Meropenem Model-Informed Precision Dosing in the Treatment of Critically Ill Patients: Can We Use It?

Abstract

The number of pharmacokinetic (PK) models of meropenem is increasing. However, the daily role of these PK models in the clinic remains unclear, especially for critically ill patients. Therefore, we evaluated the published meropenem models on real-world ICU data to assess their suitability for use in clinical practice. All models were built in NONMEM and evaluated using prediction and simulation-based diagnostics for the ability to predict the subsequent meropenem concentrations without plasma concentrations (a priori), and with plasma concentrations (a posteriori), for use in therapeutic drug monitoring (TDM). Eighteen PopPK models were included for evaluation. The a priori fit of the models, without the use of plasma concentrations, was poor, with a prediction error (PE)% of the interquartile range (IQR) exceeding the ±30% threshold. The fit improved when one to three concentrations were used to improve model predictions for TDM purposes. Two models were in the acceptable range with an IQR PE% within ±30%, when two or three concentrations were used. The role of PK models to determine the starting dose of meropenem in this population seems limited. However, certain models might be suitable for TDM-based dose adjustment using two to three plasma concentrations.

Impact of Various Estimated Glomerular Filtration Rate Equations on the Pharmacokinetics of Meropenem in Critically Ill Adults

“…Due to antimicrobial stewardship efforts to restrict meropenem utilization, a prolonged study period was needed for enrollment and the sample size was modest. Nevertheless, our sample size is on par with other population PK studies of meropenem use in critically ill adults (11) and similar if not slightly larger than other studies which have explored the relationship between cystatin C-based estimates of GFR and meropenem PK. The present study excluded patients with stage 2 or higher AKI.…”

“…Across population PK studies of meropenem in the critically ill, eGFR was most commonly calculated with the Cockcroft-Gault estimated creatinine clearance (11). We are aware of two studies that incorporated cystatin C into meropenem PK evaluations (16, 17).…”

“…Next, candidate covariates with biologic plausibility and/ or previously described relationships to meropenem pharmacokinetics were then evaluated in a stepwise fashion. Candidate covariates considered included age, sex, race, ethnicity, presence of liver disease, presence of sepsis, APACHE III and SOFA scores, albumin concentration, C-reactive protein concentration, height, body surface area (BSA), and BMI (11). Weight and eGFR were modeled as time-dependent covariates.…”

“…Across population pharmacokinetic (PK) models for meropenem in critically ill patients, the primary covariate of drug clearance is estimated glomerular filtration rate (eGFR) (11). Approximately 70% of the administered meropenem dose is excreted unchanged by the kidney within 12 hours (12).…”

“…Approximately 70% of the administered meropenem dose is excreted unchanged by the kidney within 12 hours (12). The majority of meropenem PK studies have used a creatinine-based calculation of GFR as a covariate for drug clearance (11). As the terminal byproduct of skeletal muscle catabolism, numerous nonrenal factors influence the serum creatinine concentration in critically ill patients.…”