Estimation of linezolid exposure in patients with hepatic impairment using machine learning based on a population pharmacokinetic model

Abstract

Purpose: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure.

Methods: Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included.

Results: A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC_0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC_0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC_0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid.

Conclusion: In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC_0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

Keywords: Hepatic impairment; Linezolid; Machine learning; Population pharmacokinetics; Thrombocytopenia.