Corrigendum: Population Pharmacokinetics and Dosing Optimization of Imipenem in Chinese Elderly Patients

Jing Wang Qiu Fang Xuemei Luo Lu Jin Huaijun Zhu ^*

• Nanjing Drum Tower Hospital, Nanjing, China

IntroductionImipenem is a prominent member of the carbapenem class of antibiotics, recognized for its extensive antibacterial coverage against Gram-positive, Gram-negative, and anaerobic bacteria, thus widely used in the treatment of lower respiratory tract infections, abdominal infections, urinary tract infections, septicemia, infective endocarditis, reproductive system infections, bone and joint infections, as well as mixed infections and severe infections caused by unidentified pathogens (Zhanel et al., 2007; Papp-Wallace et al., 2011). Normally, it is quickly metabolized into an inactive compound by the enzyme dehydropeptidase (DHP-1) in the kidney's brush-border, and therefore must be co-formulated with cilastatin, a DHP-1 inhibitor, which could prevent the occurrence of renal tubular necrosis and prolongs the therapeutic effect of imipenem (Koucheki et al., 2021). Imipenem is a hydrophilic molecule with a short plasma half-life of about one hour and exhibits low plasma protein binding (approximately 20%). As a time-dependent antibiotic, its bactericidal activity is best measured by the pharmacokinetic/pharmacodynamic (PK/PD) index of maintaining free plasma concentration above the minimum inhibitory concentration of the pathogens (fT>MIC), aiming for at least 40% of the dosing interval (Gomez et al., 2015; Dinh et al., 2022). As reported by multiple clinical researches, it requires higher pharmacodynamic index of 100% fT>MIC for critically ill patients (Bai et al., 2024). However, the PK profiles of carbapenems were notably altered in elderly patients due to their altered physiological and pathological change and more frequent use of concomitant medications. Elderly individuals are more prone to infections due to various factors such as underlying diseases (e.g., cardiovascular diseases, diabetes), polypharmacy, decreased physical function, and compromised immune system (Mangoni and Jackson, 2004; Medellín-Garibay et al., 2022). Several literature reviews have extensively documented the pharmacokinetic changes in elderly patients (Klotz, 2009; Benson, 2017). Meanwhile, there exists considerable interpatient variability in the influence of age on pharmacokinetics, leading to increased variability in these parameters compared to younger patient cohorts. As reported by Abdulla (Abdulla et al., 2021), age was found to be significantly correlated with TDM target attainment of β-lactam antibiotic therapy. This association may be related to the decline of renal function in elderly patients. However, there is limited pharmacokinetic research on the use of imipenem in elderly patients at present. Only one preliminary study (Pietroski et al., 1991) is accessible, which comprises a limited cohort of merely thirteen patients.The main goal of this research was to evaluate the pharmacokinetic characteristics of imipenem in elderly patients through nonlinear mixed effects modeling (NONMEM). Important factors influencing changes in imipenem exposure were discovered, and suitable dosage suggestions were put forward based on the final model which might promote the judicious use of imipenem in geriatric patients. Materials and methodsStudy design and ethics This research obtained authorization from the Scientific and Research Ethics Committee of Nanjing Drum Tower Hospital, the affiliated institution (No. 2023-380-02), and all methodologies were executed in compliance with ethical guidelines. We performed a retrospective observational study spanning from October 2021 to April 2024. The participants who fulfilled the inclusion criteria were as follows:1) patients aged 60 years or above, 2) patients who received imipenem and cilastatin sodium for injection and 3) plasma concentrations were monitored. The exclusion criteria were as follows: 1) incomplete clinical evaluation (unavailable data on renal function, biochemical indicators and other information; 2) patients undergoing extracorporeal membrane oxygenation (ECMO); 3) other factors deemed unsuitable for this study by the researchers. Data collection and sampling scheduleDemographic factors, including sex, age, and body weight, along with medication details such as dosage, dosing frequency, and administration timing, as well as laboratory results including white blood cell count (WBC), hemoglobin (HGB), platelet count (PLT), globulin (GLO), apolipoprotein A (APOA), apolipoprotein B (APOB), estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALT), albumin (ALB), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), total protein (TP), alkaline phosphatase (AKP), total bilirubin (TBIL), direct bilirubin (DBIL), and creatinine (CR) were gathered using a standardized format through the hospital's electronic medical record system. The creatinine clearance rate (CLCR) was calculated by Cockcroft-Gault Equation.Quantification of voriconazole concentrations The patients were administered imipenem empirically, receiving an infusion dose ranging from 250mg to 1000mg with the administration intervals varied from every 6 hours to every 12 hours. The infusion rate was established based on the actual infusion duration documented in the Electronic Health Record. In this study, the concentrations of imipenem present in plasma were analyzed using HPLC. Sample plasma of 300 μL was mixed with 20 μL of 5-hydroxyindole-3-acetic acid (1 mg·mL-1) and 100 μL of 3-morpholine propyl sulfonic acid solution (0.5 mol·L-1), which was used as stabilizer. The solution was subjected to vortexing for 30 seconds and subsequently transferred to an ultrafiltration centrifuge tube, where it was centrifuged at 4 °C for 10 minutes at 12,000 rpm. After centrifugation, a 30 μL aliquot of the ultrafiltrate was injected into the analytical system. The mobile phase utilized for chromatographic separation comprised methanol and 10 mmol·L-1 potassium dihydrogen phosphate in a ratio of 6:94 (v/v, pH 6.8), which was filtered through a 0.45 μm hydrophilic polypropylene filter. The separation was performed on a TSK gel ODS-100V column (250×4.6 mm, 5 μm) maintained at a constant temperature of 30 °C. The UV detector was set at 300 nm and the overall detection time was 12 minutes. The calibration curves demonstrated acceptable linearity over 0.5–50 μg⋅mL-1, with a limit of quantitation (LOD) of 0.5 μg⋅mL-1 for imipenem.