# Population pharmacokinetics of colistin sulfate in critically ill patients based on NONMEM

## TL;DR

This study develops a population pharmacokinetic model for colistin sulfate in critically ill patients to optimize dosing and reduce risks.

## Contribution

The study introduces a population pharmacokinetic model for colistin sulfate and identifies optimal dosing regimens based on patient characteristics.

## Key findings

- A two-compartment model best describes colistin sulfate pharmacokinetics in critically ill patients.
- Creatinine clearance and weight are significant covariates affecting drug elimination and volume of distribution.
- Optimal dosing regimens depend on MIC values and renal function to avoid nephrotoxicity and ensure therapeutic efficacy.

## Abstract

As the last defense against multidrug-resistant gram-negative bacteria, colistin sulfate’s clinical use, which is often empirical, risks resistance and adverse reactions. This study aimed to develop a population pharmacokinetic (PPK) model of colistin sulfate for critically ill patients and determine the optimal dosing regimen. This retrospective study included 204 critically ill patients. We used a validated LC-MS/MS method to measure its plasma concentrations and RIFLE criteria for nephrotoxicity evaluation. NONMEM developed PPK models. Monte Carlo simulations set dosing regimens based on the probability of target attainment (PTA). A two-compartment model adequately described the data, creatinine clearance and weight were covariates for elimination rate and central volume, respectively. Only 11.8% had nephrotoxicity. With Monte Carlo simulations, all regimens except the maintenance dose of 0.5 MU administered every 12 h achieved > 90% PTA at the minimum inhibitory concentration (MIC) ≤ 0.5 mg/L. However, at MIC > 0.5 mg/L, the routine regimen resulted in insufficient exposure. Based on our PPK model, the dose of intravenous colistin sulfate should be adjusted according to creatinine clearance (CrCL) and weight. For critically ill patients with infections, under the conventional treatment regimens, when the MIC is ≥ 1 mg/L, it is difficult for patients to achieve the ideal therapeutic effect in terms of exposure dose. When CrCL is below 10 ml/min, the regimen of 1 MU every 8 h used could cause the potential for increasing nephrotoxicity risk, which is significantly concerned.

The online version contains supplementary material available at 10.1038/s41598-025-03503-9.