Aims: The objectives of this study were to determine the population pharmacokinetics (PK) model of polymyxin B in critically ill patients with or without extracorporeal membrane oxygenation (ECMO) support that investigated the influence of ECMO on PK variability and to identify an optimal dosing strategy. Methods: Forty-four critically ill patients were enrolled, including eight patients with ECMO support. Eight serial serum samples were collected from each patient at steady state. The population PK was determined using NONMEM and Monte Carlo simulation was performed to evaluate the exposures of different dosing regimens. Results: The PK analyses included 342 steady-state concentrations and a two-compartment model was optimal for polymyxin B PK data modelling. In the final model, creatinine clearance (CLCR) was the significant covariate on CL (typical value 1.27 L/h; between-subject variability 15.1%) and ECMO did not show a significant impact on the polymyxin B PK. Additionally, we found that the PK parameter estimates of patients with and without ECMO support were mostly similar. Based on Monte Carlo simulations, the dose escalation of polymyxin B in patients with increased CLCR improved the probability of achieving required exposure. For patients with CLCR≤120 mL/min, a dosage regimen of 100mg every 12h may represent the optimal regimen at an MIC of 1 mg/L. Conclusion: The impact of ECMO on the polymyxin B PK is likely to be minimal. Our study showed a potential relationship between CLCR and polymyxin B CL, and the dose of polymyxin B should be adjusted in patients with increased CLCR.

Objectives: A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an evidence-based practice guideline for individualized medication of HDMTX. Methods: The practice guideline was launched by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. The guideline was developed following the WHO handbook for guideline development and the methodology of evidence-based medicine (EBM). The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were conducted to synthesis available evidence. A multicenter cross-sectional study was conducted by questionnaires to evaluate patients’ perception and willingness on individualized medication of HDMTX. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and to grade the strength of recommendations. Results: Multidisciplinary working groups were included in this guideline, including clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic specialists. A total of 124 patients were involved to integrate patient values and preferences. Finally, the guideline presents 28 recommendations, regarding evaluation prior to medication (renal function, liver function, pleural effusion, comedications, genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitoring (necessity, method, timing, target concentration), leucovorin rescue (initial timing, dosage regimen and optimization), management of toxicities. Of them, 12 are strong recommendations. Conclusions: We developed an evidence-based practice guideline with respect to HDMTX medication using a rigorous and multidisciplinary approach. This guideline provides comprehensive and practical recommendations involving the whole process of HDMTX medication to health care providers.