 1182.24% and 63.39% to 152.25%. All models showed relatively high RMSE. CONCLUSIONS: Some of the published models showed reasonably low levels of bias but had some problems with imprecision, and extensive evaluation is needed before model application in clinical practice.
Background: The pharmacokinetic/pharmacodynamic (PK/PD) index of carbapenems that best correlates with in vivo antimicrobial activity is percent time of dosing interval in which free drug concentration remains above MIC (%fT > MIC), while the magnitudes of the PK/PD index of carbapenems remains undefined in critically ill sepsis patients. Methods: A sepsis rat model was first developed by comparing the survival outcomes after intraperitoneal injection of different inoculum size (1−10 × 107 CFU) of Pseudomonas aeruginosa ATCC9027 (MIC = 0.125 mg/L) in neutropenic rats. The PK characteristics of the model drug meropenem in the developed sepsis rat model was then evaluated, and PK modeling and simulation was applied to design meropenem dosing regimens attaining various PD targets (40%fT > MIC, 100%fT > MIC, and 100%fT > 4 × MIC). The microbiological response and survival outcomes for different meropenem treatment regimens were investigated in the rat sepsis model (n = 12 for each group). Results: The optimal inoculum for the rat sepsis model was 1 × 107 CFU of Pseudomonas aeruginosa ATCC9027. A one-compartment model with first-order absorption best described the PK of meropenem in sepsis rats. Pronounced survival prolongation and lower hazard risk were observed in the treatment groups of 50 or 75 mg/kg/q2.4h (100%fT > MIC) and 75 mg/kg/q2h (100%fT > 4 × MIC) compared to the 75 mg/kg/q6h (40%fT > MIC) group, while meropenem groups with PD targets of 100%fT > MIC and 100%fT > 4 × MIC showed comparable survival curves. Microbiological response for different PD targets is inconclusive due to irregular bacterial counts in blood samples. Conclusions: The PD target of 40%fT > MIC is suboptimal for sepsis rats, and the aggressive 100%fT > 4 × MIC target does not provide a survival benefit against the target of 100%fT > MIC.
